Early-onset Diabetes Research Articles

Type 1 Diabetes in Children and Adolescents.

Type 1 Diabetes in Children and Adolescents.

Longitudinal Study of Rhesus Monkeys Determines That Amylase and Lipase Levels Are Significant Risk Factors for Type 2 Diabetes Mellitus

Decreased levels of amylase have been reported in type 2 diabetes (T2DM), however, longitudinal within subject study ranging from healthy normal levels to preT2DM and overt DM has not previously been conducted in humans or in nonhuman primates. Rhesus monkeys provide the ideal subjects for this study as they are maintained under constant dietary and environmental conditions, and have, to date, been shown to have the same gastrointestinal/pancreas physiology and pathophysiology as humans. They frequently develop T2DM spontaneously and naturally, with no experimental intervention, and with life time rates of T2DM estimated to be 20 to 30 %. Adult rhesus monkeys were studied for a minimum of 3 years and a maximum of 20 years, with a minimum of 2 metabolic parameter measurements per year. These parameters included fasting plasma glucose (FPG), fasting plasma insulin (FPI), complete blood chemistry, and lipid profiles. Body fat was determined by the tritiated water dilution method or by the dual energy xray absorptiometry (DEXA). Insulin sensitivity was quantified by the euglycemic hyperinsulinemic clamp method. These parameters were used to identify the phases in the progression of monkeys from normal to overt diabetes as follows: normal = phases 1–3; metabolic syndrome = phases 4–6, impaired glucose tolerance= phase 7, and overt type 2 diabetes = phase 8. Diabetic monkeys requiring insulin treatment were excluded from this study. Human criteria were used to define MetSyn, IGT and T2DM. Normal healthy serum amylase levels were determined for the first time and shown to be 253 ±5.1 U/L for adults 7 to 11 yrs old (“human years” about 21 to 35 yrs), with normal lipase levels of 29.7± 1.6 U/L. Serum amylase levels declined with age by about 25%, with no change in serum lipase levels with age. In those that progressed through phases 4 to 8 reaching overt type 2 diabetes, serum amylase showed significantly greater declines from ages 13 to 20 yrs with progressive and parallel declines in metabolic parameters, including insulin sensitivity, and HDL cholesterol levels and increases in serum triglycerides and subsequently increases in fasting plasma glucose. The significant rise in serum triglycerides and the decline in amylase together serve as excellent early predictors of the progression to overt T2DM. These risk factors were highly predictive of both early and late onset diabetes. The lower amylase levels observed previously in people with diabetes were clearly not a consequence of diabetes, but were in fact markers of impending diabetes. Such biomarkers are likely to be useful in predicting the development of T2DM in patients years before the disease becomes overt.This study was carried out in accord with the FASEB principles for the use of animals in research.Support or Funding InformationThe work was supported by NIA N01AG31012 and NIA HHSN2532008002C to BCH, and the Department of Health Research, Government of India Human Resources Development Fellowship to UKC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Late adulthood mortality among African-American and white American people with Type 1 diabetes according to age at diabetes diagnosis.

To estimate the overall and cause-specific mortality in a population of African-Americans and white Americans with a low socio-economic status who had young-onset insulin-treated diabetes and had survived beyond the age of 40 years, and to examine whether any excess risk varied according to age at diabetes onset. Using the Southern Community Cohort Study, we conducted a mortality follow-up of a cohort of mostly low-income participants aged 40-79 years (mean 50 years) at cohort entry with insulin-treated diabetes diagnosed before age 30 years (n=475) and without diabetes (n=62 266). Childhood onset was defined as diabetes diagnosed before age 20 years (n=162), while young-adulthood onset was defined as diabetes diagnosed between ages 20 and 29 years (n=313). Cause-specific mortality was based on both underlying and contributing causes of death, obtained from death certificates. Multivariable Cox analysis was performed. During follow-up (mean 9.5 years), 38.7% of those with and 12.9% of those without diabetes died. Compared with those without diabetes, increases in mortality rate were generally similar among those with childhood- and young-adulthood-onset diabetes for deaths from: all causes (childhood: hazard ratio 4.3, CI 3.3-5.5; young adulthood: hazard ratio 4.9, CI 4.0-5.8); ischaemic heart disease (childhood: hazard ratio 5.7, CI 3.5-9.4; young adulthood: hazard ratio 7.9, CI 5.6-11.0); heart failure (childhood: hazard ratio 7.3, CI 4.2-12.7; young adulthood: hazard ratio 5.4, CI 3.3-8.9); sepsis (childhood: hazard ratio 10.3, CI 6.1-17.3; young adulthood: hazard ratio 8.8, CI 5.7-13.5); renal failure (childhood: hazard ratio 15.1, CI 8.6-26.5; young adulthood: hazard ratio 18.2, CI 12.3-27.1); respiratory disorders (childhood: hazard ratio 3.9, CI 2.3-6.7; young adulthood: hazard ratio 5.3, CI 3.7-7.7); suicide/homicide/accidents (childhood: hazard ratio 2.3, CI 0.72-7.0; young adulthood: hazard ratio 5.8, CI 3.4-10.2); and cancer (childhood: hazard ratio 2.1, CI 0.98-4.4; young adulthood: hazard ratio 1.2, CI 0.55-2.5). We observed high excess long-term mortality for all-cause, renal failure, ischemic heart disease and heart failure mortality in African-American and white American people with early-onset insulin-treated diabetes.

Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals

BackgroundDiagnosis of monogenic as well as atypical forms of diabetes mellitus has important clinical implications for their specific diagnosis, prognosis, and targeted treatment. Single gene mutations that affect beta-cell function represent 1–2% of all cases of diabetes. However, phenotypic heterogeneity and lack of family history of diabetes can limit the diagnosis of monogenic forms of diabetes. Next-generation sequencing technologies provide an excellent opportunity to screen large numbers of individuals with a diagnosis of diabetes for mutations in disease-associated genes.MethodsWe utilized a targeted sequencing approach using the Illumina HiSeq to perform a case-control sequencing study of 22 monogenic diabetes genes in 4016 individuals with type 2 diabetes (including 1346 individuals diagnosed before the age of 40 years) and 2872 controls. We analyzed protein-coding variants identified from the sequence data and compared the frequencies of pathogenic variants (protein-truncating variants and missense variants) between the cases and controls.ResultsA total of 40 individuals with diabetes (1.8% of early onset sub-group and 0.6% of adult onset sub-group) were carriers of known pathogenic missense variants in the GCK, HNF1A, HNF4A, ABCC8, and INS genes. In addition, heterozygous protein truncating mutations were detected in the GCK, HNF1A, and HNF1B genes in seven individuals with diabetes. Rare missense mutations in the GCK gene were significantly over-represented in individuals with diabetes (0.5% carrier frequency) compared to controls (0.035%). One individual with early onset diabetes was homozygous for a rare pathogenic missense variant in the WFS1 gene but did not have the additional phenotypes associated with Wolfram syndrome.ConclusionTargeted sequencing of genes linked with monogenic diabetes can identify disease-relevant mutations in individuals diagnosed with type 2 diabetes not suspected of having monogenic forms of the disease. Our data suggests that GCK-MODY frequently masquerades as classical type 2 diabetes. The results confirm that MODY is under-diagnosed, particularly in individuals presenting with early onset diabetes and clinically labeled as type 2 diabetes; thus, sequencing of all monogenic diabetes genes should be routinely considered in such individuals. Genetic information can provide a specific diagnosis, inform disease prognosis and may help to better stratify treatment plans.

Monogenic Diabetes Not Caused By Mutations in Mody Genes: A Very Heterogenous Group of Diabetes.

Monogenic diabetes represents a heterogeneous group of disorders resulting from a single gene defect leading to disruption of insulin secretion or a reduction in the number of beta cells. Despite the classification of monogenic diabetes into neonatal diabetes or maturity onset diabetes of the young (MODY) according to age of onset, not every case can be classified into those 2 groups. We evaluated patients with monogenic diabetes diagnosed during the last 10 year period. Type 1 DM, MODY, and patients with negative autoantibodies and no mutation in a known gene were excluded from the study. Thirteen patients were diagnosed with monogenic diabetes in Department of Pediatric Endocrinology, Ankara University School of Medicine, Ankara, Turkey. Five of them were diagnosed after 6 months of age. Five had a KATP channel defect. Mutations in genes resulting in destruction of beta cells were detected in 7 patients, with 4 cases having a WFS, 2 an LRBA, and one a IL2RA mutation. Additional systemic findings were seen in 6/13 patients, with 5/6 having severe immune system dysfunction. Treatment with sulphonylurea was successful in two patients.. The other patients were given insulin in differing doses. Four patients died during follow-up, three of which had immune system dysfunction. Monogenic diabetes can be diagnosed after 6 months of age, even with positive autoantibodies. Immune dysfunction was a common feature in our cohort and should be investigated in all patients with early-onset monogenic diabetes. Mortality of patients with monogenic diabetes and additional autoimmunity was high in our cohort and is likely to reflect the multisystem nature of these diseases.

