Type 1 Diabetes: Cellular, Molecular & Clinical Immunology

Chapter 9 - Epidemiology of Type I Diabetes (Revised 11/3/2010)

Marian Rewers, MD, PhD1, Jill Norris, PhD2, Adam Kretowski, MD, PhD

1Barbara Davis Center for Childhood Diabetes, UCD, Aurora, CO
2Department of Preventive Medicine & Biometrics, UCD, Aurora, CO


Type 1 Diabetes
Type 1 diabetes accounts for about 10% of all diabetes, affecting approximately 1.4 million people in the U.S., and 10-20 million globally (1,2). About 40% of persons with type 1 diabetes develop the disease before 20 years of age, thus making it one of the most common severe chronic diseases of childhood. In the U.S., where 30,000 new cases occur each year, type 1 diabetes affects 1:300 children and as many as 1:100 adults during the life span (3,4). Type 1 diabetes is the leading cause of end-stage renal disease, blindness, and amputation, and a major cause of cardiovascular disease and premature death in the general population (5). This disease results in over $5 billion in medical care expenditures per year, with costs for patients over 10 times those for persons without diabetes (6). Both the U.S. Public Health Service (7) and the American Diabetes Association (8) have identified needs in the area of prevention of type 1 diabetes. Population-based studies, as well as family studies and laboratory data, have provided new insights into the pathogenesis of type 1 diabetes, its associated risk factors and its natural history. They also allowed development of plans for primary and secondary prevention of diabetes in persons with ongoing ß-cell autoimmunity.
This chapter considers the whole spectrum of type 1 diabetes - from genetic susceptibility, through ß-cell autoimmunity without diabetes, to clinical type 1 diabetes. Special emphasis is given to epidemiological data relevant to the primary and secondary prevention.

Natural History of Type 1a Diabetes
The American Diabetes Association and the World Health Organization have revised the classification of diabetes mellitus (9,10). The new classification of diabetes is now primarily based on pathogenesis rather than on the requirement for insulin therapy. Based on the new system, type 1 diabetes (previously defined as insulin-dependent or juvenile diabetes) is caused by ß cell destruction, often immune mediated, that leads to loss of insulin secretion and absolute insulin deficiency. The etiologic agents that cause the autoimmune process and ß cell destruction are not well established. Type 1 diabetes also includes cases that are thought not to be immune mediated, but are characterized by absolute insulin deficiency (insulinopenia).
The current classification of diabetes mellitus distinguishes type 1a (autoimmune) (11) and type 1b (not immune-mediated) form that remains poorly defined (12,13). Type 1a is the most common form of diabetes among children and adolescents of European origin, usually characterized by acute onset and dependence on exogenous insulin for survival. In adults, the disease is nearly as frequent as in children, but often less dramatic onset may lead to misclassification as type 2 and a delayed insulin treatment. About 60% of persons with type 1 diabetes are diagnosed as adults.
The natural history of type 1a diabetes (Figure 1) includes four distinct stages:
1) pre-clinical ß-cell autoimmunity with progressive defect of insulin secretion;
2) onset of clinical diabetes;
3) transient remission; and
4) established diabetes associated with acute and chronic complications and premature death.

B-cell autoimmunity
In most patients, the etiology of the autoimmune process and ß-cell destruction is not known (14). The process is mediated by macrophages and T lymphocytes with detectable autoantibodies to various ß-cell antigens. Currently, autoimmunity is defined by the presence of autoantibodies (11), because their measurement is reliable and standardized across laboratories, in contrast to the cellular markers. The initial islet cell antibody (ICA) assay, using immunofluorescence and pancreatic tissue (15) has been notoriously difficult to standardize and has been replaced by a combination of specific ß-cell autoantibodies to insulin (IAA) (16,17,18), glutamic acid decarboxylase (GAD) (19,20), and tyrosine phosphatase ICA512 (IA-2) (21). These tests have been shown to be quite sensitive and predictive in relatives of type 1 diabetes patients (22,23) and in the general population (24). However, to avoid false or only transiently positive results duplicate testing and independent sample retesting should be considered in the prediction strategy (25,26,27,28).

Progression from ß-cell autoimmunity to clinical diabetes
The duration of pre-clinical ß-cell autoimmunity is variable and precedes the diagnosis of diabetes by up to 13 years (29,30). In persons with persistent autoantibodies, there is an early loss of spontaneous pulsatile insulin secretion, progressive reduction in the acute insulin response to intravenous glucose load, followed by decreased response to other ß-cell secretagogues, impaired oral glucose tolerance and fasting hyperglycemia (31). However, a non-progressive ß-cell defect has been shown to exist for many years in monozygotic twins and other relatives of type 1 diabetes persons. The recent studies show that detailed characterization of islet autoantibodies that include determination of titer, epitope specificity, IgG subclass and affinity would improve diabetes prediction in autoantibody-positive relatives and subjects at risk from general population (32,33,34). The highest risks for progression to type 1 diabetes is associated with high-titer IA-2A and IAA, IgG2, IgG3, and/or IgG4 subclass of IA-2A and IAA, and antibodies to the IA-2-related molecule IA-2beta (32,35,36). Using models based on these antibody characteristics, autoantibody-positive relatives can be classified into groups with risks of diabetes ranging from 7 to 89% within 5 years (36).
Moreover IAA affinity, measured by competitive radiobinding assay, can further stratify the risk of type 1 diabetes development (36,37,38). IAA affinity in multiple antibody-positive children is on average 100-fold higher than in children who remained single IAA positive or became autoantibody negative. All high-affinity IAAs require conservation of human insulin A chain residues 8-13 and are reactive with proinsulin, while lower-affinity IAAs are dependent on COOH-terminal B chain residues and do not bind proinsulin. 92% of children who developed multiple islet autoantibodies or diabetes are correctly identified by high-affinity IAA and 82% who did not develop multiple islet autoantibodies or diabetes are correctly identified by low-affinity IAA (36).
Studies in the first-degree relatives of type 1 diabetes patients (30,39,40) and in school children with no family history of type 1 diabetes (41,42,43,44,45) have reported ICA "remission" rates between 10-78%. Newer data suggest that while individual islet-specific autoantibodies may fluctuate in titers, it is very unusual to observe remission after two or more of such autoantibodies were present for even a few months (46). Some people may loose ß-cell autoantibodies or remain positive but do not progress to diabetes due to incomplete penetrance of susceptibility genes or insufficient exposure to the causative environmental agent(s). It is possible that ß-cell autoimmunity remits spontaneously in genetically resistant persons or when the offending factor is removed, similar to celiac disease. Age also plays a role, because children younger than 10 years have a 3-fold increased risk of progressing from autoimmunity to type 1 diabetes, compared to older relatives (47).
ß-cell autoimmunity may remit and reappear in the course of viral infections or variable exposure to dietary causal factors (26,27). The cumulative ß-cell damage and increases in insulin resistance with obesity and physical inactivity, may eventually cause diabetes at a later age. Those people in whom the disease process is slow may present with type 1 diabetes as adults, develop diabetes that does not require insulin treatment, or may even escape diabetes altogether. Markers of autoimmunity can be detected in 14-33% of diabetes patients classified on clinical grounds as “Type 2” (48,49) and are associated with early failure of oral hypoglycemic drug therapy and insulin dependence in these patients. A term “latent autoimmune diabetes of adults” (LADA) (50) has been coined for this slowly progressing form of type 1 diabetes.

Clinical Onset of Type 1 Diabetes
Most epidemiological data on type 1 diabetes are based on a clinical, standard definition that has been widely used for a long time: 1) physician diagnosis of diabetes , 2) daily insulin injections instituted at the time of diagnosis, and 3) residence by the patient in the area of registration at the time of first insulin administration. This practical definition is not taking into account the nuances of etiological classification into Type 1a, 1b, and other forms of diabetes.
In industrialized countries, 20-40% of type 1 diabetes patients younger than 20 years presents in diabetic ketoacidosis (DKA) (51,52,53,54). Younger age, female gender, HLA-DR4 allele (55), lower socioeconomical status and lack of family history of diabetes have been associated with more severe presentation. Younger children present with more severe symptoms at diagnosis, because children younger than 7 have lost on average 80% of the islets, compared to 60% in those 7-14 year old and 40% in those older than 14 (56). Case fatality in industrialized countries ranges between 0.4-0.9% (57). While brain edema is believed to be the major cause of onset death, the risk factors are poorly understood and heterogeneous.
Both DKA and onset deaths are largely preventable, because most of the patients have typical symptoms of polyuria, polydipsia, and weight loss for 2-4 weeks prior to diagnosis. The diagnosis is straightforward in almost all cases, based on the symptoms, random blood glucose over 200 mg/dl and/or HbA1c >7%. Oral glucose tolerance test (OGGT) is rarely needed for diagnosis. In questionable cases, negative OGGT allows ruling out current diabetes and, in combination with negative ß-cell autoantibodies, offers reassurance that diabetes is not around the corner. Traditionally, nearly all children with newly diagnosed type 1 diabetes were hospitalized. More recently, an increasing proportion of these children have been managed on an outpatient basis, especially in urban centers with specialized diabetes education and treatment facilities. In Colorado, USA, the proportion of children receiving only outpatient care at onset increased from 6% in 1978 to 35% in 1988 (58) and 75% in 2000. Hospitalization at onset does not improve short-term outcomes such as readmission for DKA or severe hypoglycemia (51,54), if adequate family education and follow-up is available on outpatient basis. Onset hospitalizations and subsequently acute complications have similar predictors: biological (younger age, lower endogenous insulin secretion) and psychosocial (lower socioeconomic status, limited access to health care, dysfunctional family).

Prevalence of type 1 diabetes
Initial examination of a disease generally begins with cross-sectional data on its prevalence (i.e., the number of people in the population who have the disease at a given point in time). Selected estimates of type 1 diabetes prevalence in different populations with at least 90% ascertainment of cases are shown in Table 9.1 (see the end of the chapter).
The prevalence of type 1 diabetes in children aged less than 15 years ranges from 0.05 to 0.3% in most European and North American populations (59). Comparisons of prevalence data may be subject to considerable bias, since prevalence is determined not only by disease incidence, but also by case survival, which may vary markedly across populations. Prevalence data, however, are useful in determining the public health impact of type 1 diabetes. For example, in the early 1990's, the number of type 1 diabetic patients 0-19 years of age in United States was estimated at approximately 123,000 individuals (60). However, in 2000, with the growth of this segment of the U.S. population to over 80 million, there were approximately 160,000 children with type 1 diabetes.



Incidence of type 1 diabetes

Geographic location: One of the most striking characteristics of type 1 diabetes is the large geographic variability in the incidence (61,62,63) (Fig.9. 2). Scandinavia and the Mediterranean island of Sardinia have the highest incidence rates in the world while Oriental populations have the lowest rates. A child in Finland is 400 times more likely to develop diabetes than one in China. While there is a strong south-north gradient in the incidence, ‘hot-spots’ in warm climates have been reported (Sardinia, Puerto Rico, Kuwait). The geographic and ethnic variations in type 1 diabetes reflect the prevalence of susceptibility genes or that of causal environmental factors, or both.
In the general population, the prevalence of ß-cell autoimmunity appears to be roughly proportional to the incidence of type 1 diabetes in the populations (64,65). In contrast, the prevalence of ß-cell autoimmunity in first-degree relatives of type 1 diabetic persons does not differ dramatically between high and low risk countries. The incidence of ß-cell autoimmunity is higher in relatives younger than 5 years (3.7%/yr), compared to those 5-9 yr old (0.5%/yr) (66). During 5 years of follow-up, none of the relatives older than 10 has developed ß-cell autoimmunity (66), suggesting that ß-cell autoimmunity develops primarily before the age of 5 and that it may remit in many cases (44,45).
The clinical picture of the disease is similar in low- and high-risk areas (67,68), making it unlikely that the inter-population difference is due to misclassification of different types of diabetes. However, in many populations (69,70) type 2 diabetes is an increasing or already the predominant form of diabetes in children (71) making correct diagnosis and treatment increasingly difficult.


Age: Type 1 diabetes incidence peaks at the ages of 2, 4-6 and 10-14 years, perhaps due to alterations in the pattern of infections or increases in insulin resistance. Recently published data suggest that in many populations the highest rate of incidence is observed in the 10-14 age group, while the highest annual increase is in the 0-4 yrs age children (Figure 9.2.1). The age-distribution of type 1 diabetes onset is similar across geographic areas and ethnic groups (68) (see also Figure 3). There have been only a few studies that have examined the incidence of type 1 diabetes in adults, mainly because of the difficulty of distinguishing type 1 diabetes from insulin-requiring type 2 diabetes in older individuals. The incidence decreases in the third decade of life (72,73,74), only to increase again in the fifth to seventh decades of life (75,76). It has been speculated that the incidence of type 1 diabetes increases again in the fifth through seventh decades of life (39,40), but there is no hard evidence of such increase, and it is not known whether there are etiologic differences between childhood- and adult-onset type 1 diabetes.

A. incidence of Type 1 diabetes

B. annual increase in incidence

Figure 9.2.1. Current (1988-2002) trends in incidence of type 1 diabetes (A) and rates of annual incidence increase (B) in different age groups: 0-4, 5-9 and 10-14 yrs.


The prevalence of ICA decreased with age in first-degree relatives participating in DPT-1 screening. It is not known whether the etiology differs between childhood- and adult-onset type 1diabetes, but it was not apparent among adult participants in the UKPDS. Over 30% of those aged 25-34 were positive for ICA and/or GAD autoantibodies, but the prevalence decreased with age, to less than 10% in those aged 55-65 (77). The presence of the autoantibodies and age of presentation of diabetes were strongly associated with the presence of the HLA-DRB1*03/DRB1*04-DQB1*0302 genotype (78).

Race and ethnicity: The incidence data from early 1990 suggested a significant racial difference in type 1 diabetes risk in multiracial populations, although not of the same magnitude as the geographic differences (Table 9.2). In the U.S., non-Hispanic whites were about one and a half times as likely to develop type 1 diabetes as African Americans (79) or Hispanics (80) (Figure 9.3). This was similar to the differences reported from Montreal, where children of British descent had about one and a half the risk of type 1 diabetes in children of French descent (84) (Table 9.2).

T1a=positive auto-antibodies
T1=insulinopenia without auto-antibodies
T2=high insulin secretion without auto-antibodies
Hybrid=features of both T1a and T2
Untyped=preserved insulin secretion without auto-antibodies

NHW=Non-Hispanic White
AA-African American
API-Asian/Pacific Islander
AI-America Indian

Figure 9.2.2. Epidemiology of diabetes in children and adolescents 0-9 yrs and 10-19 yrs old in USA (2002).

Interestingly, recent data from the SEARCH study have shown a rising trend in type 1 diabetes not only in non-Hispanic white population, but also among Hispanic and African American children (Figure 9.2.2) (81). In fact, however the number of new type 1 diabetic patients of African-American origin aged 10–14 years has risen significantly during the last 10-15 years and the incidence of type 1 diabetes in this age group is almost equal in the white and African-American populations, it is still almost twofold difference between non-Hispanic white and African-American children in the incidence of type 1 type in younger children (0-9 yr) (81,82). One could suspect that the marked increase in incidence in the African-American population may be in part due to misclassification of cases actually having type 2 diabetes, as there is an epidemic of type 2 diabetes in children in the U.S., which largely affects African-American children over the age of 10 years and many cases of type 2 diabetes require treatment with insulin at the time of diagnosis. It is unlikely, however, that the increased incidence of type 1 diabetes in African-American children can be explained only by misclassification. The diagnosis type 1 diabetes in the SEARCH study was confirmed by the presence of insulinopenia and diabetic auto-antibodies (81). Similarly to this observation, the high annul increase in the incidence of type 1 diabetes has been recently reported among the children of south Asian immigrants (Indian, Pakistani, Bangladeshi) in UK (83). Children living in south Asia have a low incidence of type 1 diabetes, so it is worth to emphasize that migrants to the UK have similar overall rates of type 1 diabetes to the indigenous British population (83).



95% Confidence Interval

Allegheny County, PA (80)












Non-Hispanic White






Montreal, Canada (84)





7.5 - 8.9













Figure 9.3. Incidence of T1 DM in Colorado, 1978-88.

Little data concerning ß-cell autoimmunity is available for non-Caucasian populations. Among 86,000 relatives of type 1 diabetic patients screened for the DPT-1 trail, lower prevalence of ICA was observed in Asian Americans (2.6%) and in Hispanics (2.7%), compared to African Americans (3.3%) or non-Hispanic whites (3.9%). Lower prevalence of GAD antibodies has also been reported in Oriental compared to Caucasian type 1 diabetes patients (84,85).

Gender: In general, males and females have similar risk of type 1 diabetes (86), with the pubertal peak of incidence in females preceding that in males by 1-2 years. In lower-risk populations, such as Japan or U.S. blacks, there is a female preponderance, while in high-risk groups, there is a slight male excess (3,61,87). DPT-1 screening data have shown that male sex was associated with the appearance of autoimmunity (the presence of ICA and having two or more antibodies), but not with type 1 diabetes (88). It seems to suggest that male relatives with the known risk factor of ICA are less likely to progress to overt disease than comparable female relatives or that women develop different antibody responses (88). Interestingly, even within Europe, all populations with an incidence higher than 20/100,000 (Sardinia, UK, Italy, Finland, Norway, etc) had male excess, whereas those with a rate below 4.5/100,000 (the Baltic countries, Macedonia, Yugoslavia, Romania, etc) had female excess (59,89,90).

Figure 9.4. Gender differences in the incidence of type 1 diabetes.

Type 1 diabetes diagnosed in adulthood seems to be associated with male excess with a male:female ratio between 1.3 and 2.15 in most populations of European origin (91,92,93,94,95), but there is considerably less information concerning type 1 diabetes with onset in adult life. These findings contrast with data from animal models of type 1 diabetes (the NOD mouse), in which diabetes progression is almost twice as common in females (96). Several pathways for these differences have been explored, such as the effects of sex hormones, hormone substitution, and pregnancy on autoimmunity, the relationship between genetic risk factors for diabetes and sex (97), but the reasons for these differences are yet not known.

Time: The incidence of type 1 diabetes varies markedly over time, both seasonally and annually. In the Northern Hemisphere, the incidence declines during the warm summer months; similarly in the Southern Hemisphere, the seasonal pattern exhibits a decline during the warm months of December and January, implicating a climatic factor (98). This seasonal pattern appears to occur only in older children (99,100), suggesting that factors triggering diabetes may be related to school attendance. The observed seasonality does not appear to be an artifact of health care seeking or access, but the seasonal patterns differ by the HLA-DR genotype (101,102).
Most population-based registries have shown an increase in type 1 diabetes incidence over time (103,104,105,106,107,108). Periodic outbreaks, sometimes of pandemic proportion, e.g., during 1984-86 (104) appear to be superimposed on a steady secular increase in incidence.

Figure 9.5. Type 1 diabetes incidence is rising 3-5% /year in different geographic region with different incidence rate.

While the increase in type 1 diabetes incidence has affected all age groups, several studies reported particular increase among the youngest children (109,110,111,112,113). No reliable information is available concerning potential seasonal or annual variation in the incidence of ß-cell autoimmunity.
Genetic models are unable to explain the apparent temporal changes in the incidence (114). Few studies have analyzed time trends using modeling procedures, looking specifically at the effects of age, calendar period, or birth cohort on the incidence of type 1 diabetes (115,116,117,118). Figure 9.5 displays examples of different types of changes in the incidence of childhood onset type 1 diabetes that have been observed from late 1960s to mid 1980s: periodic outbreaks superimposed on a steady secular increase (Finland), and outbreaks with little secular increase (Poland). These non-linear calendar period effects were attributed to environmental factors causing epidemic peaks. The most recent study covering the period from 1984 to 1996 found only a strong linear effect of an increase of 2.3% per year, suggesting that the causal role of unknown environmental factors is diffusing over time (118). Importantly, the increase in incidence was seen in the age group 0 to 14 years and also in the age group on 15-29 years. The incidence is increasing both in low and high incidence populations. The rates have doubled over the past 30 years in countries with very high (Finland) and moderately high incidence (Colorado, USA) and even have tripled in countries known as a low risk area (Poland) (Figure 9.5).
A recent analysis of data on published incidence trends showed that the incidence of type 1 diabetes is globally increasing by 3.0% per year, and that the incidence of type 1 diabetes will be 40% higher in 2010 than in 1998 (119). The polio model, where autoimmune diabetes results from delayed exposure to infection that is benign when encountered in early childhood could explain the recent increase in the incidence but not the shift in diagnosis to earlier ages. Alternative explanation invokes the congenital rubella model where increased hygiene has led to a decline in herd immunity to common infections among women in child-bearing age (120). These women are more likely to develop viremia during pregnancy resulting in congenital persistent infection of ß-cells and early onset type 1 diabetes in the offspring. This model could explain both the increasing incidence of diabetes and the decreasing age of disease onset.

Genetic factors
Family history of type 1 diabetes: In moderate type 1 diabetes risk areas, such as the United States, the risk of type 1 diabetes by the age of 20 years is approximately 1:300 (Table 9.3). The risk is increased to about 1:50 in offspring of type 1 diabetes mothers and 1:15 in offspring of type 1 diabetes fathers (the reason for this parental gender difference is not known). The risk to siblings of type 1 diabetes probands ranges from 1:12 to 1:35 (121,122) and is further increased, in HLA-identical siblings (123). Recent analysis in Colorado has shown that in siblings, the overall risk of type 1 diabetes by age 20 years is 4.4%, and significantly higher in siblings of probands diagnosed under age 7 years than in those diagnosed later. In parents, the overall risk by age 40 years is 2.6% and twofold higher in fathers (3.6%) than in mothers (1.7%) of probands (124). It is estimated that by the age of 60 years approximately 10% of the first degree relatives develop type 1 diabetes (125). Family history of type 1 diabetes is a surrogate measure of the combination of type 1 diabetes genes and environmental exposures shared by family members.
The risk of ß-cell autoimmunity is higher, because not all autoantibody positive children develop diabetes by the age of 20. Prevalence estimates from cross-sectional studies shown in Table 9.1 are obviously less precise than cumulative incidence rates available for clinical diabetes.

Risk Group

Type 1 Diabetes

Pre-Diabetic Autoimmunity

General Population
All HLA genotypes



Family Members
Maternal offspring
Paternal offspring
Siblings (all)
Monozygotic twins
HLA-identical siblings

1:12 - 1:35


Table 9.3. Risk by the age of 20 years of type 1 diabetes and beta-cell autoimmunity in the general population and family members of type 1 diabetic patients.

'Familial' cases represent about 10% of type 1 diabetes and do not appear to be etiologically different from 'sporadic' cases in terms of the HLA-DR, DQ gene frequencies, seasonality of onset and prevalence of islet autoantibodies (126). 'Familial' cases tend to have lower HbA1c and higher C-peptide levels than 'sporadic' cases, because relatives recognize diabetes symptoms earlier, however, these differences disappear soon after diagnosis.

Candidate genes: The primary loci of genetic susceptibility to type 1 diabetes have been mapped to the HLA-DR, DQ (127,128,129,130) and recently also to the DP region (131). While 50 percent of non-Hispanic whites in the United States have HLA-DR3 or DR4 allele, at least one of these alleles is present in 95 percent of patients with type 1 diabetes (132,133). The estimated risk for general population children who have the HLA-DR3/4,DQB1*0302 genotype is approximately 1:15 (134). Only 2.4% of the general population carries this genotype, compared to 30-40% of type 1 diabetes patients.
No particular HLA type seems to be associated with ß-cell autoimmunity, although associations between different patterns of insulin, IA-2A or GAD autoantibodies and HLA-DR, DQ phenotypes have been reported (135,136,137). In the DAISY study HLA DR3/4-DQ8 genotype predicted both persistence of autoantibodies and progression to diabetes among young first degree relatives of T1D patients and infants identified by newborn screening for HLA genotypes associated with diabetes (136). Significant difference in the prevalence of IAA, IA-2A, GADA and multiple autoantibodies has been observed between siblings of T1D children with the strongest susceptibility DR3/DR4 genotype and those with alleles other then DR3 and DR4 (136,137). 90% of the first-degree relatives (137) and general population children who stay persistently autoantibody positive (41,138) express the HLA-DRB1*04, DQB1*0302.
Data from the Type 1 Diabetes Prediction and Prevention Study have shown that titres of ICA, GADA and IA2A antibodies in unaffected children form general population are also dependent on the genetic risk (137).
The HLA-DR2, DQB1*0602 haplotype, which almost completely protects from type 1 diabetes (127), is found in about 15% of GAD and IAA positive young relatives of type 1 diabetes patients (135,136,137). None of the sibling, taking part in the DIPP study, who carried DQB1*0602 allele, had IAA, IA-2A or multiple antibodies. The frequency of children tested positive for ICA (1.3%) or GADA (0.3%) also tended to be lower in comparison to those without protective allele (137). In addition, it was recently observed that among ICA positive relatives with DQB1*0602, identified by the DPT-1 study, only 19% had multiple “biochemical type” autoantibodies and these markers were not associated with abnormal glucose tolerance (139).
Persistent islet autoimmunity was also found to be associated with non-HLA genes: insulin gene (INS-23Hph1 polymorphism in children with DR3/4 genotype) and genes coding cytokines involved in the Th1 regulatory pathway: IL-13, IL-4, IL4 receptor; but not with CTLA-4 SNPs (140).
Candidate genes outside the HLA region are being identified (141,142,143,144,145, 146,147). Genes encoding proteins involved in T-cell activation: CTLA-4, PTPN22, VNTR of insulin gene have been reported to have the functional variants associated with type 1 diabetes and contribute in 5-10% to genetic risk (148,149,150,151,152).
It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date (153).Perhaps even more subjects with ß-cell autoimmunity need to be genotyped to precisely determine the role of HLA and additional type 1 diabetes candidate genes in the initiation of autoimmunity and progression to diabetes.

