Childhood Diabetes Study Research Articles

Sustained low-grade inflammation in young participants with childhood onset type 1 diabetes: The Norwegian atherosclerosis and childhood diabetes (ACD) study

Background and aimsPersons with type 1 diabetes (T1D) have increased mortality from cardiovascular disease. Early inflammation is important in the development of atherosclerosis. We aimed to evaluate the extent of inflammation and difference in mean over a five-year period in young persons with T1D compared to healthy controls. MethodsThe Norwegian Atherosclerosis and Childhood Diabetes (ACD) study is a prospective population-based cohort study on atherosclerosis development in childhood-onset T1D compared to healthy controls, with follow-ups every fifth year. The original study cohort consisted of 314 children with T1D on intensive insulin treatment and 120 healthy controls of similar age. Circulating levels of VCAM-1, TNA-α, P-selectin, E-selectin, CRP, IL-6, IL-18, MCP-1, MMP-9 and TIMP-1 were measured by ELISAs at baseline and at the five-year follow-up. ResultsThe group with T1D had mean age 13.7 (SD = 2.8) years, disease duration 5.6 (SD = 3.4) years and HbA1c 68 (SD = 13.1) mmol/mol at baseline. Levels of almost all inflammatory markers were significantly increased in the group with T1D compared to controls, and significant mean-difference between the two groups over the five-year period was observed in four markers: IL-18, P-selectin, E-selectin and TIMP-1. ConclusionsThe early low-grade inflammation present in young individuals with T1D five years after diagnosis is sustained at ten-year disease duration, with moderate changes for most markers of inflammation over time. The evolving inflammatory profile indicates an accelerated chain of events in the progression of early atheromatosis in T1D.

Associations between Macular OCT Angiography and Nonproliferative Diabetic Retinopathy in Young Patients with Type 1 Diabetes Mellitus.

Methods OCTA of both eyes was performed in a cross-sectional study of 14 to 30-year-old individuals with at least 10-year duration of T1D and controls recruited from the Norwegian Atherosclerosis and Childhood Diabetes (ACD) study. Vessel density (VD) and foveal avascular zone (FAZ) area in the superficial and deep capillary plexus (SCP and DCP), total retinal volume (TRV), and central macular thickness (CMT) were calculated using automated software. Univariate and multivariate ordered logistic regression (OLR) models were used accordingly. Results We included 168 control eyes and 315 T1D eyes. Lower VD in DCP (OR 0.65, 95% CI 0.51–0.83), longer diabetes duration (OR 1.51, 95% CI 1.22–1.87), and higher waist circumference (OR 1.08, 95% CI 1.02–1.14) were significantly associated with progression of NPDR. VD in SCP and DCP were significantly lower in T1D patients without diabetic retinopathy than in controls. Conclusions Sparser VD in DCP is significantly associated with severity of NPDR, supporting that OCTA might detect the earliest signs of NPDR before it is visible by ophthalmoscopy.

Annexin V+ Microvesicles in Children and Adolescents with Type 1 Diabetes: A Prospective Cohort Study

Background Type 1 diabetes is a chronic disease including hyperglycemia and accelerated atherosclerosis, with high risk of micro- and macrovascular complications. Circulating microvesicles (cMVs) are procoagulant cell fragments shed during activation/apoptosis and discussed to be markers of vascular dysfunction and hypercoagulability. Limited knowledge exists on hypercoagulability in young diabetics. We aimed to investigate cMVs over a five-year period in children/adolescents with type 1 diabetes compared with controls and any associations with glycemic control and cardiovascular risk factors. We hypothesized increased shedding of cMVs in type 1 diabetes in response to vascular activation. Methods The cohort included type 1 diabetics (n = 40) and healthy controls (n = 40), mean age 14 years (range 11) at inclusion, randomly selected from the Norwegian Atherosclerosis and Childhood Diabetes (ACD) study. Citrated plasma was prepared and stored at -80°C until cMV analysis by flow cytometry. Results Comparable levels of Annexin V (AV+) cMVs were observed at inclusion. At five-year follow-up, total AV+ cMVs were significantly lower in subjects with type 1 diabetes compared with controls; however, no significant differences were observed after adjusting for covariates. In the type 1 diabetes group, the total AV+, tissue factor-expressing AV+/CD142+, neutrophil-derived AV+/CD15+ and AV+/CD45+/CD15+, and endothelial-derived AV+/CD309+ and CD309+/CD34+ cMVs were inversely correlated with HbA1c (r = ‐0.437, r = ‐0.515, r = ‐0.575, r = ‐0.529, r = ‐0.416, and r = ‐0.445, respectively; all p ≤ 0.01), however, only at inclusion. No significant correlations with cardiovascular risk factors were observed. Conclusions Children/adolescents with type 1 diabetes show similar levels of AV+ cMVs as healthy controls and limited associations with glucose control. This indicates that our young diabetics on intensive insulin treatment have preserved vascular homeostasis and absence of procoagulant cMVs.