Study on the impact of family history of diabetes among type 2 diabetes mellitus patients in an urban area of Kancheepuram district, Tamil Nadu

Background: Type 2 diabetes mellitus (T2DM) is a commonly occurring chronic non communicable disease. Family history of diabetes is one of the important non modifiable risk factor for occurrence of the disease. This study was done to assess the percentage of positive family history of diabetes among T2DM patients and its association with age of onset and complications of diabetes. Methods: This is a descriptive cross sectional study done in an urban health training centre of a medical college. Using purposive sampling technique, 215 diabetic patients were selected as study participants. Data collection was done by structured questionnaire. Data analysis was done using SPSS 17. Results: Among the study participants, 62.3% were females. The mean age of the participants was 56.08±10.04. Nearly 68.8% of T2DM patients had family history of Diabetes, among them 25.1% of them had diabetic mother and 15.3% had diabetic father. Among the study group of T2DM patients, 51.6% had diabetic complications. The family history of diabetes with age of onset and complications had statistically significant association among the study group. Conclusions: This study shows that persons with positive family history of diabetes are more prone to early onset of diabetes and developing complications. So appropriate behavioural changes and modification must be practiced to delay or prevent the occurrence of the disease. Early diagnosis and treatment is a must to prevent the complications in the vulnerable people.

Screening and Treatment for Early-Onset Gestational Diabetes Mellitus: a Systematic Review and Meta-analysis.

We conducted a systematic review to evaluate the current evidence for screening and treatment for early-onset gestational diabetes mellitus (GDM) RECENT FINDINGS: Many of the women with early GDM in the first trimester do not have evidence of hyperglycemia at 24-28weeks' gestation. A high proportion (15-70%) of women with GDM can be detected early in pregnancy depending on the setting, criteria used and screening strategy. However, there remains no good evidence for any of the diagnostic criteria for early-onset GDM. In a meta-analysis of 13 cohort studies, perinatal mortality (relative risk (RR) 3.58 [1.91, 6.71]), neonatal hypoglycemia (RR 1.61 [1.02, 2.55]), and insulin use (RR 1.71 [1.45, 2.03]) were greater among early-onset GDM women compared to late-onset GDM women, despite treatment. Considering the high likelihood of benefit from treatment, there is an urgent need for randomized controlled trials that investigate any benefits and possible harms of treatment of early-onset GDM.

NCB5OR Deficiency in the Cerebellum and Midbrain Leads to Dehydration and Alterations in Thirst Response, Fasted Feeding Behavior, and Voluntary Exercise in Mice

Cytosolic NADH-cytochrome-b5-oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues. We have previously reported that global ablation of NCB5OR in mice results in early-onset lean diabetes with decreased serum leptin levels and increased metabolic and feeding activities. The conditional deletion of NCB5OR in the mouse cerebellum and midbrain (conditional knock out, CKO mice) results in local iron dyshomeostasis and altered locomotor activity. It has been established that lesion to or removal of the cerebellum leads to changes in nutrient organization, visceral response, feeding behavior, and body weight. This study assessed whether loss of NCB5OR in the cerebellum and midbrain altered feeding or metabolic activity and had an effect on serum T3, cortisol, prolactin, and leptin levels. Metabolic cage data revealed that 16 week old male CKO mice had elevated respiratory quotients and decreased respiratory water expulsion, decreased voluntary exercise, and altered feeding and drinking behavior compared to wild-type littermate controls. Most notably, male CKO mice displayed higher consumption of food during refeeding after a 48-h fast. Echo MRI revealed normal body composition but decreased total water content and hydration ratios in CKO mice. Increased serum osmolality measurements confirmed the dehydration status of male CKO mice. Serum leptin levels were significantly elevated in male CKO mice while prolactin, T3, and cortisol levels remain unchanged relative to wild-type controls, consistent with elevated transcript levels for leptin receptors (short form) in the male CKO mouse cerebellum. Taken together, these findings suggest altered feeding response post starvation as a result of NCB5OR deficiency in the cerebellum.