Figure 9.7. Genes encoding proteins involved in T-cell activation (HLA II class genes, CTLA-4, PTPN22, VNTR insulin gene) play a key role in type 1 diabetes.

Environmental factors
Twin (154) and family studies indicate that genetic factors alone cannot explain the etiology of type 1 diabetes. Seasonality, increasing incidence and epidemics of type 1 diabetes as well as numerous ecological, cross-sectional and retrospective studies suggest that certain viruses and components of early childhood diet may cause type 1 diabetes (155).

Viruses: Herpesviruses (156,157), mumps (158,159), rubella (160,161), retroviruses (162,163), and rotavirus (164) have been implicated. Viral infections appear to initiate autoimmunity rather than precipitate diabetes in subjects with autoimmunity. Two or more infections with similar viruses may be needed - mice persistently expressing a viral protein in the ß-cells do not develop ß-cell autoimmunity unless exposed to the same virus later in life (165,166). ICA or IAA has been detected after mumps (158), rubella, measles, chickenpox (167), Coxsackie (168), ECHO4 (169), and rotavirus (164) infections. Newborns and infants are particularly likely to develop a persistent infection and among patients with congenital rubella syndrome, 70% have ICA (160).
An increased incidence of type 1 diabetes in patients with congenital rubella syndrome (CRS) is particularly interesting. While CRS is responsible for a minute proportion of type 1 diabetes and there is little evidence that postnatal rubella exposure to the wild strain (167) or to the MMR vaccine (170) causes type 1 diabetes, CRS provides an example of viral persistence leading to type 1 diabetes. The incubation period of type 1 diabetes in CRS patients is 5-20 years (161) and persistent rubella virus infection of the pancreas has been demonstrated in some cases. While CRS is not associated with particular HLA-DR alleles, the distribution of the HLA-DR3 and 4 alleles among patients with CRS and diabetes resembles that in non-CRS type 1 diabetes patients (160). Finally, a molecular mimicry has been reported between a rubella virus protein and a 52 kD ß-cell autoantigen (171).
The evidence is strongest for picornaviruses, which include human (enteroviruses and rhinoviruses) and animal pathogens (e.g., mouse EMC virus and Theiler's virus). Enteroviruses have been most strongly linked to human type 1 diabetes, but convincing proof of causality remains elusive (for review see 172,173). Case and autopsy reports (174,175), epidemics of type 1 diabetes associated with concurrent epidemics of enteroviruses (176,177) and multiple cross-sectional seroepidemiological studies (172) have been suggestive, but not entirely convincing. At least 90% of type 1 diabetes patients demonstrate prolonged period of ß-cell autoimmunity that is hardly compatible with an acute cytolytic enteroviral infection being a major cause. Enteroviral infection could, however, initiate ß-cell autoimmunity through molecular mimicry between CBV P2-C protein and GAD (178)) or a persistent ß-cell infection with impairment of insulin secretion and expression of self-antigens.
Cross-sectional studies of anti-Coxsackie antibodies in ß-cell autoimmunity have been week and inconclusive (179) and have been recently replaced by studies based on detection of picornaviral RNA in bodily fluids using PCR. Prospective studies of non-diabetic relatives and general population children found a strong relation between enteroviral infections, defined by PCR, and development of islet autoantibodies in Finland (180,181,182) but not in the U.S (616). Studies from Finland (180) and Sweden (183,184) have suggested in utero enteroviral infections can lead to type 1 diabetes in a significant proportion of the cases.
According to polio hypothesis low rate of enterovirus infections in background population is the reason that young infants may have increased susceptibility to the diabetogenic effect of enteroviruses, as they are not protected by maternal or their own antibodies (185,186,187,188). In line with this hypothesis there are recent observations from Europe, which shows that the frequency of enterovirus antibodies is higher in serum samples taken from pregnant women in countries with a low or intermediate incidence of type 1 diabetes compared with high-incidence countries (185). An inverse correlation between the incidence of type 1 diabetes and enterovirus infections is observed in the background population in different European countries (188).
There is accumulating evidence that mechanism of viral infection leading to b-cell destruction may be related to the induction of interferon a (189,190). Significant overexpression of INF-a in the pancreatic islets and higher serum levels INF-a have been documented in newly diagnosed patients with type 1 diabetes (189). It is also known that INF-a can decrease insulin synthesis/secretion, induce B-cell apoptosis and has a strong influence on innate immune system (190,191).
Viral infections through the generation of double-stranded RNA may induce INF-a production and by a direct cytolytic effect on pancreatic B-cells or indirect activation of innate immune system could trigger of autoimmunity in genetically susceptible individuals (G*). It was recently demonstrated that poly I:C (polyinosinic: polycytidylic acid) – a synthetic double-stranded RNA – stimulates INF-a and induces autoimmune diabetes mainly by activation of toll-like receptors, and its effect on an immune response is related the genetic background in different animal models (191).
Additional factors (186,192,193,194, 195) and season of birth (196) have been associated with type 1 diabetes.


Possible protective effect of infections: In animal models, viral infection may protect the host from developing type 1 diabetes (187,188). Evidence for such a protective effect in humans still needs confirmation (200,201,202).
According to so called “hygiene hypothesis” infectious agents could have a protective effect on autoimmunity development (203). The beneficial mechanisms of an early exposure (in utero or during the first weeks/months of life) of viral, bacterial or parasitic antigens are not known, however the role of the regulatory immune CD4 T cells stimulation, toll-like receptors and superantigens (by activation of T cell clones expressing specific receptor V gene) is discussed (203).
This hypothesis is supported by the evidence that multiple viral infections prevent autoimmune diabetes in NOD mouse and by the numerous studies showing that improvement of socio-economic status, higher level of sanitation and better medical care (for example: use of antibiotics) is associated with increased incidence of type 1 diabetes in humans (200,201,202).

Routine childhood immunization: None of the routine childhood immunization have been shown to increase the risk of diabetes (170,202,204,205) or pre-diabetic autoimmunity (206,207, 208).

Dietary factors: Cow's milk or wheat introduced at weaning trigger insulitis and diabetes in animal models (209) perhaps through a molecular mimicry (210). Human data are conflicting, but predominantly negative (211,212,213,214,215,216,217). An ecological study suggested an association between decrease in breast-feeding and increase in type 1 diabetes incidence between 1940 and 1980 (218). Subsequent case-control studies have shown a negative (219,220), positive (221) or no association (222,223,224). Certain studies (219,225,226) but not others (221,223,224) suggested a dose-response relationship between the duration of breast-feeding and protection from type 1 diabetes.

Figure 9.8. Potential mechanisms of the association between infant diet and beta-cell autoimmunity. (I tried to change the text in this figure, but could not – is there a way for someone else to do it?  I would change exposition to exposure (in two places above).

A meta-analysis found a 50% increase in type 1 diabetes risk associated with a breast-feeding duration of less than 3 months, and exposure to breast-milk substitutes prior to 3 months of age (226), but a subsequent meta-analysis reported much lower risk estimates, and suggested that these findings may be false positives due to study bias (227). Breast-feeding may be viewed as a surrogate for the delay in the introduction of diabetogenic substances present in formula or early childhood diet. More recent cohort studies failed to find an association between breast-feeding and age at introduction of cow’s milk  and beta-cell autoimmunity (207,215,217, 230, 231, 519). Preliminary data from the Finnish TRIGR study suggests that incidence of ICA antibodies is significantly lower in children fed until the age of 6-8 months with the casein hydrolysate in comparison to the group with conventional cow's milk-based formula (186). Interestingly, another study from Finland suggested that current cow’s milk consumption was more closely linked to pre-diabetic autoimmunity and diabetes than infant exposure (216,230). In addition, the reports that newly diagnosed diabetic children, compared with age-matched controls, have higher levels of serum antibodies against cow's milk and beta-lactoglobulin (228) as well as against bovine serum albumin (229) have been difficult to reproduce (209).
In addition to breast milk substitutes, such as infant formulas, the infant is exposed to other dietary antigens in the first year of life that may impact oral tolerance. In the United States, cereals are often the first solid foods to which the infant is exposed, making cereals a potentially important dietary factor to study when defining the role of diet in the development of type 1 diabetes. Like all foods, cereals have antigenic characteristics that could play a role in oral tolerance in infants. Because gluten is the environmental trigger for clinical symptoms of celiac disease, another childhood autoimmune disease, and because gluten is a component of many cereals, gluten has been studied in the context of type 1 diabetes as a potentially important environmental exposure as well.

In the BB diabetes-prone rat, gluten precipitates the onset of IA (520). Macfarlane et al. identified a wheat storage protein called glb1 that may be associated with islet damage, by observing that antibodies to this protein were detectable in patients with diabetes but not in nondiabetic patients (521).  Moreover, the timing of introduction of cereals (and/or gluten) during infancy, has been examined in all three prospective studies of the development of IA. Both BABYDIAB and DAISY have shown an increased risk for IA associated with exposure to cereals prior to the third month of life when compared with introduction in the 4th to 6th month of life. Norris et al. found that the timing of introduction of any type of cereal was associated with an increased IA risk and also found that there appears to be a U-shaped relationship between risk and age at introduction, the nadir of the curve occurred with introduction in the 4th to 6th months of life (231). In contrast, Ziegler et al. showed the association with gluten specifically and found that a further protective effect was conferred if foods containing gluten were introduced after the 6th month (232). It is important to note that both studies found that the introduction of cereals at less than 3 months of age resulted in the highest relative risk, particularly in those with the high risk HLA-DR3/4, DQB1*0302 genotypes (Figure 9.9). These data suggest that there are specific times in infancy wherein exposure is associated with an increased risk of developing IA. The risk associated with early exposure may suggest a mechanism involving an aberrant immune response to cereal antigens in an immature gut immune system among susceptible individuals.

offspring of T1D mothers
Ziegler, JAMA 2003;290:1721

HLA-DR3/4,DQB1*0302 children
relatives & general population
Norris, JAMA 2003;290:1713


Figure 9.9. Timing of the introduction of solid cereals into infant diet and the risk of islet autoantibodies.

When examining the role of cereals along with the timing of introduction, it is also important to consider whether the increased IA risk is associated with one specific antigen (gluten for example), or if it is associated with general antigenic stimulation arising from exposure to an assortment of food antigens. It is interesting that Norris et al. found an effect of timing of cereal introduction in both gluten-containing and non-gluten-containing cereals (231) whereas Ziegler et al. found the association in gluten-containing solid foods but not in non-gluten-containing solid foods (232). Given the difference in the defined dietary variables (the non-gluten containing food variable in Ziegler et al. contained non-cereal foods) it is difficult to determine whether the two studies actually contradict each other. Interestingly, the Finnish prospective study (DIPP) did not find an association between the timing of introduction to wheat-based foods and the development of IA.  However, to further support the idea that general antigenic stimulation is more important than the actual antigen in this disease process is the finding in the DIPP study that early introduction of fruits, berries and root vegetables was associated with increased risk for IA (519).  

Interestingly, Norris et al. found evidence that a child who is still breast feeding at the time of introduction to cereals has a reduced risk of IA regardless of the timing of cereal introduction (231).  A similar protective relationship between breast feeding and introduction of gluten has been observed in celiac disease (525). These findings suggest that while not protective independently, breast feeding may be a protective mediator in the relationship between other dietary factors, including but not limited to cereals, and IA.


Vitamin D3 supplementation
There is increasing evidence that vitamin D3 might contribute to pathogenesis and prevention of type 1 diabetes. Active vitamin D3 prevents type 1 diabetes in animal models, modifies T-cell differentiation, modulates dendritic cell action and modulates cytokine secretion, shifting the balance to regulatory T cells. It seems possible that birth seasonality in children and/or the presence of seasonal pattern at diagnosis of type 1 diabetes could be explained by variation in endogenous vitamin D production during different year season (236,237). The monthly averages of maximal daily temperature and daily hours of sunshine were inversely related to the number of new patients per month in Belgium (238).

Multiple studies have examined the role of vitamin D in the pathogenesis of type 1 diabetes. The EURODIAB multi-center case-control study found that diabetic children were less likely to have been given vitamin D supplements in infancy than control children (522).  This finding is similar to that found in the previously described case-control study form Norway, where diabetic children were less likely to have been given cod liver oil supplements during infancy compared to controls (235), if one were to assume that it is the vitamin D found in cod liver oil rather than the omega-3 fatty acids that is responsible.  In a large historical prospective study from Finland, Hypponen et al. studied vitamin D supplementation in infants and found an increased risk for type 1 diabetes in those children who received no vitamin D supplementation compared with those who did receive supplements (234). Aside from cod liver oil and vitamin supplements, the primary sources of vitamin D are sunlight, fatty fish, and vitamin D fortified dairy foods.   The aforementioned studies were limited in that they were only able to examine vitamin D from supplements, and were not able to examine vitamin D exposure from foods.  In a small study within DAISY, Fronczak et al. investigated vitamin D intake during pregnancy and found that increased intake of vitamin D from foods was associated with lower risk of IA in the offspring, but no such association was seen for vitamin D intake from supplements (233).

 Investigators in DAISY reported that higher omega-3 fatty acid intake during childhood was associated with a lower risk of islet autoimmunity (Hazard Ratio [HR]:  0.45), and likewise, that higher omega-3 fatty acid levels in the erythrocyte membrane were associated with a lower risk of islet autoimmunity (HR: 0.63) (523) (Figure 9.10). 




Chemical compounds: Streptozotocin (239,240) or dietary nitrates and nitrosamines (241) induce ß-cell autoimmunity in animal models. Circumstantial evidence suggests a connection between type 1 diabetes and consumption of foods and water containing nitrates, nitrites or nitrosamines (242,243,244). Multiple hits of dietary ß-cell toxins may render genetically resistant individuals susceptible to diabetogenic viruses leading to type 1 diabetes (245).

Weight gain, insulin resistance - “ the accelerator hypothesis”: It has recently been hypothesized that excess weight gain and increase in insulin resistance in early childhood is a trigger event, which initiates the autoimmunity leading to b-cell destruction and type 1 diabetes development (246,247). The rising blood glucose (glucotoxicity) accelerates beta-cell apoptosis directly or by inducing beta-cell immunogens in genetically predisposed subjects. This so called 'Accelerator Hypothesis' seems to be supported by several epidemiological case-control and population based cohort studies (246,248,249,250). A study from Norway found almost linear correlation between incidence rate of type 1 diabetes and birth weight (249). The risk of type 1 diabetes was higher by more than twofold in children with birth weight > 4500g in comparison to newborns with the lowest birth weight (<2000 g) (249). In the Childhood Diabetes in Finland Study children <15 years of age who developed type 1 diabetes were heavier and taller throughout childhood than birth date- and sex-matched controls (250). In this nationwide case-control study ten percent increment in relative weight was associated with a 50-60% increase in the risk of type 1 diabetes before 3 years of age and a 20-40% increase from 3 to 10 years of age (250). The most recent epidemiological observations suggest that high birth weight could possibly result from a moderating effect on intrauterine growth of HLA genotypes conferring a high risk of diabetes (251). An analysis of DAISY children showed that weight and velocity of increase in weight was not associated with development of islet autoimmunity, nor type 1 diabetes in autoimmune children (524).  However, this same study showed that increased velocity of growth in height was associated with risk of islet autoimmunity, and risk of T1D in autoimmune children. The wide variation in childhood type 1 diabetes incidence rates within the different populations could also be partially explained by indicators of national and individual prosperity. These indicators could reflect differences in environmental risk factors such as nutrition or lifestyle that are important in determining the risk of type 1 diabetes. The EURODIAB study has shown a positive association of the incidence rates with the value of gross domestic product (252). 

The Environmental Determinants of Diabetes in the Youth (TEDDY): To resolve the controversy about the role of environmental factors in the pathogenesis of type 1 diabetes -The Environmental Determinants of Diabetes in the Youth (TEDDY), a large international project, with the aim to evaluate the putative environmental triggers during the 15-year follow-up of several thousand newborn babies identified with HLA-DR, DQ genotypes associated with type 1 diabetes, has recently been initiated (155).

Gene-environment interactions: Type 1 diabetes is likely caused by an interactive effect of genetic and environmental factors within a limited age-window. While both the susceptibility genes and the candidate environmental exposures appear to be quite common, the disease is still uncommon, raising a possibility of low penetrance (253).
In mice, the host's genes restrict the diabetogenic effect of picornaviruses in a manner compatible with a recessive trait not related to the MHC. In humans, on the other hand, susceptibility to diabetogenic enteroviruses appears to be genetically restricted by HLA-DR and DQ alleles (172). However, the allelic specificity is controversial (55,254,255,256) and may depend on the viral type and epidemicity. In general, the HLA-DR3 allele, present in most patients with type 1 diabetes, is associated with viral persistence.

Figure 9.6. Odds ratios for type 1 diabetes by exposure to whole cow’s milk prior to 3 months of age in low- and high- risk individuals, as determined by a genetic marker on the HLA-DQB1 chain (255).

Very few studies have examined a possibility of an interaction between the HLA genes and dietary exposures (255,230) (see Fig. 9.6). The epidemiological data are limited, but suggest that an early exposure to cow's milk in relatives with HLA-DR3/4, DQB1*0302, DR3/3 or DRx/4, DQB1*0302 is not associated with development of ß-cell autoantibodies (257,258). It is unclear whether other genes are involved.

Remission ("Honeymoon Period"): Shortly after clinical onset, most of the patients experience a transient fall in insulin requirements due to improving ß-cell function. Total and partial remissions have been reported in, respectively, 2-12% and 18-62% of young type 1 diabetes patients (54,259,260). Older age and less severe initial presentation of diabetes (259,260,261,262) and low or absent ICA (262,263,264) or IA-2 (265) have been consistently associated with deeper and longer remission (5). Evidence relating GAD autoantibodies (262,265,266), non-Caucasian origin, HLA-DR3 allele, female gender and family history of type 1 diabetes to a less severe presentation, greater frequency of remission and slower deterioration of insulin secretion is inconclusive. Most studies (259,263), but not all (260,261), agree that preserved ß-cell function is associated with better glycemic control (lower HbA1c) and preserved ß-cell glucagon response to hypoglycemia (267). The prevalence of ICA (but not GAA) decreases from 87% at the time of type 1 diabetes diagnosis to 38-62% 2-3 years later (263,268), faster in young boys, subjects lacking HLA-DR3 and 4, and those diagnosed between July and December (268).
The natural remission is always temporary, ending with a gradual or abrupt increase in exogenous insulin requirements. Destruction of ß-cells is complete within 3 years of diagnosis in most young children, especially those with the HLA DR3/4 genotype (218). It is much slower and often only partial in older patients (270), 15% of who still have some ß-cell function preserved 10 years after diagnosis (271).

Established Diabetes
Acute complications
: Acute complications of type 1 diabetes: DKA, hypoglycemia and infections are described in detail in other chapters. The risk of hospital admission for acute complication is 30/100 patient-years (p-yrs) in the first year of the disease and 20/100 p-yrs in the subsequent 3 years (54). Age and sex-specific incidence pattern suggest that the risk of ketoacidosis is increased in adolescent girls (272). The preventable or potentially modifiable risk factors comprise lack of health insurance, high HbA1C levels and mental problems (272,273). An estimated 26% of the patients have at least one episode of severe hypoglycemia within the initial 4 years of diagnosis, with little relation to the demographic or socioeconomical factors. The incidence of severe hypoglycemic episodes varies between 6 and 20 per 100 person-years, depending on age, geographic location, and intensity of insulin treatment (54,272).

: Insulin treatment dramatically prolongs survival but it does not cure diabetes. Although the absolute mortality at onset and within the first 20 years of type 1 diabetes is low (3-8%), it is 5 times higher for diabetic males and 12 times higher for diabetic females, compared to the general population (274,275). In the Allegheny County population-based registry (Pennsylvania, USA) as of January 1999 the cumulative survival rates were 98.0% at 10 years, 92.1% at 20 years and 79.6% at 30 years duration of type 1 diabetes (276). A significant improvement in the survival rate between the group of patients diagnosed during 1965-1969 and the cohort diagnosed ten years later (1975-1979) has been observed (276). Higher mortality compared with the background population, but lower compared to previous studies and other countries has been also recently reported from Norway (277). The overall mortality was higher in males than females and the excess mortality was similar for both genders (277).
Cardiovascular disease and renal disease are the most common causes of death of type 1 diabetic subjects accounting for 44% and 21% respectively (278). Analyses of mortality from the cohort of patients with type 1 diabetes have also shown that cerebrovascular mortality (stroke of nonhemorrhagic origin) is raised at all ages in these patients (279). The risk of mortality from ischaemic heart disease is exceptionally high in young adult women, with rates similar to those in men under the age of 40 with type 1 diabetes (280,281).
The excess mortality is lowest in Scandinavia, intermediate in the U.S. and highest in countries where type 1 diabetes is rare, e.g. Japan (282,283), probably due to a combination of the quality of care and access. Even in Finland, at least a half of the death is due to currently preventable causes such as acute complications, infections and suicide (284). On the other hand, 40% of the patients survive over 40 years and a half of these have no major complications.
Moreover WHO Multinational Study of Vascular Disease in Diabetes performed in 10 centers throughout the word from 1975 to 1987 showed that age-adjusted all cause mortality rates were significantly higher in type 1 diabetes compared with type 2 diabetes.
Survival and avoidance of complications have been related to better metabolic control (285), but genetic factors also appear to be involved. In the EURODIAB study the predictors for cardiovascular mortality were blood pressure, serum cholesterol, proteinuria and retinopathy, but not fasting plasma glucose (286). In line with this observation, insulin resistance-related factors, but not glycemia, predicted coronary artery disease in type 1 diabetes during 10-year follow-up in the Pittsburgh Epidemiology of Diabetes Complications study (287).
The strongest predictors for five-year mortality in patients with type 1 are amputations (hazard ratio, HR=5.08) and poor visual acuity (HR=1.74) (275).
Inconsistent associations have been reported between diabetic nephropathy and HLA-DR4 (288) and several genes involved in blood pressure regulation (285,289,290,291,292,293,294,295). Polymorphisms of paraoxonase (296,297) and A-IV (298) appear to play an important role in development of coronary artery disease in type 2 diabetes patients, but have not been extensively studied in persons with type 1 diabetes.

Microvascular complications: The high incidence, associated severe morbidity (299), mortality (300), and enormous health care expenditures(301,302,303) make T1DM a prime target for interventions.
The Diabetes Control and Complications Trial demonstrated the efficacy of tight glycemic control in reducing the risk of late complications of type 1 diabetes (304,305,306). Unfortunately, increased risk of hypoglycemia associated with tight control (307,308) and compliance problems have hampered full implementation of the trial recommendations, especially in children. Importantly, studies, including ours, have shown that factors other than hyperglycemia contribute significantly to development of microvascular complications.

