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Analysis of the Type 2 Diabetes-Associated Single Nucleotide Polymorphisms in the Genes IRS1, KCNJ11, and PPARG2 in Type 1 Diabetes
Abstract and Figures
It has been proposed that type 1 and 2 diabetes might share common pathophysiological pathways and, to some extent, genetic background. However, to date there has been no convincing data to establish a molecular genetic link between them. We have genotyped three single nucleotide polymorphisms associated with type 2 diabetes in a large type 1 diabetic family collection of European descent: Gly972Arg in the insulin receptor substrate 1 (IRS1) gene, Glu23Lys in the potassium inwardly-rectifying channel gene (KCNJ11), and Pro12Ala in the peroxisome proliferative-activated receptor gamma2 gene (PPARG2). We were unable to confirm a recently published association of the IRS1 Gly972Arg variant with type 1 diabetes. Moreover, KCNJ11 Glu23Lys showed no association with type 1 diabetes (P > 0.05). However, the PPARG2 Pro12Ala variant showed evidence of association (RR 1.15, 95% CI 1.04-1.28, P = 0.008). Additional studies need to be conducted to confirm this result.
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... We found that people with diabetes were more likely to develop depressive symptoms, which was consistent with previous studies (Eftychi et al., 2004;Moulton et al., 2015;Scherrer et al., 2011). On the one hand, epidemiology interpretation for this link indicated that depressive symptoms and diabetes shared similar environmental and lifestyle factors, including childhood adversity experience, socioeconomic deprivation, and reduced physical activity (Moulton et al., 2015). ...
... On the other hand, biological pathways evidence suggested diabetes led to depression by causing abnormalities in neurotransmitter metabolism, through an effect of hyperglycemia or via the altered glucose transport (Anderson et al., 2001;Engum, 2007;Renn et al., 2011). Diabetes also resulted in inflammatory processes and reductions in neurotrophic function, which in turn reduced plasticity of neuronal networks and subsequent depression (Eftychi et al., 2004;Scherrer et al., 2011). ...
Background:
Co-morbid diabetes and depression is common; however, little evidence was regarding the effect of education on this association. This study aimed to investigate the role of education in the effect of diabetes on depressive symptoms in China.
Methods:
We used data from the China Health and Retirement Longitudinal Study, including 6,921 participants free from depressive symptoms in three waves of cohort study from 2011. We assessed the depressive symptoms based on Center for Epidemiological Studies-Depression scale. We fitted Cox proportional hazards regression models to examine the effect of baseline diabetes on the subsequent depressive symptoms.
Results:
Participants with diagnosed diabetes were more likely than their nondiabetic peers to develop depressive symptoms only in 45-64 years group, with a hazard ratio of 1.30 (95% CI: 1.05, 1.61). In addition, the effect of diagnosed diabetes on depressive symptoms only occurred in participants with a diploma of primary school or below.
Limitations:
Information was unavailable may offer additional explanatory power.
Conclusion:
Our findings suggested that diagnosed diabetes was a chronic stressor in developing depressive symptoms, and that response to this stressor varied by individuals' educational attainment. Action to prevent and treat diabetes may contribute to the fight against depressive symptoms, especially in the lower-education population.
... Consequently, some researchers focused on the genetics of T1D while others on the genetics of T2D. Usually, pediatric patients were selected for T1D studies [11,12], while for T2D predominantly adult and obese patients were selected. Such a "black and white" vision of diabetes phenotypes led to a tendency in highlighting mainly the differences between the two phenotypes. ...
... Moreover, the restrictive selection of patients enrolled in these genetic studies excluded almost all patients with diabetes onset between 20 and 40 years, whose separate analysis could have provided some useful information for a new thinking regarding the classification of diabetes. "Intermediary" or "secondary insulin dependent" diabetes [13], known better as "Latent Autoimmune Diabetes in Adults-LADA" [14][15][16][17][18][19][20][21], placed a grey zone in-between the two major phenotypes, which later proved to be associated both with classic T1D and T2D genes [11,[22][23][24][25][26][27]. ...