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-β and Foxp3-expressing Treg cells. However, whether TGF-β and Treg cells are part of the same regulatory module, or exist largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-β receptor II (TβRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology. Ablation of the GM-CSF receptor alleviated the monocyte response and inhibited disease development. These findings reveal that TGF-β promotes T cell tolerance primarily via Foxp3-independent mechanisms and prevents autoimmunity in this model by repressing the cross talk between adaptive and innate immune systems.

The spectrum of mutations in the CEL gene in early onset diabetes patients

The spectrum of mutations in the CEL gene in early onset diabetes patients

NEUROD1-deficient diabetes (MODY6): Identification of the first cases in Japanese and the clinical features.

Only a few families with neuronal differentiation 1 (NEUROD1)-deficient diabetes, currently designated as maturity-onset diabetes of the young 6 (MODY6), have been reported, but mostly in Caucasian, and no mutation has been identified by family-based screening in Japanese. Accordingly, the phenotypic details of the disease remain to be elucidated. We examined a total of 275 subjects having diabetes suspected to be MODY who were negative for mutations in MODY1-5 referred from 155 medical institutions throughout Japan. So as not to miss low penetrant cases, we examined non-obese Japanese patients with early-onset diabetes regardless of the presence of family history by direct sequencing of all exons and flanking regions of NEUROD1 . Large genomic rearrangements also were examined. Four patients with 3 frameshift mutations and 1 missense mutation, all of which were heterozygous and 3 of which were novel, were identified. Diabetic ketosis was found occasionally in these patients even under conditions of chronic hyperglycemia, for unknown reasons. Although the capacity of early-phase insulin secretion was low in these patients, the insulin secretory capacity was relatively preserved compared to that in hepatocyte nuclear factor (HNF)1A- and HNF1B-MODY. One of the patients and 2 of their diabetic mothers were found to have some mental or neuronal abnormality. This is the first report of NEUROD1 mutations in Japanese, who have a genetic background of intrinsically lower capacity of insulin secretion. NEUROD1-deficient diabetes appears to be low penetrant, and may occur in concert with other genetic factors.

Abdominal obesity and type 2 diabetes in Asian Indians: dietary strategies including edible oils, cooking practices and sugar intake.

Obesity and type 2 diabetes are increasing in rural and urban regions of South Asia including India. Pattern of fat deposition in abdomen, ectopic fat deposition (liver, pancreas) and also low lean mass are contributory to early-onset insulin resistance, dysmetabolic state and diabetes in Asian Indians. These metabolic perturbations are further exacerbated by changing lifestyle, diet urbanization, and mechanization. Important dietary imbalances include increasing use of oils containing high amount of trans fatty acids and saturated fats (partially hydrogenated vegetable oil, palmolein oil) use of deep frying method and reheating of oils for cooking, high intake of saturated fats, sugar and refined carbohydrates, low intake of protein, fiber and increasing intake of processed foods. Although dietary intervention trials are few; the data show that improving quality of carbohydrates (more complex carbohydrates), improving fat quality (more monounsaturated fatty acids and omega 3 polyunsaturated fatty acids) and increasing protein intake could improve blood glucose, serum insulin, lipids, inflammatory markers and hepatic fat, but more studies are needed. Finally, regulatory framework must be tightened to impose taxes on sugar-sweetened beverages, oils such as palmolein, and dietary fats and limit trans fats.

Incidence of diabetes-related complications in Chinese patients with type 1 diabetes: a population-based longitudinal cohort study in Taiwan

ObjectiveTo estimate the incidence densities and cumulative incidence of diabetes-related complications in patients with type 1 diabetes for a maximum of 15-year follow-up. The estimations were further stratified by gender...