The first 142 amino acids of glutamate decarboxylase do not contribute to epitopes recognized by autoantibodies associated with Type 1 diabetes.

Glutamate decarboxylase (GAD) antibodies are the most widely used predictive marker for Type 1 diabetes, but many individuals currently found to be GAD antibody-positive are unlikely to develop diabetes. We have shown previously that radioimmunoassays using N-terminally truncated 35 S-GAD65 (96-585) offer better disease specificity with similar sensitivity to full-length 35 S-GAD65 (1-585). To determine whether assay performance could be improved further, we evaluated a more radically truncated 35 S-GAD65 (143-585) radiolabel. Samples from people with recent-onset Type 1 diabetes (n = 157) and their first-degree relatives (n = 745) from the Bart's-Oxford family study of childhood diabetes were measured for GAD antibodies using 35 S-labelled GAD65 (143-585). These were screened previously using a local radioimmunoassay with 35 S-GAD65 (1-585). A subset was also tested by enzyme-linked immunosorbent assay (ELISA), which performs well in international workshops, but requires 10 times more serum. Results were compared with GAD antibody measurements using 35 S-GAD65 (1-585) and 35 S-GAD65 (96-585). Sensitivity of GAD antibody measurement was maintained using 35 S-GAD65 (143-585) compared with 35 S-GAD65 (1-585) and 35 S-GAD65 (96-585). Specificity for Type 1 diabetes was improved compared with 35 S-GAD65 (1-585), but was similar to 35 S-GAD65 (96-585). Relatives found to be GAD antibody-positive using these truncated labels were at increased risk of diabetes progression within 15 years, compared with those positive for GAD(1-585) antibody only, and at similar risk to those found GAD antibody-positive by ELISA. The first 142 amino acids of GAD65 do not contribute to epitopes recognized by Type 1 diabetes-associated GAD antibodies. Low-volume radioimmunoassays using N-terminally truncated 35 S-GAD65 are more specific than those using full-length GAD65 and offer practical alternatives to the GAD antibody ELISA for identifying children at increased risk of Type 1 diabetes.

Type 1 Diabetes in Children and Adolescents.

Type 1 Diabetes in Children and Adolescents.

Marginal structural model to evaluate the joint effect of socioeconomic exposures on the risk of developing end-stage renal disease in patients with type 1 diabetes: a longitudinal study based on data from the Swedish Childhood Diabetes Study Group

PurposeDiabetic nephropathy is a severe complication of type 1 diabetes (T1D) that may lead to renal failure and end-stage renal disease (ESRD) demanding dialysis and transplantation. The etiology of diabetic nephropathy is multifactorial and both genes and environmental and life style–related factors are involved. In this study, we investigate the effect of the socioeconomic exposures, unemployment and receiving income support, on the development of ESRD in T1D patients, using a marginal structural model (MSM) in comparison with standard logistic regression models. MethodsThe study is based on the Swedish Childhood Diabetes Register which in 1977 started to register patients developing T1D before 15 years of age. In the analyses, we include patients born between 1965 and 1979, developing diabetes between 1977 and 1994, and followed until 2013 (n = 4034). A MSM was fitted to adjust for both baseline and time-varying confounders. ResultsThe main results of the analysis indicate that being unemployed for more than 1 year and receiving income support are risk factors for the development of ESRD. Multiple exposures over time to these risk factors increase the risk associated with the disease. ConclusionsUsing a MSM is an advanced method well suited to investigate the effect of exposures on the risk of complications of a chronic disease with longitudinal data. The results show that socioeconomic disadvantage increases the risk of developing ESRD in patients with T1D.