Genome-wide association studies (GWAS) published in the last decade raised the number of loci associated with type 1 (T1D) and type 2 diabetes (T2D) to more than 50 for each of these diabetes phenotypes. The environmental factors seem to play an important role in the expression of these genes, acting through transcription factors that bind to promoters. Using the available databases we examined the promoters of various genes classically associated with the two main diabetes phenotypes. Our comparative analyses have revealed significant architectural differences between promoters of genes classically associated with T1D and T2D. Nevertheless, five gene promoters (about 16%) belonging to T1D and six gene promoters (over 19%) belonging to T2D have shown some intermediary structural properties, suggesting a direct relationship to either LADA (Latent Autoimmune Diabetes in Adults) phenotype or to non-autoimmune type 1 phenotype. The distribution of these promoters in at least three separate classes seems to indicate specific pathogenic pathways. The image-based patterns (DNA patterns) generated by promoters of genes associated with these three phenotypes support the clinical observation of a smooth link between specific cases of typical T1D and T2D. In addition, a global distribution of these DNA patterns suggests that promoters of genes associated with T1D appear to be evolutionary more conserved than those associated with T2D. Though, the image based patterns obtained by our method might be a new useful parameter for understanding the pathogenetic mechanism and the diabetogenic gene networks.
... To date, more than 60 risk-associated loci have been identified for T1D [25][26][27], and for T2D more than 400 [28]. Increasing evidence is pointing towards a partial genetic overlap between T1D and T2D [29][30][31][32][33]. One of the most well-documented loci that are associated with both T1D and T2D is GLIS3, which encodes the GLIS family zinc finger 3. ...
Purpose of review:
Diabetes is a spectrum of clinical manifestations, including latent autoimmune diabetes in adults (LADA). However, it has been questioned whether LADA exists or simply is a group of misclassified type 1 diabetes (T1D) and type 2 diabetes (T2D) patients. This review will provide an updated overview of the genetics of LADA, highlight what genetics tell us about LADA as a diabetes subtype, and point to future directions in the study of LADA.
Recent findings:
Recent studies have verified the genetic overlap between LADA and both T1D and T2D and have contributed identification of a novel LADA-specific locus, namely, PFKFB3, and subtype-specific signatures in the HLA region. Genetic risk scores comprising T1D-risk variants have been shown to be a promising tool for discriminating diabetes subtypes and identifying patients rapidly progressing to insulin dependence. Genetic data support the existence of LADA, but further studies are needed to fully determine the place of LADA in the diabetes spectrum.
... Depression and diabetes have a moderate genetic correlation of r=0.19 (albeit with a broad CI of 0-0.46) [69] whereas various type 2 diabetes related single nucleotide polymorphisms have been associated with depression and type 2 diabetes independently. [70,71] Preliminary evidence suggests that adaptations to the in-utero environment could drive so called metabolic ageing and predispose patients to depression, potentially via epigenetic mechanisms such as DNA methylation marks. [72] Low birth weight followed by accelerated weight gain in childhood has large effects on incidence of type 2 diabetes in later life [73] and a metaanalysis [74] showed a statistically significant association between low birth weight and later depression. ...
Type 2 diabetes mellitus (T2DM) and depression are expected to be amongst the top five causes of disease burden by the year 2030. The relationship between endocrine disturbances and psychiatric conditions has intrigued many for decades. Current researches suggest a bi-directional relationship between T2DM and depression, and, the two disorders may share similar pathophysiological mechanisms. There have been studies suggesting causal pathways between T2DM and depression. Depression was associated with a 60% increase of T2DM while T2DM was associated with 15% risk of depression. Few studies have evaluated the impact of specific antidepressant therapies on glycemic control in people with diabetes. Also, it has been reported that integrated management of T2DM and depression improves medication adherence. However, no specific guidelines have been established regarding treatment of patients with comorbid T2DM and depression. The present article is an endeavor to investigate the underlying mechanisms and treatment modalities for people suffering with comorbid T2DM and depression; thereby bringing to light hitherto unexplored arenas in this field.
... Quite a few genetic variants in the PPARg2 gene have been identified which include Pro115Gln, Val290Met, Pro467Leu and the highly prevalent Pro12Ala polymorphism in PPARg2. 11,12 The Pro12Ala polymorphism is the result of a CCA-to-GCA missense mutation in codon 12 of exon B of the PPARg2. 13 Single nucleotide polymorphism (SNPs) related to PPARg2 gene have been reported on certain populations from Europe, North America and in Asia, 11,14,15 and SNP like Pro12Ala have been found to be well associated with PPARg2 gene. ...