Diabetic retinopathy: Diabetes is the most common cause of new cases of blindness in the U.S. adults. After 15+ years of T1DM, 80% of the patients have diabetic retinopathy and 25% have vision-threatening proliferative diabetic retinopathy (PDR) (309). Fundus photography is an effective method for detecting; however, this technique is used to detect disease associated with anatomic changes in the retina. Fluorescein angiography may detect earlier changes, such as breakdown of the blood-retinal barrier manifested by leakage of fluorescein, however, it is costly and associated with complications and is generally used to evaluate more severe diabetic retinopathy, e.g., macular edema, prior to laser photocoagulation. Novel sensitive and specific markers are needed to detect meaningful early changes predictive of incidence and progression of diabetic retinopathy and subsequent visual loss. Such markers could also potentially shorten the duration of clinical trials or allow smaller sample sizes by allowing more precise detection of regression or progression of diabetic retinopathy.
Alterations in retinal blood flow and loss of retinal pericytes (310) precede the earliest clinical stages of diabetic retinopathy. In contrast to the loss of retinal pericytes, changes in retinal arterial blood flow can be detected non-invasively using laser Doppler velocimetry (311), video fluorescein angiography (312) or pulsatile ocular blood flow (313). T1 DM patients with no retinopathy or mild NPDR show dilated major retinal arteries with reduced blood flow velocity, compared to that in non-diabetic controls (312,314). With increasing duration of diabetes and progression of retinopathy, retinal blood flow shows a bimodal pattern of a transition from reduced to increased (311,315).

Diabetic nephropathy: Historically, diabetic nephropathy would affect 30-50% of T1DM patients throughout the initial 20 years of the disease (316,317,318). While there has been an evidence for a secular decline in the incidence of nephropathy in T1DM (317,319,320), this decline may have leveled off (321) and the cumulative risk remains at least 20%-30%.

The incidence peaks 10-15 years after diagnosis and then declines, suggesting that only a subset of the patients is susceptible to diabetic nephropathy. Increased urinary albumin excretion or microalbuminuria (MA) has been shown to be an early manifestation of diabetic nephropathy, rather than merely a prognostic factor (322,323,324). Since MA strongly predicts progression to later stages of diabetic nephropathy (overt proteinuria and end-stage renal disease) (325,326), current standards of care include screening for MA and treatment of those positive for MA with ACE inhibitors (327,328,329,330). However, prediction of the progression to overt nephropathy based on the presence of MA and the other risk factors is imprecise. In addition, some patients in whom MA has not increased may nonetheless develop advanced renal lesions (331). Previously, increased GFR (332,333), increased ambulatory blood pressure (334,335), and autonomic neuropathy (335,336) have shown some promise but have not gained wide acceptance.
Recent reports from patients with type 1 and type 2 diabetes suggest that podocyte loss is associated with progression of diabetic glomerulosclerosis (337,338,339,340,341).

Diabetic neuropathy: The incidence of neuropathy in EURODIAB study group was independently associated with duration of diabetes, glycosylated hemoglobin values, BMI and smoking (342).

Risk factors for microvascular complications in type 1 diabetes: Traditional epidemiological distinction between micro- and macrovascular complications of diabetes is becoming more fluid with the recognition that similar processes (e.g., glycation, hypertension, inflammation, and endothelial dysfunction) affect both vascular beds. Accurate markers of early retinal microvascular alterations may offer a powerful predictive tool concerning the risk of cumulative vascular burden and future micro- and macrovascular clinical events elsewhere in the body.


Hyperglycemia: Chronic hyperglycemia is probably the most accepted risk factor for development of microvascular complications in type 1 diabetes mellitus (304,343,344,345,346).

Blood pressure: Numerous previous studies have demonstrated that increased systolic or diastolic blood pressure is a powerful predicator of microvascular complications (347,348,349,350).

Cigarette smoking is an established risk factor for diabetic nephropathy (348,351,352). Interestingly, smoking does not appear to be an independent risk factor for diabetic retinopathy (353).

Lipids and lipoproteins: Elevated TG and low HDL-cholesterol (349,354,355), and increased total and LDL-cholesterol (348,356,357) have been reported to predict diabetic retinopathy and diabetic nephropathy.

Insulin resistance is an emergent risk factors for both macro- and microvascular complications in type 1 DM (354,355). However, it is unclear if this phenomenon is mediated by associated risk factors (350) or a common genetic determinant (358,359).

Visceral obesity, PAI-1 and markers of inflammation and endothelial dysfunction tend to cluster with microalbuminuria and insulin resistance in diabetic and nondiabetic persons and are clearly associated with macrovascular complications. The relationship of these markers to microvascular diabetic complications has been less studied (360,361). Visceral obesity (354,355), vWF and fibrynogen (362,349), C-reactive protein, IL-6, TNF-a (361) as well as PAI-1 levels (363) have been found to predict diabetic nephropathy and/or diabetic retinopathy. Most of the previous studies were cross-sectional and none has measured visceral obesity directly or analyzed all of these factors jointly. This prospective study will be in a unique position to shed new light on this cluster of novel microvascular risk factors.

Age at onset of diabetes, C-peptide: Greater severity of initial presentation, related largely to the HLA-DR/DQ genotype and age at diagnosis, predicts the faster loss of endogenous insulin production and poorer glycemic control. Lower endogenous insulin production (marked by undetectable C-peptide levels and associated with higher HbA1c) has been suggested to predict progression of diabetic retinopathy (364) and diabetic nephropathy (365). These observations are consistent with the association of microvascular complications with HLA-DR3/4 DR3/4 genotype (366,367) and faster loss of GAD autoantibodies (368).
Importantly, it has been recently found by DAISY study that early diagnosis of type 1 diabetes, in the group of children followed from prediabetic stage to diabetes onset, is associated with better preservation of insulin secretion, which resulted in lower mean insulin dose 12 months after diagnosis (369). The significance of residual insulin secretion with regard to metabolic control and to long-term complications was confirmed by data from DCCT study (370). Patients with preserved C-peptide and lower insulin requirements, fasting blood glucose and HbA1c in the intensive therapy group had 50% reduced risk for progression of retinopathy, development of microalbuminuria and 65% lower risk of severe hypoglycemia (370).

Genetics of microvascular complications: Despite the seemingly inevitable development of complications, at least half of the patients survive over 40 years and a quarter of these have no major complications (371). Retinopathy develops in virtually all patients, given enough time, but the more severe proliferative retinopathy and visual impairment appear in only up to half of the patients (371). Survival and avoidance of complications is related to better metabolic control, but patients developing microvascular complications, especially nephropathy, frequently have no identifiable classical risk factors, suggesting that the genetic component of renal disease is different from that of diabetes.
Diabetic nephropathy clearly clusters in certain families, apparently independent of glycemic control and both in type 1 (372,373,374) and type 2 diabetes (375,376,377,378,379,380). Familial clustering of diabetic nephropathy in T1DM families has been confirmed in a study incorporating the results of kidney biopsies in addition to more common measures of renal function such as urinary AER (381). The clustering is more pronounced in African Americans than Caucasians (376,378,382).
In segregation analysis of the adenine/creatinine ratio as a continuous trait in type 1 diabetes, adjusting for age, sex, and duration of diabetes, adenine/creatinine inheritance was most consistent with a Mendelian model with multifactorial inheritance (383), i.e. determined by a mixture of genes, variable effects, and environment factors such as diabetes and hypertension. Adenine/creatinine ratio heritability (h2) was estimated to be 0.27.
Inconsistent associations have been reported between diabetic nephropathy and HLA-DR4 (384) and several genes involved in blood pressure regulation (371,385,386,387,388,389). ApoE genotype may mediate well-known association between dyslipidemia and development of diabetic nephropathy (390,391,392). Matrix metalloproteinase-9 polymorphism may play a role (393). Additional genes (IL1RN, NHE5, NOS1, KLKB1, RAGE,) may be minor contributors to genetic risk. Extensive analysis of the chromosome 3 region suggested strong evidence of a nephropathy gene, but a detailed evaluation of the AGTR1 gene suggested that alleles of AGTR1 were not the source of the linkage.
The genetic components of retinopathy and other microvascular complications have been investigated to a lesser degree than nephropathy. Diabetic retinopathy clusters in families (307). Diabetic retinopathy has been associated with the presence of genetic variants of the aldose reductase promoter region, eNOS4 polymorphism of the endothelial nitric oxide synthase and DNA sequence variants of VEGF and vitamin D receptor genes (394,395,396,397,398,399,400, 401). Data concerning the role of HLA genotypes are inconsistent  (366,367,402,403,404,405) . The associations between diabetic nephropathy, diabetic retinopathy, and markers of insulin resistance may be mediated by a polymorphism in the PC-1 gene coding region (358,359).

Macrovascular complications
Coronary artery disease (CAD):
CAD is the main cause of death in persons with type 1 diabetes and accounts for a large proportion of premature morbidity and mortality in the general population. Heart disease in type 1 diabetic patients occurs earlier in life, affects women as often as men, and associated mortality is dramatically higher than that in the general population (406,407,408,409). Women with type 1 diabetes are 9 to 29 times more likely to die of CAD than nondiabetic women; the risk for men is increased 4 to 9-fold. Patients with proteinuria are at a 15-37 times increased risk of fatal CAD while the risk of those without proteinuria is 3-4-fold, compared to the general population (406,410). However, it is far from clear whether the association of CAD with nephropathy is mediated by hypertension and dyslipidemia - features of renal failure - or rather by risk factors that predispose to both nephropathy and CAD. While conventional CAD risk factors (hypertension, smoking, low HDL cholesterol and high triglycerides) increase the risk, the role of hyperglycemia, autonomic neuropathy, endothelial dysfunction, insulin resistance and diabetes duration is less established (411,412,413,414). The Pittsburgh Epidemiology of Diabetes Complications Study has recently suggested that, among endothelial dysfunction markers, E-selectin concentration is an independent predictor of CAD (415,416). In type 1 diabetic patients, atherosclerosis is more diffuse (417,418), leading to higher case fatality (419,420), higher cardiac failure (421) and restenosis rates (422), and shorter survival (422,423), compared to the general population. These poor outcomes emphasize the need for primary prevention of CAD in type 1 diabetic patients. Silent ischemia is common - 24% of asymptomatic patients older than 35 yrs had ischemia on exercise test, Holter monitoring or dynamic thallium scintigraphy and 10% had coronary stenosis greater than 50% by angiography (424).
In asymptomatic young subjects with type 1 diabetes the incidence of CAD is increasing 1-2% per year and by their mid 40s 70% of men and 50% of women develop CAC (Coronary Artery Calcification) - a marker of atherosclerotic plaque (425,426).
Small clinical studies using B-mode imaging of carotid arteries have suggested that type 1 diabetic patients have significant atherosclerosis as early as at the age of 10-19 yrs and strongly associated with diabetes duration (427,428). This observation was recently confirmed by EDIC study (429). After six years of follow-up the progression of the intima-media thickness of the common carotid artery was significantly greater in patients with type 1 diabetes in comparison to the controls and was associated with age, mean HbA1C, LDL/HDL ratio, smoking, systolic blood pressure and urinary albumin excretion rate (429).
However, it is still little known about the risk factors for progression of asymptomatic coronary artery disease to clinical endpoints. To address this issue, 6 years ago, the study Coronary Artery Calcification (CAC) in Type 1 Diabetes (CACTI), was initiated (430,431,432,433,434,435,436,437). The measurement of CAC by electron beam tomography is one of the new techniques (besides the ultrasound imaging of carotid arteries and potentially coronary magnetic resonance imaging) for noninvasive monitoring of cardiovascular disease progression (438,439). CAC has been shown to correlate well with the invasive method of coronary lumen estimation (angiography) and arterial wall intimal architecture (IVUS) (435,438). The initial data from the CACTI study suggest that gender-related differences in insulin sensitivity may explain the increase in CAC in women compared with men with type 1 diabetes (431). Moreover a common promoter polymorphism in the hepatic lipase gene (LIPC-480C>T) was found to be associated with the extent of coronary calcification in a dose dependent manner (431). Among type 1 diabetic patients greater progression of CAC was observed in subjects with HbA1C values >7.5%, higher levels of soluble IL-2 receptor and low plasma adiponectin (416,430,433) One third of the patients enrolled into the CACTI had hypertension, but only half of those were well treated and controlled (434). The other half was either treated, but uncontrolled or not treated at all. Even worse, nearly half of the patients had dyslipidemia, according to the ATP III criteria and very few of these were successfully treated (432). This CACTI data suggest that appropriate blood pressure and lipid disturbances treatment issues should be addressed before one move to interventions targeting novel risk factors, such as adiponectin or markers of inflammation (432,434).

Type 1 diabetes can be diagnosed at any age, but clinical course, genetic, and environmental determinants appear to be heterogenous by age. The common pathway begins with pre-clinical ß-cell autoimmunity with progressive defect of insulin secretion, followed by onset of hyperglycemia, transient usually partial remission, and finally complete insulinopenia associated with acute and chronic complications and premature death. Current research effort is focused on identification of the genetic and environmental determinants of this process and the ways they interact.



Year of Study

Age (y)

(per 100,000)

United States

SEARCH study:

Non-Hispanic White

African American


Asian/Pacific Islander

American Indian/Alaska Native

All Race/Ethnicity









South Carolina*




Montana and Wyoming:

American Indians








Rochester, MD




Erie County, PA












Sardinia (men only)




Portugal (men only)








UK, North Wales



280 (F), 400 (M)

UK, Leicester




Czech Republic
























Australia, Oceania, Middle East

Canterbury, New Zealand







Papua New Guinea




Tasmania, Australia









 * All types of diabetes
Table 9.1. Prevalence of childhood type 1 diabetes, from selected studies.




Region /ethnicity

Time of study



Cases/ 100.000

95% CI

Time trend



United States

6 centres









African American




Asian/Pacific Island


American Indian


6 centres









African American




Asian/Pacific Island


American Indian


Montana and Wyoming

American Indians




















African American:










African American







Newfoundland (Avalon Peninsula)






























Region /ethnicity

Time of study



Cases/ 100.000

95% CI

Time trend



Bosnia and Herzegovina



















































Nationwide study








































































Three cities study















Antwerp district







Czech Republic




















North Rine-Westphalia
















Nine centers







Northern part




Central part




Southern part





(Northwest Italy)







Turin province



M: 10.7 F: 9.8













United Kingdom








Devon, Cornwall














South Asian origin




Caucasian origin











South Asian origin





Caucasian origin



















































South-eastern part


















1989- 1999










Australia, Oceania, Asia, Middle East

Papua New Guinea









Western part







New Zealand

















Northern part








Beijing area










































Jews origin


Arab origin










Saudi Arabia

Eastern Province








N.S.=not significant increase or no increase NA= no available data, I-increase

Table 9.2. Current incidence of type 1 diabetes (data published 2000-2005).






References - Chapter 9

1. Rewers M.  The changing face of the epidemiology of insulin-dependent diabetes mellitus (IDDM): Research designs and models of disease causation.  Ann Med 23:419-426,  1991.

2. Libman I, Songer T, LaPorte R.  How many people in the U.S. have IDDM?  Diabetes Care 16:841-842,  1993.

3. Rewers M, LaPorte RE, King H, Tuomilehto J.  Trends in the prevalence and incidence of diabetes: insulin-dependent diabetes mellitus in childhood.  World Health Stat Q 41:179- 189,  1988.

4. Patrick SL, Moy CS, LaPorte RE.  The world of insulin-dependent diabetes mellitus: what international epidemiologic studies reveal about the etiology and natural history of IDDM.  Diabetes Metab Rev 5:571-578, 1989.

5. Chase HP, MacKenzie TA, Burdick J, Fiallo-Scharer R, Walravens P, Klingensmith G, Rewers M. Redefining the clinical remission period in children with type 1 diabetes. Pediatr Diabetes. 2004 Mar;5(1):16-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15043685&query_hl=9

6. Songer TJ.  Health services and costing in diabetes.  Med J Aust 152:115-117 ,  1990.

7. US Public Health Service DoHaHSM.  Healthy people 2000: National health promotion and disease prevention objectives.  MD, USA: Us Departme-1991.

8. Skyler JS, Crofford OB, Dupre J, Eisenbarth GS, Fathman GC, Gale EAM, Goldstein D, Harmon JT, Haymond MW, Jackson RA, Kahn R, Krischer J, Maclaren NK, Palmer JP, Silverman R, Simon R.  Prevention of Type 1 diabetes mellitus.  Diabetes 39:1151-1152,  1990.

9. American Diabetes Association.  Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care 20:1183-1197,  1997.

10. Alberti KG, Zimmet PZ.  Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation [see comments].  Diabet Med 15:539-553,  1998. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9686693&query_hl=28

11. Atkinson MA, Eisenbarth GS.  Type 1 Diabetes: New Perspectives on Disease Pathogenesis and Treatment.  Lancet 2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11476858&query_hl=31

12. Maugendre D, Chaillous L, Rohmer V, Lecomte P, Marechaud R, Sai P, Marre M, Charbonnel B,  Allannic H, Delamaire M.  Multiple antibody status in type 1 diabetic patients and subjects at various risk with islet-cell antibodies.  Diabetes Metab 23:320-326,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9342546&query_hl=33

13. Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y.  A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group.  New Engl J Med 342:301-307,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10655528&query_hl=37

14. Rewers M, Norris J, Dabelea D. Epidemiology of type 1 Diabetes Mellitus. Adv Exp Med Biol. 2004;552:219-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15622966&query_hl=39

15. Bottazzo GF, Florin-Christensen A, Doniach D.  Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies.  Lancet 2:1279-1283,  1974.

16. Palmer JP, Asplin CM, Clemons P, Lyen K, Tatpati O, Raghu PK, Paquette TL.  Insulin antibodies in insulin-dependent diabetics before insulin treatment.  Science 222:1337-1339,  1983.

17. Vardi P, Dib SA, Tuttleman M, Connelly JE, Grinbergs M, Radizabeh A, Riley WJ, Maclaren NK,  Eisenbarth GS, Soeldner JS.  Competitive insulin autoantibody assay. Prospective evaluation of subjects at high risk for development of type I diabetes mellitus.  Diabetes 36:1286-1291,  1987.

18. Williams AJK, Bingley PJ, Bonifacio E, Palmer JP, Gale EAM.  A novel micro-assay for insulin autoantibodies.  J Autoimmun 10:473-478,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9376075&query_hl=42

19. Baekkeskov S, Nielsen JH, Marner B, Bilde T, Ludvigsson J, Lernmark Å.  Autoantibodies in newly diagnosed diabetic children immunoprecipitate specific human pancreatic islet cell proteins.  Nature 298:167- 169,  1982.

20. Baekkeskov S, Aanstoot H-J, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, DeCamilli P.  Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase [published erratum appears in Nature 1990 Oct 25;347(6295):782].  Nature 347:151-156,  1990.

21. Rabin DU, Pleasic SM, Shapiro JA, Yoo-Warren H, Oles J, Hicks JM, Goldstein DE, Rae PM.  Islet cell antigen 512 is a diabetes-specific islet autoantigen related to protein tyrosine phosphatases.  J Immunol 152:3183-3188,  1994.

22. Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, Chase HP, Eisenbarth GS.  Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies.  Diabetes 45:926- 933,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8666144&query_hl=44

23. Bingley PJ, Christie MR, Bonifacio E, Bonfanti R, Shattock M, Fonte MT, Bottazzo GF, Gale EA.   Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives.  Diabetes 43:1304-1310,  1994.

24. Bingley PJ, Bonifacio E, Williams AJ, Genovese S, Bottazzo GF, Gale, EA.  Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers.  Diabetes 46:1701-1710,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9356015&query_hl=46

25. Barker JM, Barriga KJ, Yu L, Miao D, Erlich HA, Norris JM, Eisenbarth GS, Rewers M; Diabetes Autoimmunity Study in the Young. Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). J Clin Endocrinol Metab. 2004 Aug;89(8):3896-902.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15292324&query_hl=48

26. Yu J, Yu L, Bugawan TL, Erlich HA, Barriga K, Hoffman M, Rewers M, Eisenbarth GS. Transient antiislet autoantibodies: infrequent occurrence and lack of association with "genetic" risk factors. J Clin Endocrinol Metab. 2000 Jul;85(7):2421-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10902788&query_hl=50

27. Stanley HM, Norris JM, Barriga K, Hoffman M, Yu L, Miao D, Erlich HA, Eisenbarth GS, Rewers M; Diabetes Autoimmunity Study in the Young (DAISY). Is presence of islet autoantibodies at birth associated with development of persistent islet autoimmunity? The Diabetes Autoimmunity Study in the Young (DAISY). Diabetes Care. 2004 Feb;27 (2): 497-502. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14747235&query_hl=52

28. Rewers M. Islet autoantibodies in cord blood: maternal, fetal, or neither? Diabetes Metab Res Rev. 2002 Jan-Feb;18(1):2-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11921412&query_hl=54

29. Bonifacio E, Bingley PJ, Shattock M, Dean BM , Dunger D, Gale EAM, Bottazzo GF.  Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes.  Lancet 335:147-149,  1990.

30. Johnston C, Millward BA, Hoskins P, Leslie RD, Bottazzo GF, Pyke DA.  Islet-cell antibodies as predictors of the later development of type 1 (insulin-dependent) diabetes. A study in identical twins.  Diabetologia 32:382-386,  1989.

31. McCulloch DKPalmer JP.   The appropriate use of B-cell function testing in the preclinical period of Type 1 diabetes.  Diabetic Med 8:800-804,  1991.

32. Eisenbarth GS, Moriyama H, Robles DT, Liu E, Yu L, Babu S, Redondo M, Gottlieb P, Wegmann D, Rewers M. Insulin autoimmunity: prediction/precipitation/ prevention type 1A diabetes. Autoimmun Rev. 2002 May;1(3):139-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12849007&query_hl=56

33. Miao D, Yu L, Tiberti C, Cuthbertson DD, Rewers M, di Mario U, Eisenbarth GS, Dotta F. ICA512 (IA-2) epitope specific assays distinguish transient from diabetes associated autoantibodies. J Autoimmun. 2002 Mar;18(2):191-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11908951&query_hl=58

34. Robles DT, Eisenbarth GS, Wang T, Erlich HA, Bugawan TL, Babu SR, Barriga K, Norris JM, Hoffman M, Klingensmith G, Yu L, Rewers M; Diabetes Autoimmunity Study in the Young. Millennium award recipient contribution. Identification of children with early onset and high incidence of anti-islet autoantibodies. Clin Immunol. 2002 Mar;102(3):217-24.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11890708&query_hl=60

35. Park YS, Kawasaki E, Kelemen K, Yu L, Schiller MR, Rewers M, Mizuta M, Eisenbarth GS, Hutton JC. Humoral autoreactivity to an alternatively spliced variant of ICA512/IA-2 in Type I diabetes. Diabetologia. 2000 Oct;43(10):1293-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11079748&query_hl=62

36. Schlosser M, Koczwara K, Kenk H, Strebelow M, Rjasanowski I, Wassmuth R, Achenbach P, Ziegler AG, Bonifacio E. In insulin-autoantibody-positive children from the general population, antibody affinity identifies those at high and low risk. Diabetologia. 2005 Jul 12; [Epub ahead of print] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16010521&query_hl=64

37. Achenbach P, Koczwara K, Knopff A, Naserke H, Ziegler AG, Bonifacio E. Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes.J Clin Invest. 2004, 114: 589-97 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15314696&query_hl=66

38. Achenbach P, Warncke K, Reiter J, Naserke HE, Williams AJ, Bingley PJ, Bonifacio E, Ziegler AG. Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics. Diabetes. 2004 Feb;53(2):384-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14747289&query_hl=68

39. Spinas GA, Matter L, Wilkin T, Staffelbach O, Berger W.  Islet-cell and insulin autoantibodies in first-degree relatives of type I diabetics: a 5-year follow-up study in a Swiss population.  Adv Exp Med Biol  246:209-214,  1988.

40. Thivolet C, Beaufrere B, Betuel H, Gebuhrer L, Chatelain P, Durand A, Tourniaire J, Francois R.  Islet cell and insulin autoantibodies in subjects at high risk for development of type 1 (insulin-dependent) diabetes mellitus: the Lyon family study.  Diabetologia 31:741-746,  1988.

41. Maclaren N, Horne G, Spillar R, Barbour H, Harrison D, Duncan J.  The feasibility of using ICA to predict IDDM in US school children.  Diabetes 39 (Suppl.1):122A-1990.

42. Landin-Olsson M, Palmer JP, Lernmark A, Blom A, Sundkvist G, Nystrom L, Dahlquist G.  Predictive value of islet cell and insulin autoantibodies for Type 1 (insulin-dependent) diabetes mellitus in a population- based study of newly-diagnosed diabetic and matched control children.  Diabetologia 35:1068-1073,  1992.

43. Karjalainen JK.  Islet cell antibodies as predictive markers for IDDM in children with high background incidence of disease.  Diabetes 39:1144-1150,  1990.