Reduced HDL function in children and young adults with type 1 diabetes

BackgroundPatients with type 1 diabetes (T1D) are at increased risk of cardiovascular disease (CVD). Measures of high-density lipoprotein (HDL) function provide a better risk estimate for future CVD events than serum levels of HDL cholesterol. The objective of this study was to evaluate HDL function in T1D patients shortly after disease onset compared with healthy control subjects.MethodsParticipants in the atherosclerosis and childhood diabetes study were examined at baseline and after 5 years. At baseline, the cohort included 293 T1D patients with a mean age of 13.7 years and mean HbA1c of 8.4%, along with 111 healthy control subjects. Their HDL function, quantified by HDL-apoA-I exchange (HAE), was assessed at both time points. HAE is a measure of HDL’s dynamic property, specifically its ability to release lipid-poor apolipoprotein A-I (apoA-I), an essential step in reverse cholesterol transport.ResultsThe HAE-apoA-I ratio, reflecting the HDL function per concentration unit apoA-I, was significantly lower in the diabetes group both at baseline, 0.33 (SD = 0.06) versus 0.36 (SD = 0.06) %HAE/mg/dL, p < 0.001 and at follow-up, 0.34 (SD = 0.06) versus 0.36 (SD = 0.06) %HAE/mg/dL, p = 0.003. HAE-apoA-I ratio was significantly and inversely correlated with HbA1c in the diabetes group. Over the 5 years of the study, the mean HAE-apoA-I ratio remained consistent in both groups. Individual changes were less than 15% for half of the study participants.ConclusionsThis study shows reduced HDL function, quantified as HAE-apoA-I ratio, in children and young adults with T1D compared with healthy control subjects. The differences in HDL function appeared shortly after disease onset and persisted over time.

Soluble RAGE and atherosclerosis in youth with type 1 diabetes: a 5-year follow-up study.

BackgroundAdvanced glycation end products (AGEs) play a role in the development of late complications and atherosclerosis in diabetes by engaging the receptor for advanced glycation end products, RAGE. Receptor binding leads to activation of the vascular endothelium and increased inflammation in the vessel wall. The soluble variants of the receptor, endogenous secretory RAGE (esRAGE) and the cleaved cell-surface part of RAGE, which together comprise soluble RAGE (sRAGE), are suggested to have a protective effect acting as decoys for RAGE. We aimed to test whether high levels of soluble variants of RAGE could be protective against atherosclerosis development.MethodsParticipants in the prospective atherosclerosis and childhood diabetes study were examined at baseline (aged 8–18) and at follow-up after 5 years. Both sRAGE and esRAGE were measured by immunoassay in 299 patients with type 1 diabetes and 112 healthy controls at baseline and 241 patients and 128 controls at follow-up. The AGEs methylglyoxal-derived hydroimidazolone-1 (MG-H1) and carboxymethyllysine (CML) were measured by immunoassay. The surrogate markers of atherosclerosis assessed were carotid intima-media thickness (cIMT), C-reactive protein (CRP) and Young’s modulus, measures of arterial wall thickness, inflammation and arterial stiffness, respectively.ResultsLevels of sRAGE and esRAGE correlated strongly both at baseline and at follow-up in both diabetes patients and controls. With increasing age, mean values of both variants declined, independent of gender, diabetes or pubertal stage. In the diabetes group, multiple regression analysis showed a positive association between both variants of soluble RAGE and cIMT. There was no significant relationship with Young’s modulus, but a negative association between sRAGE at baseline and CRP at follow-up. The ratios between the AGEs and the variants of soluble RAGE were increased in diabetes patients compared to controls.ConclusionsThe results show a possible protective effect of high levels of sRAGE at baseline against inflammation 5 years later, but not on arterial stiffness or wall thickness, in this cohort of adolescents and young adults with T1D.

Type 1 Diabetes in Children and Adolescents

Type 1 Diabetes in Children and Adolescents

Translation in Action: Advancing Public Health and Clinical Care in Diabetes

We have many opportunities, as scientists and clinicians and as family and community members, to affect the epidemic of diabetes, both in terms of prevention and in terms of taking care of people with diabetes. Each year, the American Diabetes Association (ADA) President of Health Care and Education gives a speech reflecting on work the individual has done and how this relates to a given theme around diabetes. I am a bit of a different type of person in this role in that my professional life has been maybe 2% clinical practice in nutrition and 98% diabetes research, plus teaching and mentoring graduate students in epidemiology and nutrition. So I have chosen to reflect on diabetes research from a translational perspective, towards advancing public health and clinical care. As is the case for many of you, I have functioned in two worlds, or three when you count my family (which is its own world with five kids). It is no accident that my position as a faculty member at the University of North Carolina (UNC) and my volunteer service for ADA are linked by the ADA's stated mission “to prevent and cure diabetes and to improve the lives of all people affected by diabetes.” In fact, I teach my students that involvement in their professional societies, and particularly the ADA, is, in fact, an important way to ensure that the research we do is translated into public health initiatives and clinical practice. First, I'll focus on improving health for children with diabetes. Most of my work during the past 8–10 years has focused primarily on kids. First and foremost is the SEARCH for Diabetes in Youth study, which is the largest, multicenter epidemiological study of childhood diabetes in the United States. I have been involved with this project for about …