Diabetes is one of the most fatal and vastly heritable metabolic disorders across the globe primarily due to the associated long-term effects including uncontrolled blood sugar levels, blindness, renal and cardiac problems. One of the diabetes related genes peroxisome proliferated activated receptor gamma 2 (PPARγ2) plays significant role in insulin metabolism and is expressed predominantly in adipose tissues. Single nucleotide polymorphism (SNPs) like Pro12Ala, is known to be associated with PPARγ2 gene. In this study, we have made an effort to investigate the prevalence of Pro12Ala allele in the diabetic population of Guwahati, Assam. A total of 50 human subjects with control subjects were included in the study. The data obtained revealed that 49 out of 50 samples carried the Pro/Pro allele, while 1 individual carried the Pro/Ala allele. Results obtained in the study indicate the existence of insignificant link between the targeted SNP Pro12Ala and type 2 diabetes in the sampled population, whereas in contrast we found a strong association of the SNP Pro12Pro with diabetes. The present study shows that there is a need to carry out an extensive study with a large population, which would give us the better picture of occurrence of this SNP in Northeast Indian population.
ONECUT1 gene, encoding hepatocyte nuclear factor 6, is involved in pancreas and liver development. ONECUT1 mutations impair the function of pancreatic β-cells and control a transcriptional/epigenetic machinery regulating endocrine development. Homozygous nonsense and missense mutations at ONECUT1_p.E231 and a homozygous frameshift mutation at ONECUT1_p.M289 were reported in neonatal diabetes individuals of French, Turkish, and Indian ethnicity, respectively. Additionally, heterozygous variants were observed in Northern European T2D patients, and Italian patients with neonatal diabetes and early-/late-onset T2D. Examining diverse populations, such as Arabs known for consanguinity, can generalize the ONECUT1 involvement in diabetes. Upon screening the cohorts of Kuwaiti T1D and MODY families, and of Kuwaiti and Qatari T2D individuals, we observed two homozygous variants—the deleterious missense rs202151356_p.H33Q in one MODY, one T1D, and two T2D individuals, and the synonymous rs61735385_p.P94P in two T2D individuals. Heterozygous variants were also observed. Examination of GTEx, NephQTL, mQTLdb and HaploReg highlighted the rs61735385_p.P94P variant as eQTL influencing the tissue-specific expression of ONECUT1, as mQTL influencing methylation at CpG sites in and around ONECUT1 with the nearest site at 677-bases 3′ to rs61735385_p.P94P; as overlapping predicted binding sites for NF-kappaB and EBF on ONECUT1. DNA methylation profiles of peripheral blood from 19 MODY-X patients versus eight healthy individuals revealed significant hypomethylation at two CpG sites—one located 617-bases 3′ to the p.P94P variant and 8,102 bases away from transcription start; and the other located 14,999 bases away from transcription start. Our study generalizes the association of ONECUT1 with clinical diversity in diabetes.
There is evidence pointing towards shared etiological features between type 1 diabetes (T1D) and type 2 diabetes (T2D) despite both phenotypes being considered genetically distinct. However, the existence of shared genetic features for T1D and T2D remains complex and poorly defined. To better understand the link between T1D and T2D, we employed an integrated functional genomics approach involving extensive chromatin interaction data (Hi-C) and expression quantitative trait loci (eQTL) data to characterize the tissue-specific impacts of single nucleotide polymorphisms associated with T1D and T2D. We identified 195 pleiotropic genes that are modulated by tissue-specific spatial eQTLs associated with both T1D and T2D. The pleiotropic genes are enriched in inflammatory and metabolic pathways that include mitogen-activated protein kinase activity, pertussis toxin signaling, and the Parkinson’s disease pathway. We identified 8 regulatory elements within the TCF7L2 locus that modulate transcript levels of genes involved in immune regulation as well as genes important in the etiology of T2D. Despite the observed gene and pathway overlaps, there was no significant genetic correlation between variant effects on T1D and T2D risk using European ancestral summary data. Collectively, our findings support the hypothesis that T1D and T2D specific genetic variants act through genetic regulatory mechanisms to alter the regulation of common genes, and genes that co-locate in biological pathways, to mediate pleiotropic effects on disease development. Crucially, a high risk genetic profile for T1D alters biological pathways that increase the risk of developing both T1D and T2D. The same is not true for genetic profiles that increase the risk of developing T2D. The conversion of information on genetic susceptibility to the protein pathways that are altered provides an important resource for repurposing or designing novel therapies for the management of diabetes.