Can present biasedness explain early onset of diabetes and subsequent disease progression? Exploring causal inference by linking survey and register data

Diabetes is a major cause of morbidity, disability, mortality and health care resource use. The increasing prevalence of diabetes may therefore have dramatic future consequences for western societies. Diabetes entails a significant self-management component and it has previously been estimated that people with diabetes provide about 95% of their own care. Despite increased focus, self-management skills including basic knowledge acquisition, problem solving and setting realistic goals are often not mastered. The main contribution of this paper is to provide evidence that the heterogeneity in self-management and health outcomes amongst diabetes patients is partly attributable to individual differences in time-inconsistent preferences in terms of present biased behaviour. Using a unique data set consisting of survey data from 2014 merged with registry data on a sample of 79 chronically ill patients, we present empirical evidence that present biased individuals are more prone to onset of diabetes at an early age, and have a poorer prognosis after diagnosis. Furthermore, we conclude that present biasedness has a casual effect on the onset and management of diabetes.

A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions

Wolfram syndrome (WS) is a progressive neurodegenerative disease characterized by early-onset optic atrophy and diabetes mellitus, which can be associated with more extensive central nervous system and endocrine complications. The majority of patients harbour pathogenic WFS1 mutations, but recessive mutations in a second gene, CISD2, have been described in a small number of families with Wolfram syndrome type 2 (WFS2). The defining diagnostic criteria for WFS2 also consist of optic atrophy and diabetes mellitus, but unlike WFS1, this phenotypic subgroup has been associated with peptic ulcer disease and an increased bleeding tendency. Here, we report on a novel homozygous CISD2 mutation (c.215A > G; p.Asn72Ser) in a Moroccan patient with an overlapping phenotype suggesting that Wolfram syndrome type 1 and type 2 form a continuous clinical spectrum with genetic heterogeneity. The present study provides strong evidence that this particular CISD2 mutation disturbs cellular Ca2+ homeostasis with enhanced Ca2+ flux from the ER to mitochondria and cytosolic Ca2+ abnormalities in patient-derived fibroblasts. This Ca2+ dysregulation was associated with increased ER-mitochondria contact, a swollen ER lumen and a hyperfused mitochondrial network in the absence of overt ER stress. Although there was no marked alteration in mitochondrial bioenergetics under basal conditions, culture of patient-derived fibroblasts in glucose-free galactose medium revealed a respiratory chain defect in complexes I and II, and a trend towards decreased ATP levels. Our results provide important novel insight into the potential disease mechanisms underlying the neurodegenerative consequences of CISD2 mutations and the subsequent development of multisystemic disease.

The characteristics of newly diagnosed adult early-onset diabetes: a population-based cross-sectional study

To investigate the characteristics of newly diagnosed early-onset diabetes in the Chinese population, 2801 newly diagnosed diabetes participants without known diabetes or pre-diabetes in a national cross-sectional survey were analysed. Participants were divided into quartiles (22–43, 44–52, 53–61 and >61 years) according to age of diabetes onset and the first group were defined as early-onset diabetes group. Early-onset diabetes group had lower systolic blood pressure (SBP), total cholesterol, low density lipoprotein cholesterol, 2-hour post prandial blood glucose and urine albumin creatinine ratio. There was no difference in body mass index, Homeostasis model assessment (HOMA) of beta cell function and diabetes family history between early-onset diabetes participants and any other age groups. HOMA of insulin resistance (IR) scores and disposition index 30 minutes after glucose load (DI30) were increased in early-onset diabetes participants. The beta cell function declination was more deteriorated in early-onset diabetes participants. Male gender, triglycerides, HOMA-IR and DI30 were positively associated with an earlier age at diagnosis. In conclusion, patients diagnosed with diabetes at a younger age are characterized by a similar cardiovascular risk profile with increased insulin resistance and more severe beta cell failure than patients diagnosed at a later age.

IMAGe and Related Undergrowth Syndromes: The Complex Spectrum of Gain-of-Function CDKN1C Mutations.

CDKN1C is a cyclin-dependent kinase Inhibitor and negative regulator of cellular proliferation. Recently, gain-of-function mutations in the PCNA domain of CDKN1C have been reported as the genetic basis of various growth-retarded syndromes including IMAGe syndrome, Russell Silver syndrome as well as a novel undergrowth syndrome that additionally exhibited early adulthood onset diabetes. This review summarizes the key clinical features and the molecular advances that have contributed to our understanding of this complex phenotypic spectrum.

Effect of Salacia reticulata W. and Clitoria ternatea L. on the cognitive and behavioral changes in the streptozotocin-induced young diabetic rats.