44. Yu J, Yu L, Bugawan TL, Erlich HA, Barriga K, Hoffman M, Rewers M, Eisenbarth GS.  Transient anti-islet autoantibodies: infrequent occurrence and lack of association with genetic risk factors.  J Clin Endocrinol Metab 85:2421-2428,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10902788&query_hl=70

45. Lindberg BA, Ericsson UB, Kockum I, Lernmark A, Landin-Olsson M, Sundkvist G, Ivarsson SA.  Prevalence of beta-cell and thyroid autoantibody positivity in schoolchildren during three-year follow-up.  Autoimmunity 31 :175-185,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10739334&query_hl=72

46. Yu J, Yu L, Bugawan TL, Erlich HA, Barriga K, Hoffman M, Rewers M, Eisenbarth GS.  Transient anti-islet autoantibodies: infrequent occurrence and lack of association with genetic risk factors.  J Clin Endocrinol Metab 85:2421-2428,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10902788&query_hl=70

47. Riley WJ, Maclaren NK, Krischer J, Spillar RP, Silverstein JH, Schatz DA , Schwartz S, Malone J, Shah S, Vadheim C, Rotter JI.  A prospective study of the development of diabetes in relatives of patients with insulin-dependent diabetes.  N Engl J Med 323:1167-1172,  1990. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2215594&query_hl=74

48. Groop LC, Bottazzo GF, Doniach D.  Islet Cell Antibodies Identify Latent Type I Diabetes in Patients Aged 35-75 Years at Diagnosis.  Diabetes 35:237-241,  1986.

49. Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR.   Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin- dependent onset of disease.  Diabetes 42:359-362,  1993.

50. Zimmet PZ, Tuomi T, Mackay IR, Rowley MJ, Knowles W, Cohen M, Lang DA.  Latent autoimmune diabetes mellitus in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency.  Diabet Med 11:299-303,  1994.

51. Hamman RF, Cook M, Keefer S, Young WF, Finch JL, Lezotte D, McLaren B, Orleans M, Klingensmith G, Chase HP.  Medical care patterns at the onset of insulin-dependent diabetes mellitus: association with severity and subsequent complications.  Diabetes Care 8 (Suppl 1):94-100,  1985.

52. Karjalajnen S, Salema P, IIonen J.  A comparison of childhood and adult type 1 diabetes mellitus.  N Engl J Med 320:881- 886,  1989.

53. Levy-Marchal C, Papoz L, de Beaufort C, Doutreix J, Froment V, Voirin J, Czernichow P.  Clinical and laboratory features of type I diabetic children at time of diagnosis.  Diabetic Med 9:279-284,  1992.

54. Pinkney JH, Bingley PJ, Sawtell PA, Dunger DB, Gale EAM, The Bart's-Oxford Study Group.  Presentation and progress of childhood diabetes mellitus: A prospective population-based study.  Diabetologia 37:70-74,  1994.

55. Eberhardt MS, Wagener DK, Orchard TJ, LaPorte RE, Cavender DE, Rabin BS, Atchison RW, Kuller LH, Drash AL, Becker DJ.  HLA heterogeneity of insulin-dependent diabetes mellitus at diagnosis. The Pittsburgh IDDM Study.  Diabetes 34:1247-1252,  1985.

56. Foulis AK, Liddle CN, Farquharson MA, Richmond JA, Weir RS.  The histopathology of the pancreas in type I diabetes (insulin dependent) mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom.  Diabetologia 29:267-274,  1986.

57. Childhood Diabetes Research Committee MoHaWJ, Polish Diabetes Research Group P, The Netherlands Institute for Preventive Health Care L, Diabetes Research Center of Pittsburgh P.  How frequently do children die at the onset of insulin-dependent diabetes?  Analyses of registry data from Japan, Poland, the Netherlands, and Allegheny County, Pennsylvania.  Diab Nutr Metab 3:57-62,  1990.

58. Kostraba JN, Gay EC, Rewers M, Chase HP, Klingensmith GJ, Hamman RF.  Increasing trend of outpatient management of children with newly diagnosed IDDM. Colorado IDDM registry, 1978-88.  Diabetes Care 15:95- 100,  1992.

59. Rewers M, LaPorte RE, King H, Tuomilehto J.  Trends in the prevalence and incidence of diabetes: insulin-dependent diabetes mellitus in childhood.  World Health Stat Q 41:179- 189,  1988.

60. Libman I, Songer T, LaPorte R.  How many people in the U.S. have IDDM?  Diabetes Care 16:841-842,  1993.

61. Diabetes Epidemiology Research International Group.  Geographic patterns of childhood insulin-dependent diabetes mellitus.  Diabetes 37:1113-1119,  1988.

62. Green A, Gale EAM, Patterson CC.  Incidence of childhood-onset insulin-dependent diabetes mellitus: the EURODIAB ACE Study.  Lancet 339:905-909,  1992.

63. Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J.  Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group.  Diabetes Care 23:1516-1526,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11023146&query_hl=76

64. Rewers MKostraba JN.  Epidemiology of Type I diabetes.  1994.

65. Adojaan B, Knip M, Vahasalo P, Karjalainen J , Kalits I, Akerblom HK.  Relationship between the incidence of childhood IDDM and the frequency of ICA positivity in nondiabetic children in the general population.  Diabetes Care 19:1452-1454,  1996.

66. Pilcher CC, Dickens K, Elliott RB.  ICA only develop in early childhood.  Diabetes Res Clin Pract 14(Suppl. 1):s82-s82,  1991.

67. Tajima N, LaPorte RE, Hibi I, Kitagawa T, Fujita H, Drash AL.   A comparison of the epidemiology of youth-onset insulin- dependent diabetes mellitus between Japan and the United States (Allegheny County, Pennsylvania).  Diabetes Care 8(Suppl 1) :17-23,  1985.

68. Rewers M, Stone RA, LaPorte RE, Drash AL, Becker DJ, Walczak M, Kuller LH.  Poisson regression modeling of temporal variation in incidence of childhood insulin-dependent diabetes mellitus in Allegheny County, Pennsylvania, and Wielkopolska, Poland, 1970-1985.  Am J Epidemiol 129:569-581, 1989.

69. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeitler P.  Increased incidence of non-insulin-dependent diabetes mellitus among adolescents.  Journal of Pediatrics 128:Part 1):608-615,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8627431&query_hl=78

70. Rosenbloom AL, Joe JR, Young RS, Winter WE.  Emerging epidemic of type 2 diabetes in youth.  Diabetes Care 22:345-354,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10333956&query_hl=80

71. Dabelea D, Hanson RL, Bennett PH, Roumain J , Knowler WC, Pettitt DJ.  Increasing prevalence of Type II diabetes in American Indian children.  Diabetologia 41:904-910,  1998. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9726592&query_hl=82

72. Joner GSovik O.  The incidence of type 1 (insulin-dependent) diabetes mellitus 15- 29 years in Norway 1978-1982.  Diabetologia 34:271-274,  1991.

73. Muntoni SSongini M.  High incidence rate of IDDM in Sardinia. Sardinian Collaborative Group for Epidemiology of IDDM.  Diabetes Care 15:1317-1322,  1992.

74. Bruno G, Merletti F, Vuolo A, Pisu E, Giorio M, Pagano G.  Sex differences in incidence of IDDM in age group 15-29 yr. Higher risk in males in Province of Turin, Italy.  Diabetes Care 16(1):133-136,  1993.

75. Christau B, Kromann H, Andersen OO, Christy M, Buschard K, Arnung K, Kristensen IH, Peitersen B, Steinrud J, Nerup J.  Incidence, seasonal and geographic patterns of juvenile-onset insulin-dependent diabetes mellitus is Denmark.  Diabetologia 13(4):281-284,  1977.

76. Melton LJ, III, Palumbo PJ, Chu CP.  Incidence of diabetes mellitus by clinical type.  Diabetes Care  6:75-86 ,  1983.

77. Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR,  Shattock M, Bottazzo GF, Holman R.  UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group [published erratum appears in Lancet 1998 Jan 31;351(9099):376].  Lancet 350:1288-1293,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9357409&query_hl=84

78. Horton V, Stratton I, Bottazzo GF, Shattock M, Mackay I, Zimmet P, Manley S, Holman R, Turner R.  Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43). UK Prospective Diabetes Study (UKPDS) Group.  Diabetologia 42:608-616,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10333055&query_hl=86

79. Diabetes Epidemiology Research International Group.  Geographic patterns of childhood insulin-dependent diabetes mellitus.  Diabetes 37:1113-1119,  1988.

80. Kostraba JN, Gay EC, Cai Y, Cruickshanks KJ, Rewers MJ, Klingensmith GJ, Chase HP, Hamman RF.  Incidence of insulin-dependent diabetes mellitus in Colorado.  Epidemiology 3:232-238,  1992.

81. Dabelea D on behalf of SEARCH Study Group.The SEARCH for diabetes in youth study group. Abstracts of ADA, San Diego  2005:124-OR

82. Rewers M, Zimmet P. The rising tide of childhood type 1 diabetes--what is the elusive environmental trigger? Lancet. 2004 Nov 6-12;364(9446):1645-7.  Prevalence of type 1 diabetes

83. Feltbower RG, Bodansky HJ, McKinney PA, et al. Trends in the incidence of childhood diabetes in south Asians and other children in Bradford, UK Diab Med 19 (2): 162-166 FEB 2002 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11874434&query_hl=89

84. Siemiatycki J, Colle E, Campbell S, Dewar RA , Belmonte MM.  Case-control study of IDDM.  Diabetes Care 12:209-216,  1989.

85. Zimmet PZ, Rowley MJ, Mackay IR, Knowles WJ , Chen QY, Chapman LH, Serjeantson SW.  The ethnic distribution of antibodies to glutamic acid decarboxylase: presence and levels of insulin-dependent diabetes mellitus in Europid and Asian subjects.  J Diabetes Complications 7:1-7,  1993.

86. Gale EA, Gillespie KM.  Diabetes and gender.  Diabetologia 44:3-15,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11206408&query_hl=91

87. Karvonen M, Pitkaniemi M, Pitkaniemi J, Kohtamaki K, Tajima N, Tuomilehto J.  Sex difference in the incidence of insulin-dependent diabetes mellitus: an analysis of the recent epidemiological data. World Health Organization DIAMOND Project Group.  Diabetes Metab Rev 13:275-291,  1997.

88. Krischer JP, Cuthbertson DD, Greenbaum C; Diabetes Prevention Trial-Type 1 Study Group. Male sex increases the risk of autoimmunity but not type 1 diabetes. Diabetes Care. 2004 Aug;27(8):1985-90.

89. Serban V, Timar R, Dabelea D, Green A, McKinney P, Law G.  The epidemiology of childhood-onset type 1 diabetes mellitus in Romania. ONROCAD Study Group. National Romanian Organisation for the Care of Diabetic Children and Adolescents.  J Pediatr Endocrinol Metab 14:535-541,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11393575&query_hl=93

90. Karvonen M, Pitkaniemi M, Pitkaniemi J, Kohtamaki K, Tajima N, Tuomilehto J.  Sex difference in the incidence of insulin-dependent diabetes mellitus: an analysis of the recent epidemiological data. World Health Organization DIAMOND Project Group.  Diabetes Metab Rev 13:275-291,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9509279&query_hl=95

91. Green A, Hauge M, Holm NV, Rasch LL.  Epidemiological studies of diabetes mellitus in Denmark. II. A prevalence study based on insulin prescriptions.  Diabetologia 20:468-470,  1981.

92. Bruno G, Merletti F, Vuolo A, Pisu E, Giorio M, Pagano G.  Sex differences in incidence of IDDM in age group 15-29 yr. Higher risk in males in Province of Turin, Italy.  Diabetes Care 16(1):133-136,  1993.

93. Ustvedt HJOlsen E.  Incidence of diabetes mellitus in Oslo, Norway 1956-65.  Br J Prev Soc Med 31:251-257,  1977.

94. Roglic G, Pavlic-Renar I, Sestan-Crnek S, Prasek M, Kadrnka-Lovrencic M, Radica A, Metelko Z.  Incidence of IDDM during 1988-1992 in Zagreb, Croatia.  Diabetologia 38:550-554,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7489837&query_hl=97

95. Vandewalle CL, Coeckelberghs MI, De Leeuw IH, Du Caju MV, Schuit FC, Pipeleers DG, Gorus FK.  Epidemiology, clinical aspects, and biology of IDDM patients under age 40 years. Comparison of data from Antwerp with complete ascertainment with data from Belgium with 40% ascertainment. The Belgian Diabetes Registry.  Diabetes Care 20:1556-1561,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9314635&query_hl=99

96. Risch N, Ghosh S, Todd JA.  Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: application to nonobese diabetic (NOD) mouse and human insulin- dependent diabetes mellitus (IDDM).  Am J Hum Genet 53:702-714,  1993.

97. Gale EA, Gillespie KM.  Diabetes and gender.  Diabetologia 44:3-15,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11206408&query_hl=102

98. Gamble DR.  The epidemiology of insulin-dependent diabetes, with particular reference to the relationship of virus infection to its etiology.  Epidemiol Rev 2:49-70,  1980.

99. Kostraba JN, Gay EC, Cai Y, Cruickshanks KJ, Rewers MJ, Klingensmith GJ, Chase HP, Hamman RF.  Incidence of insulin-dependent diabetes mellitus in Colorado.  Epidemiology 3:232-238,  1992.

100. Dahlquist G, Gustavsson KH, Holmgren G, Hagglof B, Larsson Y, Nilsson KO, Samuelsson G, Sterky G, Thalme B, Wall S.  The incidence of diabetes mellitus in Swedish children 0-14 years of age. A prospective study 1977-1980.  Acta Paediatr Scand 71:7-14,  1982.

101. Weinberg CR, Dornan TL, Hansen JA, Raghu PK, Palmer JP.  HLA-related heterogeneity in seasonal patterns of diagnosis in type I (insulin-dependent) diabetes.  Diabetologia 26(3):199-202,  1984.

102. Ludvigsson JAfoke AO.  Seasonality of type 1 (insulin-dependent) diabetes mellitus: values of C-peptide, insulin antibodies and haemoglobin A1c show evidence of a more rapid loss of insulin secretion in epidemic patients.  Diabetologia 32:84-91,  1989.

103. Rewers M, LaPorte R, Walczak M, Dmochowski K, Bogaczynska E.  Apparent epidemic of insulin-dependent diabetes mellitus in midwestern Poland.  Diabetes 36:106 -113,  1987.

104. Diabetes Epidemiology Research International Group.  Secular trends in incidence of childhood IDDM in 10 countries.  Diabetes 39:858-864,  1990.

105. Nystrom L, Dahlquist G, Rewers M, Wall S.  The Swedish childhood diabetes study: an analysis of the temporal variation in diabetes incidence, 1978-1987.  Int J Epidemiol 19:141-146,  1990.

106. Tuomilehto J, Rewers M, Reunanen A, Lounamaa P, Lounamaa R, Tuomilehto-Wolf E, Akerblom HK.  Increasing trend in type I (insulin-dependent) diabetes mellitus in childhood in Finland. Analysis of age, calendar time, and birth cohort effects during 1965 to 1984.  Diabetologia 34:282-287,  1991.

107. Dokheel TM.  An epidemic of childhood diabetes in the United States?  Diabetes Care 16:1606-1611,  1993.

108. Variation and trends in incidence of childhood diabetes in Europe. EURODIAB ACE Study Group.  Lancet 355:873- 876,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10752702&query_hl=103

109. Karvonen M, Pitkaniemi J, Tuomilehto J.  The onset age of type 1 diabetes in Finnish children has become younger. The Finnish Childhood Diabetes Registry Group.  Diabetes Care 22:1066-1070,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10388969&query_hl=105

110. Rosenbauer J, Herzig P, von Kries R, Neu A, Giani G.  Temporal, seasonal, and geographical incidence patterns of type I diabetes mellitus in children under 5 years of age in GermanyDiabetologia 42:1055-1059,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10447515&query_hl=107

111. Cinek O, Lanska V, Kolouskova S, Sumnik Z, Snajderova M, Ronningen KS, Vavrinec J.  Type 1 diabetes mellitus in Czech children diagnosed in 1990-1997: a significant increase in incidence and male predominance in the age group 0-4 years. Collaborators of the Czech Childhood Diabetes Registry.  Diabetic Med 17:64-69,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10691162&query_hl=109

112. Gardner SG, Bingley PJ, Sawtell PA, Weeks S, Gale EA.  Rising incidence of insulin dependent diabetes in children aged under 5 years in the Oxford region: time trend analysis. The Bart's-Oxford Study Group [see comments].  BMJ 315:713-717,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9314756&query_hl=111

113. Schoenle EJ, Lang-Muritano M, Gschwend S, Laimbacher J, Mullis PE, Torresani T, Biason-Lauber A, Molinari L.  Epidemiology of type I diabetes mellitus in Switzerland: steep rise in incidence in under 5 year old children in the past decade .  Diabetologia 44:286-289,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11317657&query_hl=113

114. Cordell HJ, Todd JA.  Multifactorial inheritance in type 1 diabetes. [Review].  Trends Genet 11:499-504,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8533167&query_hl=116

115. Rewers M, Stone RA, LaPorte RE, Drash AL, Becker DJ, Walczak M, Kuller LH.  Poisson regression modeling of temporal variation in incidence of childhood insulin-dependent diabetes mellitus in Allegheny County, Pennsylvania, and Wielkopolska, Poland, 1970-1985.  Am J Epidemiol 129:569-581,  1989.

116. Tuomilehto J, Rewers M, Reunanen A, Lounamaa P, Lounamaa R, Tuomilehto-Wolf E, Akerblom HK.  Increasing trend in type 1 (insulin-dependent) diabetes mellitus in childhood in Finland. Analysis of age, calendar time and birth cohort effects during 1965 to 1984.  Diabetologia 34:282-287,  1991.

117. Nystrom L, Dahlquist G, Rewers M, Wall S.  The Swedish childhood diabetes study. An analysis of the temporal variation in diabetes incidence 1978-1987.  Int J Epidemiol 19:141-146,  1990.

118. Bruno G, Merletti F, Biggeri A, Cerutti F, Grosso N, De Salvia A, Vitali E, Pagano G.  Increasing trend of type I diabetes in children and young adults in the province of Turin (Italy). Analysis of age, period and birth cohort effects from 1984 to 1996.  Diabetologia 44:22-25,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11206406&query_hl=118

119. Onkamo P, Vaananen S, Karvonen M, Tuomilehto J.  Worldwide increase in incidence of Type I diabetes--the analysis of the data on published incidence trends.  Diabetologia 42:1395-1403,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10651256&query_hl=120

120. Stene LC, Barriga K, Norris JM, Hoffman M, Klingensmith G, Erlich HA, Eisenbarth GS, Rewers M.  Symptoms of common maternal infections in pregnancy and risk of islet autoimmunity in early childhood. Diabetes Care. 2003 Nov;26(11):3136-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14578251&query_hl=122

121. Wagener DK, Sacks JM, LaPorte RE, MacGregor JM.  The Pittsburgh study of insulin-dependent diabetes mellitus. Risk for diabetes among relatives of IDDM.  Diabetes 31:136-144,  1982.

122. Allen C, Palta M, D'Alessio DJ.  Risk of diabetes in siblings and other relatives of IDDM subjects.  Diabetes 40:831-836,  1991.

123. Redondo MJ, Rewers M, Yu L, Garg S, Pilcher CC, Elliott RB, Eisenbarth GS.  Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: prospective twin study. BMJ. 1999 Mar 13;318(7185):698-702. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10074012&query_hl=124

124. Steck AK, Barriga KJ, Emery LM, Fiallo-Scharer RV, Gottlieb PA, Rewers MJ. Secondary attack rate of type 1 diabetes in Colorado families. Diabetes Care. 2005 Feb;28(2):296-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15677782&query_hl=126

125. Lorenzen T, Pociot F, Hougaard P, Nerup J.  Long-term risk of IDDM in first-degree relatives of patients with IDDM.  Diabetologia 37:321-327,  1994.

126. O'Leary LA, Dorman JS, LaPorte RE, Orchard TJ, Becker DJ, Kuller LH, Eberhardt MS, Cavender DE, Rabin BS, Drash AL.  Familial and sporadic insulin-dependent diabetes: Evidence for heterogeneous etiologies?  Diab Res Clin Pract 14:183-190,  1991.

127. Erlich HA, Griffith RL, Bugawan TL, Ziegler R, Alper C, Eisenbarth G.  Implication of specific DQB1 alleles in genetic susceptibility and resistance by identification of IDDM siblings with novel HLA-DQB1 allele and unusual DR2 and DR1 haplotypes.  Diabetes 40:478-481,  1991.

128. Bertrams JBaur MP.  Insulin-dependent diabetes mellitus.  348-358,  1984.

129. Todd JA.  The role of MHC class II genes in susceptibility to insulin- dependent diabetes mellitus.  Curr Top Microbiol Immunol 164:17-40,  1990.

130. Ide A, Babu SR, Robles DT, Wang T, Erlich HA, Bugawan TL, Rewers M, Fain PR, Eisenbarth GS.  "Extended" A1, B8, DR3 haplotype shows remarkable linkage disequilibrium but is similar to nonextended haplotypes in terms of diabetes risk. Diabetes. 2005 Jun;54(6):1879-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15919812&query_hl=128

131. Cruz TD, Valdes AM, Santiago A, Frazer de Llado T, Raffel LJ, Zeidler A, Rotter JI, Erlich HA, Rewers M, Bugawan T, Noble JA. DPB1 alleles are associated with type 1 diabetes susceptibility in multiple ethnic groups. Diabetes. 2004 Aug;53(8):2158-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15277401&query_hl=130

132. Rewers A, Babu S, Wang TB, Bugawan TL, Barriga K, Eisenbarth GS, Erlich HA.Ethnic differences in the associations between the HLA-DRB1*04 subtypes and type 1 diabetes.Ann N Y Acad Sci. 2003, 1005: 301-9 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14679080&query_hl=132

133. Rewers A, Babu S, Wang TB, Bugawan TL, Barriga K, Eisenbarth GS, Erlich HA. Ethnic differences in the associations between the HLA-DRB1*04 subtypes and type 1 diabetes. Ann N Y Acad Sci. 2003 Nov;1005:301-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14679080&query_hl=134

134. Rewers M, Bugawan TL, Norris JM, Blair A, Beaty B, Hoffman M, McDuffie RS, Hamman RF, Klingensmith G, Eisenbarth GS, Erlich HA.  Newborn screening for HLA markers associated with IDDM: Diabetes Autoimmunity Study in the Young (DAISY).  Diabetologia 39:807-812,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8817105&query_hl=135

135. Pugliese A, Gianani R, Moromisato R, Awdeh ZL, Alper CA, Erlich HA, Jackson RA, Eisenbarth GS.  HLA-DQB1*0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM.  Diabetes 44:608-613,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7789622&query_hl=137

136.  Barker JM, Barriga KJ, Yu L, Miao D, Erlich HA, Norris JM, Eisenbarth GS, Rewers M; Diabetes Autoimmunity Study in the Young. Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). J Clin Endocrinol Metab. 2004 Aug;89(8):3896-902. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15292324&query_hl=139

137. Kukko M, Virtanen SM, Toivonen A, Simell S, Korhonen S, Ilonen J, Simel O, Knip M. Geographical variation in risk HLA-DQB1 genotypes for type 1 diabetes and signs of beta-cell autoimmunity in a high-incidence country. Diabetes Care. 2004 Mar;27(3):676-81 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14988284&query_hl=140

138. Knip M, Kukko M, Kulmala P, Veijola R, Simell O, Akerblom HK, Ilonen J. Humoral beta-cell autoimmunity in relation to HLA-defined disease susceptibility in preclinical and clinical type 1 diabetes. Am J Med Genet. 2002 May 30;115(1):48-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12116176&query_hl=142

139. Greenbaum CJ, Eisenbarth G, Atkinson M, Yu L, Babu S, Schatz D, Zeidler A, Orban T, Wasserfall C, Cuthbertson D, Krischer J; DPT-1 study group. High frequency of abnormal glucose tolerance in DQA1*0102/DQB1*0602 relatives identified as part of the Diabetes Prevention Trial--Type 1 Diabetes.

140. Steck AK, Bugawan TL, Valdes AM, Emery LM, Blair A, Norris JM, Redondo MJ, Babu SR, Erlich HA, Eisenbarth GS, Rewers MJ. Association of non-HLA genes with type 1 diabetes autoimmunity. Diabetes. 2005 Aug;54(8):2482-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16046318&query_hl=144

141. Davies JL, Kawaguchi Y, Bennett ST, Copeman JB, Cordell HJ, Pritchard LE, Reed PW, Gough SCL, Jenkins SC, Palmer SM, Balfour KM, Rowe BR, Farrall M, Barnett AH, Bain SC, Todd JA.  A genome-wide search for human type 1 diabetes susceptibility genes.  Nature 371:130-136,  1994.