Target setting in intensive insulin management is associated with metabolic control: the Hvidoere Childhood Diabetes Study Group Centre Differences Study 2005

To evaluate glycaemic targets set by diabetes teams, their perception by adolescents and parents, and their influence on metabolic control. Clinical data and questionnaires were completed by adolescents, parents/carers and diabetes teams in 21 international centres. HbA1c was measured centrally. A total of 2062 adolescents completed questionnaires (age 14.4 +/- 2.3 yr; diabetes duration 6.1 +/- 3.5 yr). Mean HbA 1c = 8.2 +/- 1.4% with significant differences between centres (F = 12.3; p < 0.001) range from 7.4 to 9.1%. There was a significant correlation between parent (r = 0.20) and adolescent (r = 0.21) reports of their perceived ideal HbA1c and their actual HbA1c result (p < 0.001), and a stronger association between parents' (r = 0.39) and adolescents' (r = 0.4) reports of the HbA1c they would be happy with and their actual HbA1c result. There were significant differences between centres on parent and adolescent reports of ideal and happy with HbA1c (8.1 < F > 17.4;p < 0.001). A lower target HbA1c and greater consistency between members of teams within centres were associated with lower centre HbA1c (F = 16.0; df = 15; p < 0.001). Clear and consistent setting of glycaemic targets by diabetes teams is strongly associated with HbA1c outcome in adolescents. Target setting appears to play a significant role in explaining the differences in metabolic outcomes between centres.

Can we identify adolescents at high risk for nephropathy before the development of microalbuminuria?

To determine whether higher than average albumin excretion during early puberty identifies subjects who will subsequently develop microalbuminuria (MA) and clinical proteinuria. Longitudinal data from the Oxford Regional Prospective Study of Childhood Diabetes (ORPS; n = 554, median duration of follow-up 10 years; range 3.0-16.7) with assessment of albumin/creatinine ratios in three early morning urine samples collected annually. An albumin excretion phenotype was derived from longitudinal data, for each individual, defining deviation from the mean of regression models, including covariates gender, age, duration of diabetes and age at assessment. Tracking of the phenotypes was confirmed in a second independent cohort from Perth, Australia. The albumin excretion phenotype showed reasonable correlation between age 11-15 years and age 16-18 years in both cohorts, indicative of good 'tracking'. In the ORPS cohort, tertiles of the albumin excretion phenotype at aged 11-15 years were predictive of subsequent risk for the development of MA. All of the subjects developing clinical proteinuria had an albumin excretion phenotype in the upper tertile or an HbA(1c) > 9% at aged 11-15 years. Identification of adolescents at risk of diabetic nephropathy using an albumin excretion phenotype is feasible. When combined with elevated HbA(1c), it may identify subjects for trial of early intervention with angiotensin-converting enzyme inhibitors/angiotensin-II receptor antagonists and statins to improve long-term prognosis in these subjects where sustained improvement in glycaemic control may be difficult to achieve.

The Belgrade childhood diabetes study – comparison of children with Type 1 diabetes with their siblings

A case-control study was conducted in Belgrade (about 320,000 inhabitants 0-16 years old) during the period 1994-97, comprising 68 diabetic children (cases) and 68 controls chosen from the siblings of the cases. Analysis using multivariable logistic regression analysis indicated the following independent risk factors for Type 1 diabetes: higher birth order, infections during the 6 months preceding the onset of the disease and stressful events. Out of individual stressful and psychological factors, 'other' stressful events (severe accident or hospitalisation or death of a close friend, conflict with a teacher, death of a pet, failure in competition, quarrel between parents, punishment, physical attack, war in republics of former Yugoslavia and near drowning in the pool) and learning problems were independent risk factor for Type 1 diabetes. The results obtained in this study of siblings supports the hypothesis that environmental factors play a role in the development of Type 1 diabetes.