Diabetes mellitus (DM) of juvenile onset affects both the peripheral and central nervous systems (CNS). However, central effects are less documented and studied than peripheral deficits. Currently, the only feasible treatment available for type 1 DM (T1DM) is insulin which has its own limitations. Hence, an alternative therapy, especially a newer herbal formulation is very much the need of the time. The present study aimed to determine the effects of the alcoholic extracts of roots of the Salacia reticulata W. (SR) and Clitoria ternatea L. (CT) on cognitive and behavioral changes in juvenile diabetic rats. Diabetes was induced in 25-day-old Wistar rats by streptozotocin (50 mg/kg bw, IP). Animals were divided into seven groups (n=6). Rats were treated with root extracts of SR and CT (100 mg/kg BW each) for 30 days, from day 1 and day 20 of diabetes confirmation. Then, rats were tested in elevated plus maze (EPM) and Morris water maze (MWM). A statistically significant (p<0.05) difference was observed between the SRCT group and diabetic groups of rats. Apart from decreasing FBS, the combined therapy also proved beneficial as nootropic agent in rats with early-onset diabetes. However, significant improvement is observed only in the learning and memory among preventive group, but not in the curative group. SRCT, a herbal formula, when used in combination, has a more potent effect in preventing the deleterious effects of juvenile diabetes on cognitive and behavioral changes.

Sulfonylurea challenge test in subjects diagnosed with type 1 diabetes mellitus.

Patients with early onset diabetes because of defects in glucose-stimulated insulin secretion (GSIS) may respond better to sulfonylureas than insulin treatment. Such patients include those with monogenic disorders, who can be differentiated from autoimmune type 1 diabetes mellitus (T1DM) by genetic testing. Genetic testing is expensive and unknown defects in GSIS would not be diagnosed. We propose a sulfonylurea challenge test to identify patients who have been clinically diagnosed with T1DM, but those who maintain a preferentially sulfonylurea-responsive insulin secretion. A total of 3 healthy controls, 2 neonatal diabetes mellitus (NDM) subjects, 3 antibody-positive (Ab+T1DM), and 12 antibody-negative (Ab-T1DM) subjects with type 1 diabetes, were given an intravenous bolus of glucose followed by an oral dose of glipizide. Healthy controls showed a robust C-peptide increase after both glucose and glipizide, but NDM subjects showed a large increase in C-peptide only following glipizide. As expected, 2 of 3 Ab+T1DM, as well as 11 of 12 Ab-T1DM showed no response to either glucose or glipizide. However, 1 Ab-T1DM and 1 Ab+T1DM showed a small C-peptide response to glucose and a marked positive response to glipizide, suggesting defects in GSIS rather than typical autoimmune diabetes. These data demonstrate the feasibility of the sulfonylurea challenge test, and suggest that responder individuals may be identified. We propose that this sulfonylurea challenge test should be explored more extensively, as it may prove useful as a clinical and scientific tool.

PROX1 gene CC genotype as a major determinant of early onset of type 2 diabetes in slavic study participants from Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation study.

Background:The prevalence of diabetic nephropathy varies according to ethnicity. Environmental as well as genetic factors contribute to the heterogeneity in the presentation of diabetic nephropathy. Our objective was to evaluate this heterogeneity within the Caucasian population.Methods:The geo-ethnic origin of the 3409 genotyped Caucasian type 2 diabetes (T2D) patients of Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation was determined using principal component analysis. Genome-wide association studies analyses of age of onset of T2D were performed for geo-ethnic groups separately and combined.Results:The first principal component separated the Caucasian study participants into Slavic and Celtic ethnic origins. Age of onset of diabetes was significantly lower in Slavic patients (P = 7.3 × 10−20), whereas the prevalence of hypertension (P = 4.9 × 10−31) and albuminuria (5.1 × 10−9) were significantly higher. Age of onset of T2D and albuminuria appear to have an important genetic component as the values of these traits were also different between Slavic and Celtic individuals living in the same countries. Common and geo-ethnic-specific loci were found to be associated to age of onset of diabetes. Among the latter, the PROX1/PROX1-AS1 genes (rs340841) had the highest impact. Single-nucleotide polymorphism rs340841 CC genotype was associated with a 4.4 year earlier onset of T2D in Slavic patients living or not in countries with predominant Slavic populations.Conclusion:These results reveal the presence of distinct genetic architectures between Caucasian ethnic groups that likely have clinical relevance, among them PROX1 gene is a strong candidate of early onset of diabetes with variations depending on ethnicity.