142. Hashimoto L, Habita C, Beressi JP, Delepine M, Besse C, Cambon-Thomsen A , Deschamps I, Rotter JI, Djoulah S, James MR, Froguel P, Weissenbach J, Lathrop GM, Julier C.  Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q.  Nature 371:161-164,  1994.

143. Owerbach D, Gabbay KH.  The HOXD8 locus (2q31) is linked to type I diabetes: interaction with chromosome 6 and 11 disease susceptibility genes.  Diabetes 44:132-136,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7813807&query_hl=147

144. Field LL, Tobias R, Magnus T.  A locus on chromosome 15q26(IDDM3) produces susceptibility to insulin-dependent diabetes mellitus.  Nat Genet 8:189-194,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7842018&query_hl=149

145. Copeman JB, Cucca F, Hearne CM, Cornall RJ , Reed PW, Ronningen KS, Undlien DE, Nisticò L, Buzzetti R, Tosi R, Pociot F, Nerup J, Cornélis F, Barnett AH, Bain SC, Todd JA.  Linkage disequilibrium mapping of type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31-q33.  Nat Genet 9:80-85,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7704030&query_hl=151

146. Cox NJ, Wapelhorst B, Morrison VA, Johnson L, Pinchuk L, Spielman RS, Todd JA, Concannon P.  Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families.  Am J Hum Genet 69:820-830,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11507694&query_hl=153

147. Guo D, Li M, Zhang Y, Yang P, Eckenrode S, Hopkins D, Zheng W, Purohit S, Podolsky RH, Muir A, Wang J, Dong Z, Brusko T, Atkinson M, Pozzilli P, Zeidler A, Raffel LJ, Jacob CO, Park Y, Serrano-Rios M, Larrad MT, Zhang Z, Garchon HJ, Bach JF, Rotter JI, She JX, Wang CY. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat Genet. 2004, 36: 837-41 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15247916&query_hl=155

148. Steck AK, Bugawan TL, Valdes AM, Emery LM, Blair A, Norris JM, Redondo MJ, Babu SR, Erlich HA, Eisenbarth GS, Rewers MJ. Association of Non-HLA Genes With Type 1 Diabetes Autoimmunity. Diabetes. 2005 Aug;54(8):2482-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16046318&query_hl=157

149. Barratt BJ, Payne F, Lowe CE, Hermann R, Healy BC, Harold D, Concannon P, Gharani N, McCarthy MI, Olavesen MG, McCormack R, Guja C, Ionescu-Tirgoviste C, Undlien DE, Ronningen KS, Gillespie KM, Tuomilehto-Wolf E, Tuomilehto J, Bennett ST, Clayton DG, Cordell HJ, Todd JA. Remapping the insulin gene/IDDM2 locus in type 1 diabetes.Diabetes. 2004, 53: 1884-9 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15220214&query_hl=158

150. Kavvoura FK, Ioannidis JP. CTLA-4 Gene Polymorphisms and Susceptibility to Type 1 Diabetes Mellitus: A HuGE Review and Meta-Analysis.Am J Epidemiol. 2005,162:3-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15961581&query_hl=160

151. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Ronningen KS, Guja C, Ionescu-Tirgoviste C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003, 423: 506-11 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12724780&query_hl=162

152. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004, 36: 337-8 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15004560&query_hl=164

153. Dahlman I, Eaves IA, Kosoy R, Morrison VA, Heward J, Gough SC, Allahabadia A, Franklyn JA, Tuomilehto J, Tuomilehto-Wolf E, Cucca F, Guja C, Ionescu-Tirgoviste C, Stevens H, Carr P, Nutland S, McKinney P, Shield JP, Wang W, Cordell HJ, Walker N, Todd JA, Concannon P.  Parameters for reliable results in genetic association studies in common disease.  Nat Genet 30:149-150,  2002. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11799396&query_hl=167

154. Kaprio J, Tuomilehto J, Koskenvuo M, Romanov K, Reunanen A, Eriksson J, Stengard J, Kesaniemi YA.  Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland.  Diabetologia 35:1060-1067,  1992.

155. Rewers M, Zimmet P. The rising tide of childhood type 1 diabetes--what is the elusive environmental trigger?Lancet. 2004 Nov 6-12;364(9446):1645-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15530607&query_hl=170

156. Pak CY, Hyone-Myong E, McArthur RG, Yoon JW .  Association of cytomegalovirus infection with autoimmune type 1 diabetes.  Lancet 2:1-3,  1988.

157. Sairenji T, Daibata M, Sorli CH, et al.  Relating homology between the Epstein-Barr virus BOLF1  and HLA-DQw8 beta chain to recent onset type 1 -dependent) diabetes mellitus.  Diabetologia 34:33-39,  1991.

158. Helmke K, Otten A, Willems WR, Brockhaus R, Mueller-Eckhardt G, Stief T, Bertrams J, Wolf H, Federlin K.  Islet cell antibodies and the development of diabetes mellitus in relation to mumps infection and mumps vaccination.  Diabetologia 29:30-33,  1986.

159. Hyoty H, Hiltunen M, Reunanen A, Leinikki P, Vesikari T, Lounamaa R, Tuomilehto J, Akerblom HK.  Decline of mumps antibodies in type 1 (insulin-dependent) diabetic children and a plateau in the rising incidence of type 1 diabetes after introduction of the mumps-measles-rubella vaccine in Finland. Childhood Diabetes in Finland Study Group.  Diabetologia 36:1303-1308,  1993.

160. Ginsberg-Fellner F, Witt ME, Yagihashi S, Dobersen MJ, Taub F, Fedun B, Mcevoy RC, Roman SH, Davies RG, Cooper LZ, et al.  Congenital rubella syndrome as a model for type 1 (insulin- dependent) diabetes mellitus: increased prevalence of islet cell surface antibodies.  Diabetologia 27 Suppl:87-89,  1984.

161. Menser MA, Forrest JM, Bransby RD.  Rubella infection and diabetes mellitus.  Lancet 1:57-60,  1978.

162. Suenaga KYoon JW.  Association of beta-cell-specific expression of endogenous retrovirus with development of insulitis and diabetes in NOD mouse.  Diabetes 37:1722-1726,  1988.

163. Conrad B, Weidmann E, Trucco G, Rudert WA, Behboo R, Ricordi C, Rodriquez-Rilo H, Finegold D, Trucco M.  Evidence for superantigen involvement in insulin-dependent diabetes mellitus aetiology.  Nature 371:351- 355,  1994.

164. Honeyman MC, Coulson BS, Stone NL, Gellert SA, Goldwater PN, Steele CE, Couper JJ, Tait BD,  Colman PG, Harrison LC.  Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes.  Diabetes 49:1319-1324,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10923632&query_hl=172

165. Oldstone MB, Nerenberg M, Southern P, Price J, Lewicki H.  Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response.  Cell 65:319-331,  1991.

166. Ohashi PS, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, Malissen B, Zinkernagel RM, Hengartner H.  Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice.  Cell 65:305-317,  1991.

167. Bodansky HJ, Dean BM, Bottazzo GF, Grant PJ , McNally J, Hambling MH.  Islet-cell antibodies and insulin autoantibodies in association with common viral infections.  Lancet Dec 13:1351-1353,  1986.

168. Champsaur HF, Bottazzo GF, Bertrams J, Assan R, Bach C.  Virologic, immunologic, and genetic factors in insulin-dependent diabetes mellitus.  J Pediatr 100:15-20,  1982.

169. Uriarte A, Cabrera E, Ventura R, Vargas J.  Islet cell antibodies and ECHO-4 virus infection.  Diabetologia 30:590A-1987.

170. Blom L, Nystrom L, Dahlquist G.  The Swedish childhood diabetes study. Vaccinations and infections as risk determinants for diabetes in childhood.  Diabetologia 34:176-181,  1991.

171. Karounos DG, Wolinsky JS, Thomas JW.  Monoclonal antibody to rubella virus capsid protein recognizes a b-cell antigen.  J Immunol 150:3080-3085,  1993.

172. Rewers MAtkinson M.  The possible role of enteroviruses in diabetes mellitus.   353-385,  1996.

173. Graves PM, Norris JM, Pallansch MA, Gerling IC, Rewers M.  The role of enteroviral infections in the development of IDDM: limitations of current approaches.  Diabetes 46: 161-168,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9000690&query_hl=174

174. Jenson AB, Rosenberg HS, Notkins AL.  Pancreatic islet-cell damage in children with fatal viral infections.  Lancet Aug 16:354-358,  1980.

175. Yoon JW, Austin M, Onodera T, Notkins AL .  Virus-induced diabetes mellitus: Isolation of a virus from the pancreas of a child with diabetic ketoacidosis.  N Engl J Med 300:1173-1179,  1979.

176. Donsky JMassad R.  Community medicine in the training of family physicians.  J Fam Pract 8:965-971,  1979.

177. Wagenknecht LE, Roseman JM, Herman WH.  Increased incidence of insulin-dependent diabetes mellitus following an epidemic of coxsackievirus B5.  Am J Epidemiol 133:1024-1031,  1991.

178. Kaufman DL, Clare-Salzler M, Tian J, Forsthuber T, Ting GS, Robinson P, Atkinson MA, Sercarz EE, Tobin AJ, Lehmann PV.  Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes [see comments].  Nature  366:69-72,  1993.

179. Scherbaum WA, Hampl W, Muir P, Gluck M, Seibler J, Egle H, Hauner H, Boehm BO, Heinze E, Banatvala JE, Pfeiffer EF .  No association between islet cell antibodies and coxsackie B, mumps, rubella and cytomegalovirus antibodies in non-diabetic individuals aged 7-19 years.  Diabetologia 34:835-838,  1991.

180. Hyoty H, Hiltunen M, Knip M, Laakkonen M, Vahasalo P, Karjalainen J, Koskela P, Roivainen M, Leinikki P, Hovi T, .  A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group.  Diabetes  44:652-657,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7789630&query_hl=177

181. Lonnrot M, Korpela K, Knip M, Ilonen J, Simell O, Korhonen S, Savola K, Muona P, Simell T, Koskela P, Hyoty H.  Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study.  Diabetes 49:1314-1318,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10923631&query_hl=179

182. Lonnrot M, Salminen K, Knip M, Savola K, Kulmala P, Leinikki P, Hyypia T, Akerblom HK, Hyoty H.  Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. Childhood Diabetes in Finland (DiMe) Study Group.  J Med Virol 61:214-220,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10797377&query_hl=181

183. Dahlquist G, Frisk G, Ivarsson SA, Svanberg L, Forsgren M, Diderholm H.  Indications that maternal coxsackie B virus infection during pregnancy is a risk factor for childhood-onset IDDM.  Diabetologia 38:1371-1373,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8582549&query_hl=183

184. Dahlquist GG.  Viruses and other perinatal exposures as initiating events for beta- cell destruction.  Ann Med 29:413-417,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9453289&query_hl=185

185. Viskari H, Ludvigsson J, Uibo R, Salur L, Marciulionyte D, Hermann R, Soltesz G, Fuchtenbusch M, Ziegler AG, Kondrashova A, Romanov A, Kaplan B, Laron Z, Koskela P, Vesikari T, Huhtala H, Knip M, Hyoty H. Relationship between the incidence of type 1 diabetes and maternal enterovirus antibodies: time trends and geographical variation. Diabetologia. 2005 Jul;48(7):1280-7. Epub 2005 May 19 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15902401&query_hl=187

186. Akerblom HK, Virtanen SM, Ilonen J, Savilahti E, Vaarala O, Reunanen A, Teramo K, Hamalainen AM, Paronen J, Riikjarv MA, Ormisson A, Ludvigsson J, Dosch HM, Hakulinen T, Knip M; National TRIGR Study Groups. Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study. Diabetologia. 2005 May;48(5):829-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15838685&query_hl=189

187. Frisk G, Tuvemo T. Enterovirus infection with beta-cell tropic strains are frequently in siblings of children diagnosed with type 1 diabete and in association with elevated levels of GAAAD65 antibodies. J Med Virol 2004, 73: 450-9 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15170642&query_hl=191

188. Viskari H, Ludvigsson J, Uibo R, Salur L, Marciulionyte D, Hermann R, Soltesz G, Fuchtenbusch M, Ziegler AG, Kondrashova A, Romanov A, Knip M, Hyoty H. Relationship between the incidence of type 1 diabetes and enterovirus infections in different European populations: results from the EPIVIR project. J Med Virol. 2004 Apr;72(4):610-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14981763&query_hl=187

189. Devendra D, Eisenbarth GS.  Interferon alpha--a potential link in the pathogenesis of viral-induced type 1 diabetes and autoimmunity. Clin Immunol. 2004 Jun;111(3):225-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15183143&query_hl=194

190. Huang X, Yuang J, Goddard A, Foulis A, James RF, Lernmark A, Pujol-Borrell R, Rabinovitch A, Somoza N, Stewart TA.  Interferon expression in the pancreases of patients with type I diabetes.Diabetes. 1995 Jun;44(6):658-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7540571&query_hl=196

191. Devendra D, Jasinski J, Melanitou E, Nakayama M, Li M, Hensley B, Paronen J, Moriyama H, Miao D, Eisenbarth GS, Liu E.  Interferon-alpha as a Mediator of Polyinosinic:Polycytidylic Acid-Induced Type 1 Diabetes. Diabetes. 2005 Sep;54(9):2549-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16123342&query_hl=198

192. Graves PM, Rotbart HA, Nix WA, Pallansch MA, Erlich HA, Norris JM, Hoffman M, Eisenbarth GS, Rewers M. Prospective study of enteroviral infections and development of beta-cell autoimmunity. Diabetes autoimmunity study in the young (DAISY).Diabetes Res Clin Pract. 2003 Jan;59(1):51-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12482642&query_hl=200

193. McKinney PA, Parslow R, Gurney KA, Law GR, Bodansky HJ, Williams R.  Perinatal and neonatal determinants of childhood type 1 diabetes. A case-control study in Yorkshire, U.K.  Diabetes Care 22:928-932,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10372244&query_hl=202

194. Patterson CC, Carson DJ, Hadden DR, Waugh NR, Cole SK.  A case-control investigation of perinatal risk factors for childhood IDDM in northern Ireland and Scotland.  Diabetes Care 17:376-381,  1994.

195. Stene LC, Barriga K, Norris JM, Hoffman M, Erlich HA, Eisenbarth GS, McDuffie RS Jr, Rewers M. Perinatal factors and development of islet autoimmunity in early childhood: the diabetes autoimmunity study in the young. Am J Epidemiol. 2004 Jul 1;160(1):3-10.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15229111&query_hl=204

196. Rothwell PM, Staines A, Smail P, Wadsworth E, McKinney P.  Seasonality of birth of patients with childhood diabetes in Britain.  BMJ 312:1456-1457,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8664624&query_hl=207

197. Oldstone MB.  Viruses as therapeutic agents. I. Treatment of nonobese insulin- dependent diabetes mice with virus prevents insulin-dependent diabetes mellitus while maintaining general immune competence.  J Exp Med  171:2077-2089,  1990.

198. Wilberz S, Partke HJ, Dagnaes-Hansen F, Herberg L.  Persistent MHV (mouse hepatitis virus) infection reduces the incidence of diabetes mellitus in non-obese diabetic mice.  Diabetologia 34:2-5,  1991.

199. Like AA, Guberski DL, Butler L.  Influence of environmental viral agents on frequency and tempo of diabetes mellitus in BB/Wor rats.  Diabetes 40:259-262,  1991.

200. Kolb HElliott RB.  Increasing incidence of IDDM a consequence of improved hygiene?  Diabetologia 37:729-1994.

201. McKinney PA, Okasha M, Parslow RC, Law GR, Gurney KA, Williams R, Bodansky HJ.  Early social mixing and childhood Type 1 diabetes mellitus: a case- control study in Yorkshire, UKDiabet Med 17:236-242,  2000.


202. EURODIAB Substudy 2 Study Group Infections and vaccinations as risk factors for childhood type I (insulin-dependent) diabetes mellitus: a multicentre case-control investigation..  Diabetologia 43:47-53,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10663215&query_hl=214

203. Bach JF.  The effect of infections on susceptibility to autoimmune and allergic diseases.N Engl J Med. 2002 Sep 19;347(12):911-20 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12239261&query_hl=218

204. Heijbel H, Chen RT, Dahlquist G.  Cumulative incidence of childhood-onset IDDM is unaffected by pertussis immunization.  Diabetes Care 20:173-175,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9118767&query_hl=220

205. Lindberg B, Ahlfors K, Carlsson A, Ericsson UB, Landin-Olsson M, Lernmark A, Ludvigsson J, Sundkvist G, Ivarsson SA.  Previous exposure to measles, mumps, and rubella--but not vaccination during adolescence--correlates to the prevalence of pancreatic and thyroid autoantibodies.  Pediatrics 104:e12-1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10390298&query_hl=222

206. Graves PM, Barriga KJ, Norris JM, Hoffman MR, Yu L, Eisenbarth GS, Rewers M.  Lack of association between early childhood immunizations and beta-cell autoimmunity.  Diabetes Care 22:1694-1697,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10526737&query_hl=224

207. Hummel M, Fuchtenbusch M, Schenker M, Ziegler AG.  No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study.  Diabetes Care 23 :969-974,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10895848&query_hl=227

208. Hviid A., Stellfeld M., Wohlfahrt J., Melbye M.Childhood Vaccination and Type 1 Diabetes. N Engl J Med 2004; 350:1398-1404, Apr 1, 2004. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15070789&query_hl=230

209. Atkinson MA, Winter WE, Skordis N, Beppu H, Riley WM, Maclaren NK.  Dietary protein restriction reduces the frequency and delays the onset of insulin dependent diabetes in BB rats.  Autoimmunity 2:11-20,  1988.

210. Martin JM, Trink B, Daneman D, Dosch H-M, Robinson B.  Milk proteins in the etiology of insulin-dependent diabetes mellitus (IDDM).  Ann Med 23:447-452,  1991.

211. Atkinson MA, Bowman MA, Kuo-Jang K, Campbell L, Dush PJ, Shah SC, Simell O, Maclaren NK.  Lack of immune responsiveness to bovine serum albumin in insulin- dependent diabetes.  New Engl J Med 329:1853-1858,  1993.

212. Lampasona V, Ferrari M, Bosi E, Pastore MR, Bingley PJ, Bonifacio E.  Sera from patients with IDDM and healthy individuals have antibodies to ICA69 on western blots but do not immunoprecipitate liquid phase antigen.  J Autoimmun 7:665-674,  1994.

213. Martin S, Lampasona V, Dosch M, Pietropaolo M.  Islet cell autoantigen 69 antibodies in IDDM.  Diabetologia 39:747-1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8781774&query_hl=232

214. Krokowski M, Caillat-Zucman S, Timsit J, Larger E, Pehuet-Figoni M, Bach JF, Boitard C.  Anti-bovine serum albumin antibodies: Genetic heterogeneity and clinical relevance in adult-onset IDDM.  Diabetes Care 18:170-173,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7729293&query_hl=235

215. Norris JM, Beaty B, Klingensmith G, Yu L, Hoffman M, Chase HP, Erlich HA, Hamman RF, Eisenbarth GS, Rewers M.  Lack of association between early exposure to cow's milk protein and beta-cell autoimmunity: Diabetes Autoimmunity Study in the Young (DAISY).  J A M A 1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8773632&query_hl=238

216. Virtanen SM, Hypponen E, Laara E, Vahasalo P, Kulmala P, Savola K, Rasanen L, Aro A, Knip M, Akerblom HK.  Cow's milk consumption, disease-associated autoantibodies and type 1 diabetes mellitus: a follow-up study in siblings of diabetic children. Childhood Diabetes in Finland Study Group.  Diabet Med 15:730-738,  1998. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9737801&query_hl=240

217. Couper JJ, Steele C, Beresford S, Powell T , McCaul K, Pollard A, Gellert S, Tait B, Harrison LC, Colman PG.  Lack of association between duration of breast-feeding or introduction of cow's milk and development of islet autoimmunity.  Diabetes 48:2145-2149,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10535447&query_hl=242

218. Borch-Johnsen K, Joner G, Mandrup-Poulsen T, Christy M, Zachau-Christiansen B, Kastrup K, Nerup J.  Relation between breast-feeding and incidence rates of insulin-dependent diabetes mellitus.  Lancet 2:1083-1086,  1984.

219. Mayer EJ, Hamman RF, Gay EC, Lezotle DC, Savitz DA, Klingensmith GJ.  Reduced risk of IDDM among breast-fed children. The Colorado IDDM Registry.  Diabetes 37:1625-1632,  1988.

220. Kostraba JN, Dorman JS, LaPorte RE, Scott FW, Steenkiste AR, Gloninger M, Drash AL.  Early infant diet and risk of IDDM in blacks and whites. A matched case-control study.  Diabetes Care 15:626-631,  1992.

221. Nigro G, Campea L, De Novellis A, Orsini M.  Breast-feeding and insulin-dependent diabetes mellitus.  Lancet 1: 467 (Letter)-1985.

222. Blom L, Dahlquist G, Nystrom L, Sandstrom A, Wall S.  The Swedish childhood diabetes study - social and perinatal determinants for diabetes in childhood.  Diabetologia 32:7-13,  1989.

223. Kyvik KO, Green A, Svendsen A, Mortensen K.  Breast feeding and the development of type I diabetes mellitus.  Diabetic Med 9:233-235,  1992.

224. Norris JM, Barriga K, Klingensmith G, Hoffman M, Eisenbarth GS, Erlich HA, Rewers M. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA. 2003 Oct 1;290(13):1713-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14519705&query_hl=244

225. Virtanen SM, Rasanen L, Aro A, Ylonen K, Lounamaa R, Tuomilehto J, Akerblom HK, the 'Childhood Diabetes in Finland' Study Group.  Feeding in infancy and the risk of type 1 diabetes mellitus in Finnish children.  Diabetic Med 9:815-819,  1992.

226. Gerstein HC.  Cow's milk exposure and type I diabetes mellitus - a critical overview of the clinical literature.  Diabetes Care 17:13-19,  1994.

227. Norris JM, Scott FW.  A meta-analysis of infant diet and insulin-dependent diabetes mellitus: do biases play a role?  Epidemiology 7:87-92,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8664407&query_hl=246

228. Savilahti E, Akerblom HK, Tainio VM, Koskimies S.  Children with newly diagnosed insulin dependent diabetes mellitus have incresed levels of cow's milk antibodies.  Diabetes Res 7:137-140,  1988.

229. Karjalainen J, Martin JM, Knip M, Ilonen J, Robinson BH, Savilahti E, Akerblom HK, Dosch HM.  A bovine albumin peptide as a possible trigger of insulin- dependent diabetes mellitus [see comments].  N Engl J Med 327:302-307,  1992.

230. Virtanen SM, Laara E, Hypponen E, Reijonen H, Rasanen L, Aro A, Knip M, Ilonen J, Akerblom HK.  Cow's milk consumption, HLA-DQB1 genotype, and type 1 diabetes: a nested case-control study of siblings of children with diabetes. Childhood diabetes in Finland study group [In Process Citation].  Diabetes 49:912-917,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10866042&query_hl=248

231. Norris JM, Barriga K, Klingensmith G, Hoffman M, Eisenbarth GS, Erlich HA, Rewers M. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA. 2003 Oct 1;290(13):1713-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14519705&query_hl=250

232. Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA. 2003 Oct 1;290(13):1721-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14519706&query_hl=251

233. Fronczak CM, Baron AE, Chase HP, Ross C, Brady HL, Hoffman M, Eisenbarth GS, Rewers M, Norris JM. In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care. 2003 Dec;26(12):3237-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14633808&query_hl=253

234. Hyppönen E, Läärä E, Reunanen A, Jarvelin M-R, Virtanen SM. Intake of vitamin D and risk of type 1diabetes: a birth cohort study. Lancet 2001, 358:1500-1503 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11705562&query_hl=255

235. Stene LC, Joner G; Norwegian Childhood Diabetes Study Group. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am J Clin Nutr. 2003 Dec;78(6):1128-34 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14668274&query_hl=257

236. Muntoni S, Karvonen M, Muntoni S, Tuomilehto J. Seasonality of birth in patients with type 1 diabetes. Lancet. 2002 Apr 6;359(9313):1246 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11955561&query_hl=259

237. Laron Z, Lewy H, Wilderman I, Casu A, Willis J, Redondo MJ, Libman I, White N, Craig M. Seasonality of month of birth of children and adolescents with type 1 diabetes mellitus in homogenous and heterogeneous populations. Isr Med Assoc J. 2005 Jun;7(6):381-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15984382&query_hl=261

238. Weets I, Kaufman L, Van der Auwera B, Crenier L, Rooman RP, De Block C, Casteels K, Weber E, Coeckelberghs M, Laron Z, Pipeleers DG, Gorus FK; Belgian Diabetes Registry. Seasonality in clinical onset of type 1 diabetes in belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence. Diabetologia. 2004 Apr;47(4):614-21 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15298337&query_hl=263

239. Kantwerk-Funke G, Burkart V, Kolb H. Low dose streptozotocin causes stimulation of the immune system and of anti-islet cytotoxicity in mice. Clin Exp Immunol. 1991 Nov;86(2):266-70.