The Belgrade childhood diabetes study: a multivariate analysis of risk determinants for diabetes

The aim of this study was to evaluate some hypotheses about factors related to the development of type 1 diabetes mellitus. A case-control study was conducted in Belgrade during the period 1994-1997. A total of 105 recently onset diabetic and 210 control children, individually matched by age (+/-1 year), sex and place of residence, were included in the study. According to multivariate regression analysis, the following factors were related to type 1 diabetes: stressful events and symptoms of psychological dysfunction during the 12 months preceding the onset of the disease [odds ratio (OR) 3.48, 95% confidence interval (CI) 2.15-5.65; and OR 2.15, 95% CI 1.33-3.48], irregular vaccination (OR 16.98, 95% CI 1.38-208.92), infection during 6 months preceding the onset of the disease (OR 4.23, 95% CI 1.95-9.17), higher education of father (OR 1.50, 95% CI 1.05-2.14), mother's consumption of nitrosoamines-rich food during pregnancy (OR 4.33, 95% CI 1.95-9.61), alcohol consumption by father (OR 3.80, 95% CI 1.64-8.78), insulin-dependent and non-insulin-dependent diabetes mellitus in three generations of children's relatives (OR 20.04, 95% CI 4.73-84.81; and OR 5.52, 95% CI 2.45-12.46), and use of ultrasound diagnostic techniques during pregnancy (OR 0.42, 95% CI 0.17-1.00). Among non-genetic factors, those affecting the child during pregnancy are especially important because of their preventability.

Visual Metaphor as Method in Interviews with Children

A challenge to child‐centered anthropology is to develop methods of exploring children's worlds that accommodate children's own ways of communicating meaning, including nonverbal, visual means. The article proposes an approach, the Metaphor Sort Technique, and illustrates this method based on an ethnographic study of childhood diabetes and asthma. The Metaphor Sort Technique employs pictures selected by children as metaphors for their impressions of illness and its treatment. The Metaphor Sort Technique, as a feature of discourse, stimulated, complemented, and supported children's verbal utterances. The study demonstrates that when modes of discourse include visual, nonliteral tasks, this can activate a child's discursive power, reducing deference and enhancing the child's authority in an adult–child encounter.

The belgrade childhood diabetes study: association of infections and vaccinations on diabetes in childhood.

The aim of this study was to investigate whether individual infections or combination of infections or vaccination affect the risk of developing diabetes in childhood. A case-control study was conducted in Belgrade during the period between 1994 and 1997. A total of 105 recent onset diabetics were compared with 210 controls chosen among children with skin disease (the first control group). Cases and controls were individually matched by age (+/-1 year), sex, and place of residence. Eighty-six diabetic children were also compared with their brothers/sisters (the second control group). After adjustment for confounding variables, independent association with diabetes was found for infections during the 6 months preceding the onset of the disease, when cases were compared with both the first control group (OR=4.23, 95% CI, 1.95-9.17, p<0.001) and the second control group (OR=4.68, 95% CI, 2.09-10.47, p<0.001), and for regular vaccination when cases were compared with the first control group (OR=0.08, 95% CI, 0.01-0.50, p=0.03). The results obtained support the hypotheses that infections play a role in the development of type 1 diabetes and that regular vaccination has a preventive effect.

Identifying hepatic nuclear factor 1alpha mutations in children and young adults with a clinical diagnosis of type 1 diabetes.

HNF-1alpha gene mutations (MODY3) present with marked hyperglycemia in lean young adults and may, therefore, be mistaken for type 1 diabetes, with implications for individual treatment and risk of diabetes in other family members. We examined the prevalence of HNF-1alpha mutations in families with three generations of diabetes identified in a population-based study of childhood diabetes, representing a subpopulation in which misclassification was likely. In a study population of 1,470 families, 36 families (2.4%) with three affected generations were identified. In the 18 families in whom DNA samples were available, islet autoantibody testing, HLA class II genotyping, and HNF-1alpha sequencing were performed. At least one islet autoantibody was found in 13 of 14 probands, and diabetes-associated HLA class II haplotypes were found in 17 of 18. One proband, who had no islet autoantibodies and was homozygous for the protective HLA haplotype DRB1*02-DQB1*0602, had a novel HNF-1alpha heterozygous nonsense mutation (R54X). This mutation cosegregated with diabetes in the family. The proband, his brother, mother, and maternal grandmother were diagnosed with type 1 diabetes aged 14-18 years and treated with insulin (0.39-0.74 units/kg) from diagnosis. The mother has since been successfully transferred to sulfonylurea treatment. Family history alone is of limited value in identification of individuals with HNF-1alpha mutations, and we propose a stepwise approach that restricts sequencing of the HNF-1alpha gene to those with a family history of diabetes who also test negative for islet autoantibodies.