240. Elias D, Prigozin H, Polak N, Rapoport M, Lohse AW, Cohen IR.  Autoimmune diabetes induced by the beta-cell toxin STZ. Immunity to the 60-kDa heat shock protein and to insulin.  Diabetes 43:992-998,  1994.

241. Rayfield EJIshimura K.  Environmetal factors and insulin dependent diabetes mellitus.  Diabetes Metab Rev 3:925-957,  1987.

242. Helgason TJonasson MR.  Evidence for a food additive as a cause of ketosis-prone diabetes.  Lancet 2:716-720,  1981.

243. Dahlquist GG, Blom LG, Persson L-Å, Sandström AIM, Wall SGI.  Dietary factors and the risk of developing insulin dependent diabetes in childhood.  Br Med J 300:1302-1306,  1990.

244. Kostraba JN, Gay EC, Rewers M, Hamman RF.  Nitrate levels in community drinking waters and risk of IDDM.  Diabetes Care 15:1505-1508,  1992.

245. Toniolo A, Onodera T, Yoon JW, Notkins AL.  Induction of diabetes by cumulative environmental insults from viruses and chemicals.  Nature 288:383-385,  1980.

246. Wilkin TJ. The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes. Diabetologia. 2001 Jul;44(7):914-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11508279&query_hl=265

247. Bruining GJ: Association between infant growth before onset of juvenile type 1 diabetes and autoantibodies to IA-2. Lancet 356: 655–656, 2000 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10968443&query_hl=269

248. Betts P, Mulligan J, Ward P, Smith B, Wilkin T. Increasing body weight predicts the earlier onset of insulin-dependant diabetes in childhood: testing the 'accelerator hypothesis' (2). Diabet Med. 2005 Feb;22(2):144-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15660730&query_hl=271

249. Stene LC, Magnus P, Lie RT, Sovik O, Joner G; Norwegian childhood Diabetes Study Group. Birth weight and childhood onset type 1 diabetes: population based cohort study. BMJ. 2001 Apr 14;322 (7291):889-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11302899&query_hl=273

250. Hypponen E, Virtanen SM, Kenward MG, Knip M, Akerblom HK, The Childhood Diabetes in Finland Study Group: Obesity, increased linear growth, and risk of type 1 diabetes in children. Diabetes Care 23: 1755–1760, 2000 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11128347&query_hl=275

251. Larsson HE, Lynch K, Lernmark B, Nilsson A, Hansson G, Almgren P, Lernmark A, Ivarsson SA; DiPiS Study Group. Diabetes-associated HLA genotypes affect birthweight in the general population. Diabetologia. 2005 Jul 1 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15991024&query_hl=277

252. Patterson CC, Dahlquist G, Soltesz G, Green A; EURODIAB ACE Study Group. Europe and Diabetes.Is childhood-onset type I diabetes a wealth-related disease? An ecological analysis of European incidence rates. Diabetologia. 2001 Oct;44 Suppl 3:B9-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11724424&query_hl=279

253. Khoury MJ, Flanders WD, Greenland S, Adams MJ.  On the measurement of susceptibility in epidemiologic studies.  Am J Epidemiol 129:183-190,  1989.

254. Fohlman J, Bohme J, Rask L, Frisk G, Diderholm H, Friman G,  Tuvemo T.  Matching of host genotype and serotypes of Coxsackie B virus in the development of juvenile diabetes.  Scand J Immunol 26:105-110,  1987.

255. D'Alessio DJ.  A case-control study of group B Coxsackievirus immunoglobulin M antibody prevalence and HLA-DR antigens in newly diagnosed cases of insulin-dependent diabetes mellitus.  Am J Epidemiol 135 :1331-1338,  1992.

256. Schernthaner G, Banatvala JE, Scherbaum W, Bryant J, Borkenstein M, Schober E, Mayr WR.  Coxsackie-B-virus-specific IgM responses, complement-fixing islet-cell antibodies, HLA DR antigens, and C-peptide secretion in insulin-dependent diabetes mellitus.  Lancet 2:630-632,  1985.

257. Kostraba JN, Cruickshanks KJ, Lawler-Heavner J, Jobim LF, Rewers MJ, Gay EC , Chase HP, Klingensmith G, Hamman RF.  Early exposure to cow's milk and solid foods in infancy, genetic predisposition and risk of IDDM.  Diabetes 42:288-295,  1993.

258. Norris JM, Beaty B, Klingensmith G, Yu L, Hoffman M, Chase HP, Erlich HA, Hamman RF, Eisenbarth GS, Rewers M.  Lack of association between early exposure to cow's milk protein and b-cell autoimmunity: Diabetes Autoimmunity Study in the Young (DAISY).  JAMA 276:609-614,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8773632&query_hl=284

259. Knip M, Sakkinen A, Huttunen NP, Kaar ML, Lankela S, Mustonen A, Akerblom HK.  Postinitial remission in diabetic children--an analysis of 178 cases.  Acta Paediatr Scand 71:901-908,  1982.

260. Agner T, Damm P, Binder C.  Remission in IDDM: prospective study of basal C-peptide and insulin dose in 268 consecutive patients.  Diabetes Care 10:164-169,  1987.

261. Sochett EB, Daneman D, Clarson C, Ehrlich RM.  Factors affecting and patterns of residual insulin secretion during the first year of type 1 (insulin-dependent) diabetes mellitus in children.  Diabetologia 30 :453-459,  1987.

262. Ortqvist E, Falorni A, Scheynius A, Persson B, Lernmark A.  Age governs gender-dependent islet cell autoreactivity and predicts the clinical course in childhood IDDM.  Acta Paediatr 86 :1166-1171,  1997.


263. Schiffrin A, Suissa S, Poussier P, Guttmann R, Weitzner G.  Prospective study of predictors of beta-cell survival in type I diabetes.  Diabetes 37:920-925,  1988.

264. Wallensteen M, Dahlquist G, Persson B, Landin-Olsson M, Lernmark A, Sundkvist G, Thalme B.  Factors influencing the magnitude, duration, and rate of fall of B-cell function in Type I (insulin-dependent) diabetic children followed for two years from their clinical diagnosis.  Diabetologia 31:664-669,  1988.

265. Sabbah E, Savola K, Kulmala P, Veijola R, Vahasalo P, Karjalainen J, Akerblom HK, Knip M.  Diabetes-associated autoantibodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes. The Childhood Diabetes In Finland Study Group.  J Clin Endocrinol Metab 84:1534-1539,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10323375&query_hl=287

266. Petersen JS, Dyrberg T, Karlsen AE, Molvig J, Michelsen B, Nerup J, Mandrup-Poulsen T.  Glutamic acid decarboxylase (GAD65) autoantibodies in prediction of B-cell function and remission in recent-onset IDDM after cyclosporin treatment.  Diabetes 43:1291-1296,  1994.

267. Fukuda M, Tanaka A, Tahara Y, Ikegami H, Yamamoto Y, Kumahara Y, Shima K.  Correlation between minimal secretory capacity of pancreatic beta-cells and stability of diabetic control.  Diabetes 37:81-88,  1988.

268. Kolb H, Dannehl K, Gruenklee D, Zielasek J, Bertrams J, Hubinger A, Gries FA.  Prospective analysis of islet cell antibodies in children with type I (insulin-dependent) diabetes.  Diabetologia 31:189-194,  1988.

269. Knip M, Llonen J, Mustonen A, Akerblom HK.  Evidence of an accelerated B-cell destruction in HLA-Dw3/Dw4 heterozygous children with type I (insulin-dependent) diabetes.  Diabetologia 29:347-351,  1986.

270. Pipeleers DLing Z.  Pancreatic beta cells in insulin-dependent diabetes.  Diabetes Metab Rev 8:209-227,  1992.

271. Madsbad S, Faber OK, Binder C, McNair P, Christiansen C, Transbol I.  Prevalence of residual beta-cell function in insulin-dependent diabetics in relation to age at onset and duration of diabetes.  Diabetes 27(Suppl. 1):262-264,  1978.

272. Rewers A, Chase HP, Mackenzie T, Walravens P, Roback M, Rewers M, Hamman RF, Klingensmith G. Predictors of acute complications in children with type 1 diabetes. JAMA. 2002 May 15;287(19):2511-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12020331&query_hl=289

273. Maniatis AK, Goehrig SH, Gao D, Rewers A, Walravens P, Klingensmith GJ. Increased incidence and severity of diabetic ketoacidosis among uninsured children with newly diagnosed type 1 diabetes mellitus. Pediatr Diabetes. 2005 Jun;6(2):79-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15963034&query_hl=291

274. Dorman JS, LaPorte RE, Kuller LH, Cruickshanks KJ, Orchard TJ, Wagener DK, Becker DJ, Cavender DE, Drash AL.  The Pittsburgh insulin-dependent diabetes mellitus (IDDM) morbidity and mortality study. Mortality results.  Diabetes 33: 271-276,  1984.

275. Cusick M, Meleth AD, Agron E, Fisher MR, Reed GF, Knatterud GL, Barton FB, Davis MD, Ferris FL 3rd, Chew EY; Early Treatment Diabetc Retinopathy Study Research Group. Associations of mortality and diabetes complications in patients with type 1 and type 2 diabetes: early treatment diabetic retinopathy study report no. 27. Diabetes Care. 2005 Mar;28(3):617-25.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15735198&query_hl=293

276. Nishimura R, LaPorte RE, Dorman JS, Tajima N, Becker D, Orchard TJ. Mortality trends in type 1 diabetes. The Allegheny County (Pennsylvania) Registry 1965-1999. Diabetes Care. 2001 May;24(5):823-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11347737&query_hl=295

277. Skrivarhaug T, Sandvik L, Joner G. Long-term mortality in nationwide cohort of childhood-onset type 1 diabetes in Norway. ADA 2005

278. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes.Diabetologia. 2001 Sep;44 Suppl 2:S14-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11587045&query_hl=304

279. Laing SP, Swerdlow AJ, Carpenter LM, Slater SD, Burden AC, Botha JL, Morris AD, Waugh NR, Gatling W, Gale EA, Patterson CC, Qiao Z, Keen H. Mortality from cerebrovascular disease in a cohort of 23,000 patients with insulin-treated diabetes. Stroke. 2003 Feb;34(2):418-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12574553&query_hl=306

280. Swerdlow AJ, Laing SP, Dos Santos Silva I, Slater SD, Burden AC, Botha JL, Waugh NR, Morris AD, Gatling W, Bingley PJ, Patterson CC, Qiao Z, Keen H. Mortality of South Asian patients with insulin-treated diabetes mellitus in the United Kingdom: a cohort study. Diabet Med. 2004 Aug;21(8):845-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15270787&query_hl=308

281. Laing SP, Swerdlow AJ, Slater SD, Burden AC, Morris A, Waugh NR, Gatling W, Bingley PJ, Patterson CC. Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes. Diabetologia. 2003 Jun;46(6):760-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12774166&query_hl=310

282. Major cross-country differences in risk of dying for people with IDDM. Diabetes Epidemiology Research International Mortality Study Group.  Diabetes Care 14:49-54,  1991.

283. Matsushima M, LaPorte RE, Maruyama M, Shimizu K, Nishimura R, Tajima N, for the DERI Mortality Study Group.  Geographic variation in mortality among individuals with youth-onset diabetes mellitus across the world.  Diabetologia 40:212-216,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9049483&query_hl=312

284. International evaluation of cause-specific mortality and IDDM. Diabetes Epidemiology Research International Mortality Study Group.  Diabetes Care 14:55-60,  1991.

285. Borch-Johnsen K, Nissen H, Henriksen E, Kreiner S, Salling N, Deckert T, Nerup J.  The natural history of insulin-dependent diabetes mellitus in Denmark: 1. Long-term survival with and without late diabetic complications.  Diabetic Med 4:201-210,  1987.

286. Fuller JH, Stevens LK, Wang SL.  Risk factors for cardiovascular mortality and morbidity: the WHO Mutinational Study of Vascular Disease in Diabetes. Diabetologia. 2001 Sep;44 Suppl 2:S54-64.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11587051&query_hl=314

287. Orchard TJ, Olson JC, Erbey JR, Williams K, Forrest KY, Smithline Kinder L, Ellis D, Becker DJ.  Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications Study.Diabetes Care. 2003 May;26(5):1374-9 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12716791&query_hl=316

288. Chowdhury TA, Dyer PH, Mijovic CH, Dunger DB, Barnett AH, Bain SC.  Human leucocyte antigen and insulin gene regions and nephropathy in Type I diabetes.  Diabetologia 42:1017-1020,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10491764&query_hl=318

289. Doria A, Warram JH, Krolewski AS.  Genetic predisposition to diabetic nephropathy. Evidence for a role of the angiotensin I-converting enzyme gene.  Diabetes 43:690-695,  1994.

290. Doria A, Onuma T, Gearin G, Freire MB, Warram JH, Krolewski AS.  Angiotensinogen polymorphism M235T, hypertension, and nephropathy in insulin-dependent diabetes.  Hypertension 27:1134-1139,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8621207&query_hl=320

291. Fogarty DG, Harron JC, Hughes AE, Nevin NC, Doherty CC, Maxwell AP.  A molecular variant of angiotensinogen is associated with diabetic nephropathy in IDDM.  Diabetes 45:1204-1208,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8772723&query_hl=322

292. Nagi DK, Mansfield MW, Stickland MH, Grant PJ.  Angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism, and diabetic retinopathy in subjects with IDDM and NIDDM.  Diabet Med 12:997-1001,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8582133&query_hl=324

293. Parving HH, Jacobsen P, Tarnow L, Rossing P , Lecerf L, Poirier O, Cambien F.  Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study.  BMJ 313:591-594,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8806248&query_hl=326

294. Tarnow L, Cambien F, Rossing P, Nielsen FS , Hansen BV, Ricard S, Poirier O, Parving HH.  Angiotensinogen gene polymorphisms in IDDM patients with diabetic nephropathy.  Diabetes 45:367-369,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8593944&query_hl=328

295. Tarnow L, Cambien F, Rossing P, Nielsen FS , Hansen BV, Lecerf L, Poirier O, Danilov S, Parving HH.  Lack of relationship between an insertion/deletion polymorphism in the angiotensin I-converting enzyme gene and diabetic nephropathy and proliferative retinopathy in IDDM patients.  Diabetes 44:489-494,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7729604&query_hl=330

296. Ruiz J, Blanche H, James RW, Garin MC, Vaisse C, Charpentier G, Cohen N, Morabia A, Passa P, Froguel P.  Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes [see comments].  Lancet 346:869-872,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7564671&query_hl=332

297. Garin MC, James RW, Dussoix P, Blanche H, Passa P, Froguel P, Ruiz, J.  Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes.  J Clin Invest 99:62-66,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9011577&query_hl=335

298. Rewers M, Kamboh MI, Hoag S, Shetterly SM, Ferrell RE, Hamman RF.  Apolipoprotein A-IV polymorphism associated with myocardial infarction in obese NIDDM patients. The San Luis Valley Diabetes Study.  Diabetes 43:1485-1489,  1994.

299. Retinopathy and Nephropathy in Patients with Type 1 Diabetes Four Years after a Trial of Intensive Therapy.  N Engl J Med 342:381-389,  0 AD.

300. Matsushima M, LaPorte RE, Maruyama M, Shimizu K, Nishimura R, Tajima N, for the DERI Mortality Study Group.  Geographic variation in mortality among individuals with youth-onset diabetes mellitus across the world.  Diabetologia 40:212-216,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9049483&query_hl=312

301. Songer TJ, LaPorte R, Lave JR, Dorman JS, Becker DJ.  Health insurance and the financial impact of IDDM in families with a child with IDDM.  Diabetes Care 20:577-584,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9096983&query_hl=338

302. Javitt JC, Chiang Y-P.  Economic impact of diabetes.  2:601-611,  1995.

303. Portuese E, Orchard TJ.   Mortality in insulin-dependent diabetes.  2:221-232,  1995.

304. The Diabetes Control and Complications Trial Research Group.  The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.  New Engl J Med 329:977-986,  1993.

305. The Diabetes Control and Complications Trial Research Group.  The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial.  Diabetes 44:968-983 ,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7622004&query_hl=352

306. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group.  N Engl J Med 342:381-389,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10793172&query_hl=354

307. DCCT.  Epidemiology of severe hypoglycemia in the diabetes control and complications trial. The DCCT Research Group.  Am J Med 90:450-459,  1991.

308. The Diabetes Control and Complications Trial Research Group.  Adverse events and their association with treatment regimens in the diabetes control and complications trial.  Diabetes Care 18:1415-1427,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8722064&query_hl=356

309. Klein R, Klein BEK, Moss SE, et al.  The Wisconsin Epidemiologic Study of Diabetic Retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years.  Arch Ophthalmol 102:520-526,  1984.

310. Mizutani M, Kern TS, Lorenzi M.  Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy.  J Clin Invest 97:2883-2890,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8675702&query_hl=1

311. Konno S, Feke GT, Yoshida A, Fujio N, Goger DG, Buzney SM.  Retinal blood flow changes in type I diabetes. A long-term follow-up study.  Invest Ophthalmol Vis Sci 37:1140-1148,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8631628&query_hl=3

312. Bursell SE, Clermont AC, Kinsley BT, Simonson DC, Aiello LM, Wolpert HA.  Retinal blood flow changes in patients with insulin-dependent diabetes mellitus and no diabetic retinopathy.  Invest Ophthalmol Vis Sci 37:886-897,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8603873&query_hl=5

313. Mori F, Konno S, Hikichi T, Yamaguchi Y, Ishiko S, Yoshida A.  Pulsatile ocular blood flow study: decreases in exudative age related macular degeneration.  Br J Ophthalmol 85:531-533,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11316708&query_hl=7

314. Feke GT, Buzney SM, Ogasawara H, Fujio N, Goger DG, Spack NP, Gabbay KH.  Retinal circulatory abnormalities in type 1 diabetes.  Invest Ophthalmol Vis Sci 35:2968-2975,  1994.

315. Clermont AC, Aiello LP, Mori F, Aiello LM, Bursell SE.  Vascular endothelial growth factor and severity of nonproliferative diabetic retinopathy mediate retinal hemodynamics in vivo: a potential role for vascular endothelial growth factor in the progression of nonproliferative diabetic retinopathy.  Am J Ophthalmol 124:433-446,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9323935&query_hl=9

316. Andersen AR, Christiansen JS, Andersen JK, Kreiner S, Deckert T.  Diabetic nephropathy in Type 1 (insulin-dependent) diabetes: an epidemiological study.  Diabetologia 25:496-501,  1983.

317. Krolewski AS, Warram JH, Christlieb AR, Busick EJ, Kahn CR.  The changing natural history of nephropathy in type 1 diabetes.  Am J Med 78:785-794,  1985.

318. Klein R, Klein BE, Moss SE.  The incidence of gross proteinuria in people with insulin- dependent diabetes mellitus [see comments].  Arch Intern Med 151 :1344-1348,  1991.

319. Kofoed-Enevoldsen A, Borch-Johnsen K, Kreiner S, Nerup J, Deckert T.  Declining incidence of persistent proteinuria in type I (insulin- dependent) diabetic patients in Denmark.  Diabetes 36:205-209,  1987.

320. Bojestig M, Arnqvist HJ, Hermansson G, Karlberg BE, Ludvigsson J.  Declining incidence of nephropathy in insulin-dependent diabetes mellitus.  New Engl J Med 330:15-18,  1994.

321. Tuomilehto J, Borch-Johnsen K, Molarius A, Jormanainen V, Lounamaa R, Gronhagen-Riska C, Reunanen A, Sarti C.  The unchanging incidence of hospitalization for diabetic nephropathy in a population-based cohort of IDDM patients in Finland.  Diabetes Care 20:1081-1086,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9203441&query_hl=11

322. Chavers BM, Bilous RW, Ellis EN, Steffes MW , Mauer SM.  Glomerular lesions and urinary albumin excretion in type I diabetes without overt proteinuria.  N Engl J Med 320:966-970,  1989.

323. Fioretto P, Steffes MW, Mauer M.  Glomerular structure in nonproteinuric IDDM patients with various levels of albuminuria.  Diabetes 43:1358-1364,  1994.

324. Adler SG, Kang SW, Feld S, Cha DR, Barba L, Striker L, Striker G, Riser BL, LaPage J, Nast CC.  Glomerular mRNAs in human type 1 diabetes: biochemical evidence for microalbuminuria as a manifestation of diabetic nephropathy.  Kidney Int 60:2330-2336,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11737607&query_hl=13

325. Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H.  Microalbuminuria as a predictor of clinical nephropathy in insulin- dependent diabetes mellitus.  Lancet 1:1430-1432,  1982.

326. Parving HH, Oxenboll B, Svendsen PA, Sandahl-Christiansen J, Andersen AR.  Early detection of patients at risk of developing diabetic nephropathy. A longitudinal study of albumin excretion.  Acta Endocrinol 100:550-555 ,  1982.

327. Viberti GC, Mogensen CE, Groop LC, Pauls JF , European Microalbuminuria Captopril Study Group.  Effect of Captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria.  J A M A 271:275-279,  1994.

328. Laffel LM, McGill JB, Gans DJ.  The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. North American Microalbuminuria Study Group.  Am J Med 99:497-504,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7485207&query_hl=15

329. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group.  Lancet 349:1787-1792,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9269212&query_hl=17

330. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data.  Ann Intern Med 134:370-379,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11242497&query_hl=20

331. Caramori ML, Fioretto P, Mauer M.  The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient?  Diabetes 49:1399-1408,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10969821&query_hl=22

332. Mogensen CEChristensen CK.  Predicting diabetic nephropathy in insulin-dependent patients.  N Engl J Med 311:89-93,  1984.

333. Caramori ML, Gross JL, Pecis M, de Azevedo MJ.  Glomerular filtration rate, urinary albumin excretion rate, and blood pressure changes in normoalbuminuric normotensive type 1 diabetic patients: an 8-year follow-up study.  Diabetes Care 22:1512-1516,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10480518&query_hl=24

334. Garg SK, Chase HP, Icaza G, Rothman RL, Osberg I, Carmain JA.  24-hour ambulatory blood pressure and renal disease in young subjects with type I diabetes.  J Diabetes Complications 11:263-267,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9334907&query_hl=26

335. Lafferty AR, Werther GA, Clarke CF.  Ambulatory blood pressure, microalbuminuria, and autonomic neuropathy in adolescents with type 1 diabetes.  Diabetes Care 23:533-538,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10857948&query_hl=28

336. Sundkvist GLilja B.  Autonomic neuropathy predicts deterioration in glomerular filtration rate in patients with IDDM.  Diabetes Care 16:773-779,  1993.

337. Lemley KV, Blouch K, Abdullah I, Boothroyd DB, Bennett PH, Myers BD, Nelson RG.  Glomerular permselectivity at the onset of nephropathy in type 2 diabetes mellitus.  J Am Soc Nephrol 11:2095-2105,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11053486&query_hl=30

338. Lemley KV, Abdullah I, Myers BD, Meyer TW, Blouch K, Smith WE,  Bennett PH, Nelson RG.  Evolution of incipient nephropathy in type 2 diabetes mellitus.  Kidney Int 58:1228-1237,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10972685&query_hl=32

339. Mifsud SA, Allen TJ, Bertram JF, Hulthen UL, Kelly DJ, Cooper ME, Wilkinson-Berka JL, Gilbert RE.  Podocyte foot process broadening in experimental diabetic nephropathy: amelioration with renin-angiotensin blockade.  Diabetologia 44:878-882,  2001 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11508273&query_hl=34

340. Steffes MW, Schmidt D, McCrery R, Basgen JM .  Glomerular cell number in normal subjects and in type 1 diabetic patients.  Kidney Int 59:2104-2113,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11380812&query_hl=36

341. Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, Coplon NS, Sun L, Meyer TW.  Podocyte loss and progressive glomerular injury in type II diabetes.  J Clin Invest 99:342-348,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9006003&query_hl=38

342. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH; EURODIAB Prospective Complications Study Group. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005 Jan 27;352(4):341-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15673800&query_hl=40

343. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group.N Engl J Med. 2000 Feb 10;342(6):381-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10666428&query_hl=42

344. Klein R, Klein BE, Moss SE, Cruickshanks KJ.  Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy.  Arch Intern Med 154:2169- 2178,  1994.

345. Krolewski AS, Laffel LMB, Krolewski M, Quinn M, Warram JH.  Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus.  N Engl J Med 332:1251-1255,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7708068&query_hl=47

346. Orchard TJ, Forrest KY, Ellis D, Becker DJ.  Cumulative glycemic exposure and microvascular complications in insulin- dependent diabetes mellitus. The glycemic threshold revisited .  Arch Intern Med 157:1851-1856,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9290544&query_hl=49

347. Chase HP, Garg SK, Harris S, Hoops SL, Marshall G.  High-normal blood pressure and early diabetic nephropathy.  Arch Intern Med 150:639-641,  1990.

348. Klein R, Klein BE, Moss SE, Cruickshanks KJ.  Ten-year incidence of gross proteinuria in people with diabetes.  Diabetes 44:916-923,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7621997&query_hl=51

349. Chase HP, Jackson WE, Hoops SL, Cockerham RS, Archer PG, O'Brien D. Glucose control and the renal and retinal complications of insulin-dependent diabetes. JAMA. 1989 Feb 24;261(8):1155-60. 

350. Porta M, Sjoelie AK, Chaturvedi N, Stevens L, Rottiers R, Veglio M, Fuller JH.  Risk factors for progression to proliferative diabetic retinopathy in the EURODIAB Prospective Complications Study.  Diabetologia 44:2203-2209,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11793022&query_hl=53

351. Chase HP, Garg SK, Marshall G, Berg CL, Harris S, Jackson WE, Hamman RF.  Cigarette smoking increases the risk of albuminuria among subjects with type I diabetes.  J A M A 265:614-617,  1991.

352. Scott LJ, Warram JH, Hanna LS, Laffel LM, Ryan L, Krolewski AS.  A Nonlinear Effect of Hyperglycemia and Current Cigarette Smoking Are Major Determinants of the Onset of Microalbuminuria in Type 1 Diabetes.  Diabetes 50:2842-2849,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11723069&query_hl=55

353. Moss SE, Klein R, Klein BE.  Cigarette smoking and ten-year progression of diabetic retinopathy.  Ophthalmology 103:1438-1442,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8841303&query_hl=58

354. Chaturvedi N, Sjoelie AK, Porta M, Aldington SJ, Fuller JH, Songini M, Kohner EM.  Markers of insulin resistance are strong risk factors for retinopathy incidence in type 1 diabetes.  Diabetes Care 24:284-289,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11213880&query_hl=60

355. Chaturvedi N, Bandinelli S, Mangili R, Penno G, Rottiers RE, Fuller JH.  Microalbuminuria in type 1 diabetes: rates, risk factors and glycemic threshold.  Kidney Int 60:219-227,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11422754&query_hl=62

356. Watts GF, Powrie JK, O'Brien SF, Shaw KM.  Apolipoprotein B independently predicts progression of very-low-level albuminuria in insulin-dependent diabetes mellitus.   Metabolism 45:1101-1107,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8781297&query_hl=64

357. Lam KS, Cheng IK, Janus ED, Pang RW.  Cholesterol-lowering therapy may retard the progression of diabetic nephropathy.  Diabetologia 38:604-609,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7489845&query_hl=66

358. De Cosmo S, Argiolas A, Miscio G, Thomas S, Piras GP, Trevisan R, Perin PC, Bacci S, Zucaro L, Margaglione M, Frittitta L, Pizzuti A, Tassi V, Viberti GC, Trischitta V.  A PC-1 amino acid variant (K121Q) is associated with faster progression of renal disease in patients with type 1 diabetes and albuminuria.  Diabetes 49:521-524,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10868979&query_hl=68

359. Lustman PJ, Freedland KE, Griffith LS, Clouse RE.  Fluoxetine for depression in diabetes: a randomized double-blind placebo-controlled trial.  Diabetes Care 23:618-623,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10834419&query_hl=70

360. Izuora KE, Chase HP, Jackson WE, Coll JR, Osberg IM, Gottlieb PA, Rewers MJ, Garg SK. Inflammatory markers and diabetic retinopathy in type 1 diabetes. Diabetes Care. 2005 Mar;28(3):714-5.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15735215&query_hl=72

361. Schram MT, Chaturvedi N, Schalkwijk CG, Fuller JH, Stehouwer CD; EURODIAB Prospective Complications Study Group.Markers of inflammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes--the EURODIAB Prospective Complications Study.Diabetologia. 2005 Feb;48(2):370-8.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15692810&query_hl=74

362. Jensen T.  Increased plasma concentration of von Willebrand factor in insulin dependent diabetics with incipient nephropathy.  BMJ 298:27-28,  1989.

363. Maser RE, Ellis D, Erbey JR, Orchard TJ.  Do tissue plasminogen activator-plasminogen activator inhibitor-1 complexes relate to the complications of insulin-dependent diabetes mellitus? Pittsburgh Epidemiology of Diabetes Complications Study.   J Diabetes Complications 11:243-249,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9201602&query_hl=76

364. Klein R, Klein BE, Moss SE.  The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XVI. The relationship of C-peptide to the incidence and progression of diabetic retinopathy.  Diabetes 44:796-801,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7789648&query_hl=79

365. Lustman PJ, Skor DA, Carney RM, Santiago JV, Cryer PE.  Stress and diabetic control.  Lancet 1:588-1983.

366. Rand LI, Krolewski AS, Aiello LM, Warram JH , Bakr RS, Maki T.   Multiple factors in the prediction of risk of proliferative diabetic retinopathy.  N Engl J Med 313:1433-1438,  1985.

367. Lustman PJClouse RE.  Relationship of psychiatric illness to impotence in men with diabetes .  Diabetes Care 13: 893-895,  1990.

368. Goldston DB, Kelley AE, Reboussin DM, Daniel SS, Smith JA, Schwartz RP, Lorentz W, Hill C.  Suicidal ideation and behavior and noncompliance with the medical regimen among diabetic adolescents.  J Am Acad Child Adolesc Psychiatry 36:1528- 1536, 1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10361783&query_hl=81

369. Barker JM, Goehrig SH, Barriga K, Hoffman M, Slover R, Eisenbarth GS, Norris JM, Klingensmith GJ, Rewers M; DAISY study. Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up. Diabetes Care. 2004 Jun;27(6):1399-404.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15161795&query_hl=83

370. The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial..Ann Intern Med. 1998 Apr 1;128(7):517-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9518395&query_hl=86

371. Borch-Johnsen K, Nissen H, Henriksen E, Kreiner S, Salling N, Deckert T, Nerup J.  The natural history of insulin-dependent diabetes mellitus in Denmark: 1. Long-term survival with and without late diabetic complications.  Diabetic Med 4:201-210,  1987.

372. Seaquist ER, Goetz FC, Rich S, Barbosa J.  Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320:1161- 1165,  1989.

373. Borch-Johnsen K, Norgaard K, Hommel E, Mathiesen ER, Jensen JS, Deckert T, Parving HH.  Is diabetic nephropathy an inherited complication?  Kidney Int 41:719-722,  1992.

374. The Diabetes Control and Complications Trial Research Group.  Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group.  Diabetes 46:1829-1839,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9356033&query_hl=88

375. Pettitt DJ, Saad MF, Bennett PH, Nelson RG , Knowler WC.  Familial predisposition to renal disease in two generations of Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus.  Diabetologia 33:438-443,  1990.

376. Freedman BI, Tuttle AB, Spray BJ.  Familial predisposition to nephropathy in African-Americans with non- insulin-dependent diabetes mellitus.  Am J Kidney Dis 25:710-713,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7747724&query_hl=90

377. Bergman S, Key BO, Kirk KA, Warnock DG, Rostant SG.  Kidney disease in the first-degree relatives of African-Americans with hypertensive end-stage renal disease.  Am J Kidney Dis 27:341-346,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8604702&query_hl=92

378. Spray BJ, Atassi NG, Tuttle AB, Freedman BI.  Familial risk, age at onset, and cause of end-stage renal disease in white Americans.  J Am Soc Nephrol 5:1806-1810,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7787148&query_hl=94

379. O'Dea DF, Murphy SW, Hefferton D, Parfrey PS.  Higher risk for renal failure in first-degree relatives of white patients with end-stage renal disease: a population-based study .  Am J Kidney Dis 32:794-801,  1998. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9820449&query_hl=96

380. Canani LH, Gerchman F, Gross JL.  Familial clustering of diabetic nephropathy in Brazilian type 2 diabetic patients.  Diabetes 48:909-913,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10102711&query_hl=98

381. Fioretto P, Steffes MW, Barbosa J, Rich SS, Miller ME, Mauer M.  Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs.  Diabetes 48:865-869,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10102705&query_hl=100

382. Brancati FL, Whittle JC, Whelton PK, Seidler AJ, Klag MJ.  Excess incidence of diabetic end-stage renal disease among blacks: A population-based study.  Diabetes 41(suppl 1): 128A-128A,  1992.

383. Fogarty DG, Rich SS, Hanna L, Warram JH, Krolewski AS.  Urinary albumin excretion in families with type 2 diabetes is heritable and genetically correlated to blood pressure.  Kidney Int 57:250-257,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10620206&query_hl=102

384. Chowdhury TA, Dyer PH, Mijovic CH, Dunger DB, Barnett AH, Bain SC.  Human leucocyte antigen and insulin gene regions and nephropathy in Type I diabetes.  Diabetologia 42:1017-1020,  1999. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10491764&query_hl=104

385. Doria A, Warram JH, Krolewski AS.  Genetic predisposition to diabetic nephropathy. Evidence for a role of the angiotensin I-converting enzyme gene.  Diabetes 43:690-695,  1994.

386. Doria A, Onuma T, Gearin G, Freire MB, Warram JH, Krolewski AS.  Angiotensinogen polymorphism M235T, hypertension, and nephropathy in insulin-dependent diabetes.  Hypertension 27:1134-1139,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8621207&query_hl=106

387. Fogarty DG, Harron JC, Hughes AE, Nevin NC, Doherty CC, Maxwell AP.  A molecular variant of angiotensinogen is associated with diabetic nephropathy in IDDM.  Diabetes 45:1204-1208,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8772723&query_hl=108

388. Nagi DK, Mansfield MW, Stickland MH, Grant PJ.  Angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism, and diabetic retinopathy in subjects with IDDM and NIDDM.  Diabet Med 12:997-1001,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8582133&query_hl=110

389. Tarnow L, Cambien F, Rossing P, Nielsen FS , Hansen BV, Ricard S, Poirier O, Parving HH.  Angiotensinogen gene polymorphisms in IDDM patients with diabetic nephropathy.  Diabetes 45:367-369,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8593944&query_hl=112

390. Lustman PJ, Anderson RJ, Freedland KE, de Groot M, Carney RM, Clouse RE.  Depression and poor glycemic control: a meta-analytic review of the literature.  Diabetes Care 23:934-942,  2000. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10895843&query_hl=114

391. Hamilton CLBrobeck JR.  Control of food intake in normal and obese monkeys.  Ann N Y Acad Sci 131:583-592,  1965.

392. Lustman PJ, Griffith LS, Clouse RE, Freedland KE, Eisen SA, Rubin EH, Carney RM, McGill JB.   Effects of alprazolam on glucose regulation in diabetes. Results of double-blind, placebo-controlled trial.  Diabetes Care 18:1133-1139,  1995. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7587848&query_hl=116

393. Maeda S, Haneda M, Guo B, Koya D, Hayashi K, Sugimoto T,  Isshiki K, Yasuda H, Kashiwagi A, Kikkawa R.  Dinucleotide repeat polymorphism of matrix metalloproteinase-9 gene is associated with diabetic nephropathy.  Kidney Int 60:1428-1434,  2001. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11576356&query_hl=118

394. Kao YL, Donaghue K, Chan A, Knight J, Silink M. A novel polymorphism in the aldose reductase gene promoter region is strongly associated with diabetic retinopathy in adolescents with type 1 diabetes. Diabetes. 1999, 48 (6):1338-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10342825&query_hl=120

395. Lajer M, Tarnow L, Fleckner J, Hansen BV, Edwards DG, Parving HH, Boel E. Association of aldose reductase gene Z+2 polymorphism with reduced susceptibility to diabetic nephropathy in Caucasian Type 1 diabetic patients. Diabet Med. 2004, 21: 867-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15270790&query_hl=122

396. Taverna MJ, Sola A, Guyot-Argenton C, Pacher N, Bruzzo F, Chevalier A, Slama G, Reach G, Selam JL. eNOS4 polymorphism of the endothelial nitric oxide synthase predicts risk for severe diabetic retinopathy. Diabet Med. 2002 Mar;19(3):240-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11918626&query_hl=124

397. Taverna MJ, Elgrably F, Selmi H, Selam JL, Slama G. The T-786C and C774T endothelial nitric oxide synthase gene polymorphisms independently affect the onset pattern of severe diabetic retinopathy. Nitric Oxide. 2005 May [ E-publication ahead of print] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15890549&query_hl=126

398. Kao Y, Donaghue KC, Chan A, Bennetts BH, Knight J, Silink M. Paraoxonase gene cluster is a genetic marker for early microvascular complications in type 1 diabetes. Diabet Med. 2002, 19: 212-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11918623&query_hl=128

399. Kao YL, Donaghue K, Chan A, Knight J, Silink M. A variant of paraoxonase (PON1) gene is associated with diabetic retinopathy in IDDM. J Clin Endocrinol Metab. 1998 Jul;83(7):2589-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9661650&query_hl=120

400. Ray D, Mishra M, Ralph S, Read I, Davies R, Brenchley P. Association of the VEGF gene with proliferative diabetic retinopathy but not proteinuria in diabetes. Diabetes. 2004 Mar;53(3):861-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14988276&query_hl=131

401. Taverna MJ, Selam JL, Slama G. Association between a protein polymorphism in the start codon of the vitamin D receptor gene and severe diabetic retinopathy in C-peptide-negative type 1 diabetes. Clin Endocrinol Metab. 2005 May 17; [E-publication ahead of print] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15899948&query_hl=133

402. Agardh D, Gaur LK, Agardh E, Landin-Olsson M, Agardh CD, Lernmark A. HLA-DQB1*0201/0302 is associated with severe retinopathy in patients with IDDM. Diabetologia. 1996, 39: 1313-7 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8932997&query_hl=135

403. Mimura T, Funatsu H, Uchigata Y, Kitano S, Noma H, Shimizu E, Konno Y, Amano S, Araie M, Yoshino O, Iwamoto Y, Hori S. Relationship between human leukocyte antigen status and proliferative diabetic retinopathy in patients with younger-onset type 1 diabetes mellitus. Am J Ophthalmol. 2003, 135: 844-8 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12788125&query_hl=137

404. Agardh E, Gaur LK, Lernmark A, Agardh CD. HLA-DRB1, -DQA1, and -DQB1 subtypes or ACE gene polymorphisms do not seem to be risk markers for severe retinopathy in younger Type 1 diabetic patients. J Diabetes Complications. 2004 Jan-Feb;18(1):32-6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15019597&query_hl=139

405. Wong TY, Cruickshank KJ, Klein R, Klein BE, Moss SE, Palta M, Riley WJ, Maclaren NK, Vadheim CM, Rotter JI. HLA-DR3 and DR4 and their relation to the incidence and progression of diabetic retinopathy. Ophthalmology. 2002, 109: 275-81 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11825808&query_hl=141

406. Krolewski AS, Kosinski EJ, Warram JH, Leland OS, Busick EJ, Asmal AC, Rand LI, Christlieb AR, Bradley RF, Kahn CR.  Magnitude and determinants of coronary artery disease in juvenile- onset, insulin-dependent diabetes mellitus.  Am J Cardiol 59:750-755,  1987.

407. Moss SE, Klein R, Klein BE.  Cause-specific mortality in a population-based study of diabetes.  Am J Public Health 81:1158-1162,  1991.

408. Dorman JS, LaPorte RE, Kuller LH, Cruickshanks KJ, Orchard TJ, Wagener DK, Becker DJ, Cavender DE, Drash AL.  The Pittsburgh insulin-dependent diabetes mellitus (IDDM) morbidity and mortality study. Mortality results.  Diabetes 33: 271-276,  1984.

409. Manson JE, Colditz GA, Stampfer MJ, Willett WC, Krolewski AS, Rosner B, Arky RA, Speizer FE,  Hennekens CH.  A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women.  Arch Intern Med 151:1141-1147,  1991.

410. Borch-Johnsen KKreiner S.  Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus.  Br Med J [Clin Res] 294:1651-1654,  1987.

411. Martin FIHopper JL.  The relationship of acute insulin sensitivity to the progression of vascular disease in long-term type 1 (insulin-dependent) diabetes mellitus.  Diabetologia 30:149-153,  1987.

412. Orchard TJ, Dorman JS, Maser RE, Becker DJ, Ellis D, LaPorte RE, Kuller LH, Wolfson SK, Jr., Drash AL.  Factors associated with avoidance of severe complications after 25 yr of IDDM. Pittsburgh Epidemiology of Diabetes Complications Study I.  Diabetes Care 13:741-747,  1990.

413. Orchard TJ.  From diagnosis and classification to complications and therapy. DCCT. Part II? Diabetes Control and Complications Trial.  Diabetes Care 17:326-338,  1994.

414. Lloyd CE, Kuller LH, Ellis D, Becker DJ, Wing RR, Orchard TJ.  Coronary artery disease in IDDM. Gender differences in risk factors but not risk.  Arterioscler Thromb Vasc Biol 16:720-726,  1996. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8640398&query_hl=143

415. Costacou T, Lopes-Virella MF, Zgibor JC, Virella G, Otvos J, Walsh M, Orchard TJ. Markers of endothelial dysfunction in the prediction of coronary artery disease in Type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications Study. J Diabetes Complications. 2005 Jul-Aug;19(4):183-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15993351&query_hl=145

416. Costacou T, Zgibor JC, Evans RW, Otvos J, Lopes-Virella MF, Tracy RP, Orchard TJ. The prospective association between adiponectin and coronary artery disease among individuals with type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia. 2005 Jan;48(1):41-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15616802&query_hl=147

417. Crall FV, Jr.Roberts WC.  The extramural and intramural coronary arteries in juvenile diabetes mellitus: analysis of nine necropsy patients aged 19 to 38 years with onset of diabetes before age 15 years.  Am J Med 64:221-230,  1978.

418. Valsania P, Zarich SW, Kowalchuk GJ, Kosinski E, Warram JH, Krolewski AS.  Severity of coronary artery disease in young patients with insulin- dependent diabetes mellitus.  Am Heart J 122:695-700,  1991.

419. Miettinen H, Lehto S, Salomaa V, Mahonen M, Niemela M, Haffner SM, Pyorala K, Tuomilehto J.  Impact of diabetes on mortality after the first myocardial infarction. The FINMONICA Myocardial Infarction Register Study Group [see comments].  Diabetes Care 21:69-75,  1998. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9538972&query_hl=149

420. Chun BY, Dobson AJ, Heller RF.  The impact of diabetes on survival among patients with first myocardial infarction.  Diabetes Care 20:704-708,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9135930&query_hl=151

421. Savage MP, Krolewski AS, Kenien GG, Lebeis MP, Christlieb AR, Lewis SM.  Acute myocardial infarction in diabetes mellitus and significance of congestive heart failure as a prognostic factor.  Am J Cardiol 62:665-669,  1988.

422. Rozenman Y, Sapoznikov D, Mosseri M, Gilon D, Lotan C, Nassar H, Weiss AT, Hasin Y, Gotsman MS.  Long-term angiographic follow-up of coronary balloon angioplasty in patients with diabetes mellitus: a clue to the explanation of the results of the BARI study. Balloon Angioplasty Revascularization Investigation.  J Am Coll Cardiol 30:1420-1425,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9362396&query_hl=153

423. Weintraub WS, Stein B, Kosinski A, Douglas JS, Jr., Ghazzal ZM, Jones EL, Morris DC, Guyton RA, Craver JM, King SB, III.  Outcome of coronary bypass surgery versus coronary angioplasty in diabetic patients with multivessel coronary artery disease.  J Am Coll Cardiol 31:10-19,  1998. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9426011&query_hl=156

424. Koistinen MJ.  Prevalence of asymptomatic myocardial ischaemia in diabetic subjects.  BMJ 301:92-95,  1990.

425. Orchard TJ, Olson JC, Erbey JR, Williams K, Forrest KY, Smithline Kinder L, Ellis D, Becker DJ. Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care. 2003; 26: 1374–1379 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12716791&query_hl=159

426. Soedamah-Muthu SS, Chaturvedi N, Toeller M, Ferriss B, Reboldi P, Michel G, Manes C, Fuller JH. EURODIAB Prospective Complications Study Group. Risk factors for coronary heart disease in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study. Diabetes Care. 2004; 27: 530–537 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14747240&query_hl=161

427. Yamasaki Y, Kawamori R, Matsushima H, Nishizawa H, Kodama M, Kajimoto Y, Morishima T, Kamada T.  Atherosclerosis in carotid artery of young IDDM patients monitored by ultrasound high-resolution B-mode imaging.  Diabetes 43:634-639,  1994.