Diabetes in the parents of children with Type I diabetes.

Previous studies have reported an excess of Type II (non-insulin-dependent) diabetes mellitus in parents of children with Type I (insulin-dependent) diabetes mellitus. We set out to characterise the clinical and immunogenetic features of diabetes in parents of affected children, and to test the hypothesis that there is no excess of Type II diabetes within this population. Clinical details were collected from 3164 parents of 1641 children with Type I diabetes participating in the Bart's-Oxford study of childhood diabetes. Islet cell antibodies, antibodies to GAD and IA-2, and HLA class II genotype were determined in a subset of this group. Individuals were assigned a classification of Type I diabetes on the basis of clinical features and measurement of islet autoantibodies. Of 184 parents with diabetes, 138 (75 %) were on insulin. At least one islet autoantibody was detected in 90 (59 %) of 152 parents tested, and of 116 who were HLA-typed, 23 (20 %) had the highest risk genotype HLA-DRB1(*)03-DQA1*0501-DQB1(*)0201 / DRB1*04-DQA1(*)0301-DQB1*0302. Of 46 non-insulin-treated parents, 12 had islet autoantibodies. Of all parents, 141 (4.5 %) were therefore classified as having Type I diabetes, and 31 (0.98 %) as Type II diabetes; 12 could not be classified because of missing data or samples. Autoimmune diabetes can present late and without immediate need for insulin treatment in parents of children with the disease. Previous studies have categorised this as Type II diabetes. Our study suggests that there is no excess of non-autoimmune diabetes in the families of children with Type I diabetes.

The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT): initial aims and impact of the family history of type 1 diabetes mellitus in Japanese children.

The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT) was established in July 1994 with the chief aim to improve the quality of therapy for type 1 diabetes in children, an entity far less common in Japan than in Europe. We proposed four initial research topics: (i) to determine the current status of medical care and glycemic control in Japanese children with type 1 diabetes mellitus; (ii) to standardize the measurement of hemoglobin A1c; (iii) to establish a registry of a large cohort of patients in order to enable prospective studies to improve the quality of therapy for children with type 1 diabetes in Japan; and (iv) to enable participants of the JSGIT to hold a workshop twice annually. We registered a total of 736 patients from 45 hospitals throughout Japan. Intervention via insulin treatment was instituted after 2 yr for those patients whose hemoglobin A1c level was more than 8.1%. The proportion of patients receiving multiple insulin injections increased after intervention; however, average hemoglobin A1c in females remained significantly higher than in males. We identified two forms of diabetes in Japanese children: a rapidly progressive form and a more slowly progressive form. There was a significantly higher prevalence of a family history of diabetes in first-degree relatives in the slowly progressive form. These preliminary findings are the result of the first collaborative study of childhood diabetes in Japan.

The Length of the CTLA-4 Microsatellite (AT)N-Repeat Affects the Risk for Type 1 Diabetes: For the Swedish Childhood Diabetes Study Group

CTLA-4 is important to down-regulating T cell responses and has been implicated in type 1 (insulin dependent) diabetes mellitus in both linkage and association studies. The aim of our study was to relate the polymorphic (AT)n microsatellite in the 3′ untranslated sequence of the CTLA-4 gene to diabetes risk. We studied 616 consecutively diagnosed 0-34 year-old Swedish patients and 502 matched controls by PCR-based genotyping to determine the length of the 3′-end (AT)n repeat region of the CTLA-4 gene and categorizing alleles as predominantly monomorphic short (S) or highly polymorphic (in length) long (L) alleles. The odds of type 1 diabetes of subjects with the L/L genotype was estimated to be 1.84 times that of subjects with the S/S genotype (95% CI 1.44-2.73, p=0.002). Further analysis of the long alleles, partitioned into intermediate (I) length and very long (VL) alleles, suggested that L alleles act recessively in conferring diabetes risk (p=0.0009). This study suggests that the 3′-end (AT)n repeat region of the CTLA-4 gene represents a recessive risk factor for type 1 diabetes