428. Kanters SD, Algra A, Banga JD.  Carotid intima-media thickness in hyperlipidemic type I and type II diabetic patients.  Diabetes Care 20:276-280,  1997. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9051371&query_hl=163

429. Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, Backlund JY, O’Leary DH, Genuth S. Diabetes Control and Complications Trial; Epidemiology of Diabetes Interventions and Complications Research Group. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med. 2003; 348: 2294–2303 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12788993&query_hl=165

430. Snell-Bergeon JK, Hokanson JE, Jensen L, MacKenzie T, Kinney G, Dabelea D, Eckel RH, Ehrlich J, Garg S, Rewers M. Progression of coronary artery calcification in type 1 diabetes: the importance of glycemic control. Diabetes Care. 2003 Oct;26(10):2923-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14514603&query_hl=167

431. Dabelea D, Kinney G, Snell-Bergeon JK, Hokanson JE, Eckel RH, Ehrlich J, Garg S, Hamman RF, Rewers M; The Coronary Artery Calcification in Type 1 Diabetes Study. Effect of type 1 diabetes on the gender difference in coronary artery calcification: a role for insulin resistance? The Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study. Diabetes. 2003 Nov;52(11):2833-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14578303&query_hl=169

432. Wadwa RP, Kinney GL, Maahs DM, Snell-Bergeon J, Hokanson JE, Garg SK, Eckel RH, Rewers M. Awareness and treatment of dyslipidemia in young adults with type 1 diabetes. Diabetes Care. 2005 May;28(5):1051-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15855566&query_hl=171

433. Maahs DM, Ogden LG, Kinney GL, Wadwa P, Snell-Bergeon JK, Dabelea D, Hokanson JE, Ehrlich J, Eckel RH, Rewers M. Low plasma adiponectin levels predict progression of coronary artery calcification. Circulation. 2005 Feb 15;111(6):747-53. Epub 2005 Feb 7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15699257&query_hl=173

434. Maahs DM, Kinney GL, Wadwa P, Snell-Bergeon JK, Dabelea D, Hokanson J, Ehrlich J, Garg S, Eckel RH, Rewers MJ. Hypertension prevalence, awareness, treatment, and control in an adult type 1 diabetes population and a comparable general population. Diabetes Care. 2005 Feb;28(2):301-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15677783&query_hl=175

435. Hokanson JE, MacKenzie T, Kinney G, Snell-Bergeon JK, Dabelea D, Ehrlich J, Eckel RH, Rewers M. Evaluating changes in coronary artery calcium: an analytic method that accounts for interscan variability. AJR Am J Roentgenol. 2004 May;182(5):1327-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15100140&query_hl=177

436. Snell-Bergeon JK, Hokanson JE, Kinney GL, Dabelea D, Ehrlich J, Eckel RH, Ogden L, Rewers M.  Measurement of abdominal fat by CT compared to waist circumference and BMI in explaining the presence of coronary calcium. Int J Obes Relat Metab Disord. 2004 Dec;28(12):1594-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15467773&query_hl=179

437. Hokanson JE, Cheng S, Snell-Bergeon JK, Fijal BA, Grow MA, Hung C, Erlich HA, Ehrlich J, Eckel RH, Rewers M. A common promoter polymorphism in the hepatic lipase gene (LIPC-480C>T) is associated with an increase in coronary calcification in type 1 diabetes. Diabetes. 2002 Apr;51(4):1208-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11916946&query_hl=181

438. Wadwa RP, Rewers M. Update on noninvasive detection of cardiovascular in diabetes. Curr Opin Endocrinol Diabetes 2005, 12: 267-272

439. Libby P, Nathan DM, Abraham K, Brunzell JD, Fradkin JE, Haffner SM, Hsueh W, Rewers M, Roberts BT, Savage PJ, Skarlatos S, Wassef M, Rabadan-Diehl C; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. Circulation. 2005 Jun 28;111(25):3489-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15983263&query_hl=189

440. Rewers M, Zimmet P. The rising tide of childhood type 1 diabetes--what is the elusive environmental trigger? Lancet. 2004 Nov 6-12;364(9446):1645-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15530607&query_hl=191

441. Berger B. Stenstrom G. Sundkvist G. Incidence, prevalence, and mortality of diabetes in a large population. A report from the Skaraborg Diabetes Registry. Diabetes Care. 22(5):773-8, 1999 May. 504.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10332680&query_hl=193

442. Wu D, Kendall D, Lunt H, Willis J, Darlow B, Frampton C.  Prevalence of Type 1 diabetes in New Zealanders aged 0-24 years. N Z Med J. 2005 Jul 15;118(1218):U1557. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16027748&query_hl=195

443. Urbonaite B, Zalinkevicius R, Green A. Incidence, prevalence, and mortality of insulin-dependent (type 1) diabetes mellitus in Lithuanian children during 1983-98. Pediatr Diabetes. 2002 Mar;3(1):23-30

444. Motala AA. Diabetes trends in Africa. Diabetes/Metabolism Research Reviews. 2002, 18 Suppl 3:S14-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15016171&query_hl=197

445. Samuelsson U, Sadauskaite V, Padaiga Z, Ludvigsson J; DEBS Study Group. A fourfold difference in the incidence of type 1 diabetes between Sweden and Lithuania but similar prevalence of autoimmunity. Diabetes Res Clin Pract. 2004 Nov;66(2):173-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15533585&query_hl=199

446. Macedo A, Jorge Z, Lacerda Nobre E, Pratas S, Jacome de Castro J. Prevalence of Type 1 diabetes mellitus in Portugal, 1995-1999:cohort of young men. Diabet Med. 2003 May;20(5): 418-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12752493&query_hl=201

447. Casu A, Pascutto C, Bernardinelli L, Songini M.Type 1 diabetes among Sardinian children is increasing: the Sardinian diabetes register for children aged 0-14 years (1989-1999). Diabetes Care. 2004 Jul;27(7):1623-9.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15220238&query_hl=203

448. Zhao HX, Stenhouse E, Sanderson E, et al. Continued rising trend of childhood Type 1 diabetes mellitus in Devon and Cornwall, England Diab Med 20 (2): 168-170 FEB 2003 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12581273&query_hl=205

449. Feltbower RG, Bodansky HJ, McKinney PA, et al. Trends in the incidence of childhood diabetes in south Asians and other children in Bradford, UK Diab Med 19 (2): 162-166 FEB 2002 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11874434&query_hl=207

450. Lee WR.The changing demography of diabetes mellitus in Singapore. Diabetes Research & Clinical Practice. 50 Suppl 2:S35-9, 2000 Oct. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11024582&query_hl=210

451. Joner, G, Stene L., Sovik O., the Norwegian Childhood Diabetes Study Group Nationwide, Prospective Registration of Type 1 Diabetes in Children Aged <15 Years in Norway 1989-1998: No increase but significant regional variation in incidence. Diabetes Care 2004, 27(7): 1618-1622 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15220237&query_hl=213

452. Kyvik KO, Nystrom L, Gorus F, Songini M, Oestman J, Castell C, Green A, Guyrus E, Ionescu-Tirgoviste C, McKinney PA, Michalkova D, Ostrauskas R, Raymond NT: The epidemiology of Type 1 diabetes mellitus is not the same in young adults as in children. Diabetologia 47:377–384, 2004 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14762657&query_hl=215

453. Pundziute-Lycka A, Dahlquist G, Urbonaite B, Zalinkevicius R; Swedish Childhood Diabetes Study Group; Lithuanian Childhood Diabetes Study Group. Time trend of childhood type 1 diabetes incidence in Lithuania and Sweden, 1983-2000. Acta Paediatr. 2004 Nov;93(11):1519-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15513583&query_hl=217

454. Green A, Patterson CC; EURODIAB TIGER Study Group. Europe and Diabetes. Trends in the incidence of childhood-onset diabetes in Europe 1989-1998. Diabetologia. 2001 Oct;44 Suppl 3:B3-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11724413&query_hl=219

455. Cotellessa M, Barbieri P, Mazzella M, Bonassi S, Minicucci L, Lorini R. High incidence of childhood type 1 diabetes in Liguria, Italy, from 1989 to 1998. Diabetes Care. 2003 Jun;26(6):1786-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12766110&query_hl=221

456. Bruno G, Cerutti F, Merletti F, Cavallo-Perin P, Gandolfo E, Rivetti M, Runzo C, Pinach S, Pagano G; Piedmont Study Group for Diabetes Epidemiology. Residual beta-cell function and male/female ratio are higher in incident young adults than in children: the registry of type 1 diabetes of the province of Turin, Italy, 1984-2000. Diabetes Care. 2005 Feb;28(2):312-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15677785&query_hl=223

457. Carle F, Gesuita R, Bruno G, Coppa GV, Falorni A, Lorini R, Martinucci ME, Pozzilli P, Prisco F, Songini M, Tenconi MT, Cherubini V; RIDI Study Group. Diabetes incidence in 0- to 14-year age-group in Italy: a 10-year prospective study. Diabetes Care. 2004 Dec;27(12):2790-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15562186&query_hl=225

458. Newhook LA, Curtis J, Hagerty D, Grant M, Paterson AD, Crummel C, Bridger T, Parfrey P. High incidence of childhood type 1 diabetes in the Avalon Peninsula, Newfoundland, Canada. Diabetes Care. 2004 Apr;27(4):885-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15047643&query_hl=227

459. Kawasaki E, Eguchi K. Is Type 1 diabetes in the Japanese population the same as among Caucasians? Ann N Y Acad Sci. 2004 Dec;1037:96-103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15699499&query_hl=230

460. Steck AK, Barriga KJ, Emery LM, Fiallo-Scharer RV, Gottlieb PA, Rewers MJ.  Secondary attack rate of type 1 diabetes in Colorado families. Diabetes Care. 2005 Feb;28(2):296-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15677782&query_hl=232

461. Rewers M, Zimmet P. The rising tide of childhood type 1 diabetes--what is the elusive environmental trigger? Lancet. 2004 Nov 6-12;364(9446):1645-7.  Prevalence of type 1 diabetes http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15530607&query_hl=191

462. Haynes A, Bower C, Bulsara MK, Jones TW, Davis EA. Continued increase in the incidence of childhood Type 1 diabetes in a population-based Australian sample (1985-2002). Diabetologia. 2004 May;47(5):866-70 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15095039&query_hl=234

463. Lipman TH, Chang Y, Murphy KM. The epidemiology of type 1 diabetes in children in Philadelphia 1990-1994: evidence of an epidemic. Diabetes Care. 2002 Nov;25(11):1969-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12401741&query_hl=236

464. Oeltmann JE, Liese AD, Heinze HJ, Addy CL, Mayer-Davis EJ. Prevalence of diagnosed diabetes among African-American and non-Hispanic white youth, 1999. Diabetes Care. 2003 Sep;26(9):2531-5 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12941714&query_hl=238

465. Dziatkowiak H, Ciechanowska M, Wasikowa R, Symonides-lawecka A, Bieniasz J, Trippenbach-Dulska H, Korniszewski L, Szybinski Z. Increase in the incidence of type 1 diabetes mellitus in children in three cities in Poland, 1987-1999. J Pediatr Endocrinol Metab. 2002 Sep-Oct;15(8):1153-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12387513&query_hl=240

466. Cepedano Dans A, Barreiro Conde J, Pombo Arias M; Grupo de Diabetes Infantil de Galicia.  Incidence and clinical manifestations at onset of type 1 diabetes mellitus in Galicia (Spain): 2001-2002. An Pediatr (Barc). 2005 Feb;62(2):123-7 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15701307&query_hl=243

467. Patterson CC, Dahlquist G, Soltesz G, Green A; EURODIAB ACE Study Group. Europe and Diabetes.Is childhood-onset type I diabetes a wealth-related disease? An ecological analysis of European incidence rates. Diabetologia. 2001 Oct;44 Suppl 3:B9-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11724424&query_hl=245

468. Feltbower RG, McKinney PA, Parslow RC, Stephenson CR, Bodansky HJ.Type 1 diabetes in Yorkshire, UK: time trends in 0-14 and 15-29-year-olds, age at onset and age-period-cohort modelling. Diabet Med. 2003 Jun;20(6):437-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12786676&query_hl=247

469. Kretowski A, Kowalska I, Peczynska J, Urban M, Green A, Kinalska I. The large increase in incidence of Type I diabetes mellitus in Poland. Diabetologia. 2001 Oct;44 Suppl 3:B48-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11724417&query_hl=249

470. Peczynska J, Urban M, Florys B. The epidemiology of type 1 diabetes in children and adolescents in north-east Poland in the period 1988-1999. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw. 2001;7(1):17-20 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12818142&query_hl=251

471. Cinek O, Sumnik Z, Vavrinec J.Childhood diabetes in the Czech Republic: a steady increase in incidence. Cas Lek Cesk. 2005;144(4):266-71 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15945487&query_hl=253

472. Dabelea D on behalf of SEARCH Study Group.The SEARCH for diabetes in youth study group. Abstracts of ADA, San Diego  2005:124-OR

473. Libman IM, Pietropaolo M., Arslanian SA, LaPorte RE, Becker DJ. Evidence for Heterogeneous Pathogenesis of Insulin-Treated Diabetes in Black and White Children. Diabetes Care, October 1, 2003; 26(10): 2876 - 2882. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14514595&query_hl=257

474. Gong CX, Zhu C, Yan C, Liang JP, Ni GC, Gao J, Li YC, Liu M, Peng XX, Yang Z. Survey of type 1 diabetes incidence in children from 1997 to 2000 in Beijing area. Zhonghua Er Ke Za Zhi. 2004 Feb;42(2):113-6 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15059486&query_hl=259

475. Charkaluk ML, Czernichow P, Levy-Marchal C. Incidence data of childhood-onset type I diabetes in France during 1988-1997: the case for a shift toward younger age at onset. Pediatr Res. 2002 Dec;52(6):859-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12438661&query_hl=261

476. Rosenbauer J, Icks A, Schmitter D, Giani G. Incidence of childhood Type I diabetes mellitus is increasing at all ages in Germany. Diabetologia. 2002 Mar;45(3):457-8 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11914757&query_hl=263

477. Arpi ML, Fichera G, Mancuso M, Lucenti C, Italia S, Tomaselli L, Motta RM, Mazza A, Vigneri R, Purrello F, Squatrito S. A ten-year (1989-1998) perspective study of the incidence of Type 1 diabetes http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12035936&query_hl=265

478. Kulaylat NA, Narchi H. A twelve year study of the incidence of childhood type 1 diabetes mellitus in the Eastern Province of Saudi Arabia. J Pediatr Endocrinol Metab. 2000 Feb;13(2): 135-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10711657&query_hl=267

479. Shaltout AA, Moussa MA, Qabazard M, Abdella N, Karvonen M, Al-Khawari M, Al-Arouj M, Al-Nakhi A, Tuomilehto J, El-Gammal A; Kuwait Diabetes Study Group. Further evidence for the rising incidence of childhood Type 1 diabetes in Kuwait. Diabet Med. 2002 Jun;19(6): 522-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12109439&query_hl=270

480. Willis JA, Scott RS, Darlow BA, Nesbit JW, Anderson P, Moore MP, Lunt H, Cole DR. Incidence of type 1 diabetes mellitus diagnosed before age 20 years in Canterbury, New Zealand over the last 30 years. J Pediatr Endocrinol Metab. 2002 May;15(5):637-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12014523&query_hl=272

481. Mamoulakis D, Galanakis E, Bicouvarakis S, Paraskakis E, Sbyrakis S. Epidemiology of childhood type I diabetes in Crete, 1990-2001.Acta Paediatr. 2003 Jun;92(6):737-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12856988&query_hl=274

482. Unachak K, Tuchinda C. Incidence of type 1 diabetes in children under 15 years in northern Thailand, from 1991 to 1997. J Med Assoc Thai. 2001 Jul;84(7):923-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11759972&query_hl=276

483. Pilecki O, Robak-Kontna K, Jasinski D, Bogun-Reszczynska Z, Bojko-Zbikowska M. Epidemiology of type 1 diabetes mellitus in Bydgoszcz region in the years 1997-2002. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw. 2003;9(2):77-81 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14575616&query_hl=278

484. Martinucci ME, Curradi G, Fasulo A, Medici A, Toni S, Osovik G, Lapistkaya E, Sherbitskaya E. Incidence of childhood type 1 diabetes mellitus in Gomel, Belarus. J Pediatr Endocrinol Metab. 2002 Jan;15(1):53-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11822581&query_hl=280

485. Waldhor T, Schober E, Karimian-Teherani D, Rami B; Austrian Diabetes Incidence Study Group. Regional differences and temporal incidence trend of Type I diabetes mellitus in Austria from 1989 to 1999: a nationwide study. Diabetologia. 2000 Nov;43(11):1449-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11126417&query_hl=282

486. van Wouwe JP, Mattiazzo GF, el Mokadem N, Reeser HM, Hirasing RA. The incidence and initial symptoms of diabetes mellitus type 1 in 0-14-year-olds in the Netherlands, 1996-1999. Ned Tijdschr Geneeskd. 2004 Sep 11;148(37):1824-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15495512&query_hl=284

487. Roche EF, Menon A, Gill D, Hoey HM. Incidence of type 1 diabetes mellitis in children aged under 15 years in the Republic of Ireland.J Pediatr Endocrinol Metab. 2002 Sep-Oct;15(8):1191-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12387518&query_hl=287

488. Ogle GD, Lesley J, Sine P, McMaster P. Type 1 diabetes mellitus in children in Papua New Guinea.P N G Med J. 2001 Sep-Dec;44(3-4):96-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12422979&query_hl=289

489. Lopez-Siguero JP, Del Pino-De la Fuente A, Martinez-Aedo MJ, Moreno-Molina JA. Increased incidence of type 1 diabetes in the south of Spain. Diabetes Care. 2002 Jun;25(6):1099. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12032125&query_hl=291

490. Ionescu-Tirgoviste C, Guja C, Calin A, Mota M. Related An increasing trend in the incidence of type 1 diabetes mellitus in children aged 0-14 years in Romania--ten years (1988-1997) EURODIAB study experience. J Pediatr Endocrinol Metab. 2004 Jul;17(7):983-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15301046&query_hl=293

491. Lipton R, Keenan H, Onyemere KU, Freels S.  Incidence and onset features of diabetes in African-American and Latino children in Chicago, 1985-1994. Diabetes Metab Res Rev. 2002 Mar-Apr;18(2):135-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11994905&query_hl=295

492. Rytkonen M, Moltchanova E, Ranta J, Taskinen O, Tuomilehto J, Karvonen M; SPAT Study Group; Finnish Childhood Diabetes Registry Group. The incidence of type 1 diabetes among children in Finland--rural-urban difference. Health Place. 2003 Dec;9(4):315-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14499216&query_hl=297

493. Michalkova D, Minarik P, Hlava P, Camajova J, Nazarov V; Slovak Epidemiological Study Group of Children Diabetologists. Trends in the incidence of childhood-onset type 1 diabetes in Slovakia 1985 - 2000.Cent Eur J Public Health. 2004 Jun;12(2):75-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15242023&query_hl=299

494. Samuelsson U, Lofman O. Geographical mapping of type 1 diabetes in children and adolescents in south east Sweden. J Epidemiol Community Health. 2004 May;58(5):388-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15082736&query_hl=301

495. Kondrashova A, Reunanen A, Romanov A, Karvonen A, Viskari H, Vesikari T, Ilonen J, Knip M, Hyoty H. A six-fold gradient in the incidence of type 1 diabetes at the eastern border of Finland. Ann Med. 2005;37(1):67-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15902849&query_hl=303

496. Podar T, Solntsev A, Karvonen M, Padaiga Z, Brigis G, Urbonaite B, Viik-Kajander M, Reunanen A, Tuomilehto J. Increasing incidence of childhood-onset type I diabetes in 3 Baltic countries and Finland 1983-1998. Diabetologia. 2001 Oct;44 Suppl 3:B17-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11724410&query_hl=305

497. Weets I, De Leeuw IH, Du Caju MV, Rooman R, Keymeulen B, Mathieu C, Rottiers R, Daubresse JC, Rocour-Brumioul D, Pipeleers DG, Gorus FK; Belgian Diabetes Registry. The incidence of type 1 diabetes in the age group 0-39 years has not increased in Antwerp (Belgium) between 1989 and 2000: evidence for earlier disease manifestation. Diabetes Care. 2002 May;25(5):840-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11978678&query_hl=307

498. Israel IDDM Registry Study Group. Incidence of IDDM between the ages 0-17 years in Israel in 1998--the Israel IDDM Registry Study Group—IIRSG. Harefuah. 2002 Sep;141(9):789-91, 858. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12362482&query_hl=313

499. Gyurus E, Green A, Patterson CC, Soltesz G; Hungarian Childhood Diabetes Epidemiology Study Group. Dynamic changes in the trends in incidence of type 1 diabetes in children in Hungary (1978-98). Pediatr Diabetes. 2002 Dec;3(4):194-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15016147&query_hl=315

500. Kadiki OA, Roaeid RB. Incidence of type 1 diabetes in children (0-14 years) in Benghazi Libya (1991-2000). Diabetes Metab. 2002 Dec;28(6 Pt 1):463-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12522326&query_hl=318

501. Bratina NU, Tahirovic H, Battelino T, Krzisnik C. Incidence of childhood-onset Type I diabetes in Slovenia and the Tuzia region (Bosnia and Herzegovina) in the period 1990-1998. Diabetologia. 2001 Oct;44 Suppl 3:B27-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11724412&query_hl=320

502. Schoenle EJ, Lang-Muritano M, Gschwend S, Laimbacher J, Mullis PE, Torresani T, Biason-Lauber A, Molinari L. Epidemiology of type I diabetes mellitus in Switzerland: steep rise in incidence in under 5 year old children in the past decade. Diabetologia. 2001 Mar;44(3):286-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11317657&query_hl=322

503. Raymond NT, Jones JR, Swift PG, Davies MJ, Lawrence G, McNally PG, Burden ML, Gregory R, Burden AC, Botha JL. Comparative incidence of Type I diabetes in children aged under 15 years from South Asian and White or Other ethnic backgrounds in Leicestershire, UK, 1989 to 1998.Diabetologia. 2001 Oct;44 Suppl 3:B32-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11724414&query_hl=324

504. Lora-Gomez RE, Morales-Perez FM, Arroyo-Diez FJ, Barquero-Romero J. Incidence of Type 1 diabetes in children in Caceres, Spain, during 1988-1999. Diabetes Res Clin Pract. 2005 Aug;69(2):169-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16005366&query_hl=326

505. Campbell-Stokes PL, Taylor BJ; New Zealand Children's Diabetes Working Group. Prospective incidence study of diabetes mellitus in New Zealand children aged 0 to 14 years. Diabetologia. 2005 Apr;48(4):643-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15759108&query_hl=328

506. Carrasco E, Perez-Bravo F, Dorman J, Mondragon A, Santos JL. Increasing incidence of type 1 diabetes in population from Santiago of Chile: trends in a period of 18 years (1986-2003). Diabetes Metab Res Rev. 2005 May 13; [Epub ahead of print] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15892034&query_hl=330

507. Pishdad GR. Low incidence of type 1 diabetes in Iran. Diabetes Care. 2005 Apr;28(4):927-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15793198&query_hl=333

508. Svensson J, Carstensen B, Molbak A, Christau B, Mortensen HB, Nerup J, Borch-Johnsen K: Increased risk of childhood type 1 diabetes in children born after 1985. Diabetes Care 2002, 25:2197–2201 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12453960&query_hl=335

509. Jarosz-Chobot P, Otto-Buczkowska E, Koehler B, Matlakiewicz E, Green A. Increased trend of type 1 diabetes mellitus in children's population (0-14 years) in Upper Silesia region (Poland). Med Sci Monit. 2000 May-Jun;6(3):573-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11208373&query_hl=337

510. Tzaneva V, Iotova V, Yotov Y. Significant urban/rural differences in the incidence of type 1 (insulin-dependent) diabetes mellitus among Bulgarian children (1982-1998). Pediatr Diabetes. 2001 Sep;2(3):103-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15016192&query_hl=339

511. Tsai WY. Type 1 diabetes mellitus in Taiwanese children. Acta Paediatr Taiwan. 2004 Jul-Aug;45(4):201-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15624364&query_hl=341

512. Mooney JA, Helms PJ, Jolliffe IT, Smail P; Scottish Study Group for the Care of Diabetes in the Young. Seasonality of type 1 diabetes mellitus in children and its modification by weekends and holidays: retrospective observational study. Arch Dis Child. 2004 Oct;89(10):970-3 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15383444&query_hl=343

513. Collado-Mesa F, Diaz-Diaz O, Ashkenazi I, Seasonality of birth and Type 1 diabetes onset in children (0-14 years) in Cuba. Diabet Med. 2001 Nov;18(11):939-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11703443&query_hl=345

514. Oeltmann JE, Liese AD, Heinze HJ, Addy CL, Mayer-Davis EJ. Prevalence of diagnosed diabetes among African-American and non-Hispanic white youth, 1999. Diabetes Care. 2003 Sep;26(9):2531-5 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12941714&query_hl=347

515. Rosenbauer J, Icks A, Giani G. Incidence and prevalence of childhood type 1 diabetes mellitus in Germany--model-based national estimates. Journal of Pediatric Endocrinology. 15(9):1497-504, 2002 Nov-Dec http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12503857&query_hl=349

516. Harvey JN. Craney L. Kelly D. Estimation of the prevalence of diagnosed diabetes from primary care and secondary care source data: comparison of record linkage with capture-recapture analysis. Journal of Epidemiology & Community Health. 56(1):18-23, 2002 Jan. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11801615&query_hl=351

517. Giralt Muina P, Santillana Ferrer L, Madrigal Barchino D, Merlo Garrido A, Toledo De La Torre B, Anaya Barea F. Incidence of diabetes mellitus and prevalence of type 1A diabetes mellitus in children younger than 16 years old from the province of Ciudad Real. Anales Espanoles de Pediatria. 55(3):213-8, 2001Sep. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11676895&query_hl=353

518. Blanchard JF. Dean H. Anderson K. Wajda A. Ludwig S. Depew N. Incidence and prevalence of diabetes in children aged 0-14 years in Manitoba, Canada, 1985-1993.Diabetes Care. 20(4):512-5, 1997 Apr. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9096971&query_hl=355

519. Virtanen SM, Kenward MG, Erkkola M, Kautiainen S, Kronberg-Kippilä C, Hakulinen T, Ahonen S, Uusitalo L, Niinistö S, Veijola R, Simell O, Ilonen J, Knip M. Age at introduction of new foods and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes. Diabetologia. 2006 Jul;49(7):1512-21. Epub 2006 Apr 5.



520. Scott FW, Rowsell P, Wang GS, Burghardt K, Kolb H, Flohé S. Oral exposure to diabetes-promoting food or immunomodulators in neonates alters gut cytokines and diabetes. Diabetes. 2002 Jan;51(1):73-8.



521. MacFarlane AJ, Burghardt KM, Kelly J, Simell T, Simell O, Altosaar I, Scott FW. A type 1 diabetes-related protein from wheat (Triticum aestivum). cDNA clone of a wheat storage globulin, Glb1, linked to islet damage. J Biol Chem. 2003 Jan 3;278(1):54-63. Epub 2002 Oct 29.



522. Vitamin D supplement in early childhood and risk for Type I (insulin-dependent) diabetes mellitus. The EURODIAB Substudy 2 Study Group. Diabetologia. 1999 Jan;42(1):51-4.



523. Norris JM, Yin X, Lamb MM, Barriga K, Seifert J, Hoffman M, Orton HD, Barón AE, Clare-Salzler M, Chase HP, Szabo NJ, Erlich H, Eisenbarth GS, Rewers M. Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA. 2007 Sep 26;298(12):1420-8.



524. Lamb MM, Yin X, Zerbe GO, Klingensmith GJ, Dabelea D, Fingerlin TE, Rewers M, Norris JM. Height growth velocity, islet autoimmunity and type 1 diabetes development: the Diabetes Autoimmunity Study in the Young. Diabetologia. 2009 Oct;52(10):2064-71. Epub 2009 Jun 23.



525. Ivarsson A, Hernell O, Stenlund H, Persson LA. Breast-feeding protects against celiac disease. Am J Clin Nutr. 2002 May;75(5):914-21.