Diabetes is a multifactorial disease, caused by a complex interplay between environmental and genetic risk factors. Genetic determinants of particularly type 1 diabetes (T1D) and type 2 diabetes (T2D) have been studied extensively, whereas well-powered studies of latent autoimmune diabetes in adults (LADA) are lacking. So far available studies support a clear genetic overlap between LADA and T1D, however, with smaller effect sizes of the T1D-risk variants in LADA as compared to T1D. A genetic overlap between LADA and T2D is less clear. However, recent studies, including large numbers of LADA patients, provide different lines of evidence to support a genetic overlap between T2D and LADA. The genetic predisposition to LADA is yet to be explored in a study design, like a genome-wide association study, which allows for analyses of the genetic predisposition independently of prior hypothesis about potential candidate genes. This type of study may facilitate the discovery of risk variants associated with LADA independently of T1D and T2D, and is central in order to determine if LADA should be considered as an independent diabetic subtype. Extended knowledge about the genetic predisposition to LADA may also facilitate stratification of the heterogeneous group of LADA patients, which may assist the choice of treatment. This mini-review summarizes current knowledge of the genetics of LADA, and discusses the perspectives for future studies.
Diabetes can be considered as a spectrum with type 1 diabetes mellitus (T2DM) and type 2 diabetes mellitus (T2DM) as two ends of the spectrum, and maturity-onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), and other types being the intermediates. T2DM is characterized by impaired insulin secretion, insulin resistance, or both, and is caused by the intricate interplay between genetic, epigenetic, and environmental factors. The current understanding of the genetic architecture of T2DM indicates a combination of common single-nucleotide polymorphisms (SNPs), rare variants, parent-of-origin effects, structural polymorphisms, and microRNAs, which can further be complicated by gene–gene and gene–environment interactions. The technical revolution in the form of genome-wide association studies and next-generation sequencing has allowed the identification of >100 genetic variants associated with or protecting from T2DM and diabetes-related traits. Reported SNPs account for <20% of the heritability of T2DM. There may be several reasons for these shortcomings: too simple assumptions about the genetic architecture of the disease, ignoring additive and intrauterine effects, and restricting the analysis to only SNPs associated at 5 × 10−8. To describe the full genetic architecture of T2DM, a systems genetic approach will be needed, combining GWAS, DNA methylation, histone modifications, and expression profiling, including mRNA, proteins, and metabolites in target tissues for T2DM.
The peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. The PPARγ1 and γ2 isoforms result from alternative splicing and have ligand-dependent and -independent activation domains. PPARγ2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5-10-fold more effective than that of PPARγ1. Insulin stimulates the ligand-independent activation of PPARγ1 and γ2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARγ2 in human adipocytes. Here, we report that a relatively common Pro12Ala substitution in PPARγ2 is associated with lower body mass index (BMI; P=0.027; 0.015) and improved insulin sensitivity among middle-aged and elderly Finns. A significant odds ratio (4.35, P=0.028) for the association of the Pro/Pro genotype with type 2 diabetes was observed among Japanese Americans. The PPARγ2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARγ2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.
To test the hypothesis that the genetic susceptibility to non-insulin dependent diabetes mellitus is the same as that to insulin dependent disease and to see whether glucose intolerance is associated with specific HLA haplotypes.
Population based study of men in 1989 first tested for glucose tolerance in 1984. HLA haplotypes, including HLA-A, C, B, DR, and DQ, were defined serologically. HLA haplotype data from a population based Finnish study of childhood diabetes were used for predicting non-insulin dependent diabetes and impaired glucose tolerance.
Two communities in Finland.
Representative cohort of Finnish men aged 70-89, comprising 98 men with non-insulin dependent diabetes mellitus and a randomly selected group of 74 men, who served as controls, who were tested for glucose tolerance twice within five years.
Non-insulin dependent diabetes, impaired glucose tolerance, blood glucose concentration.
Diabetes associated HLA haplotypes were present in 94% (85/90) of diabetic subjects, 79% (27/34) of subjects with impaired glucose tolerance, and only 13% (3/23) of non-diabetic subjects. In this group of elderly men sensitivity of the diabetes associated HLA haplotypes for non-insulin dependent diabetes and impaired glucose tolerance was 90%, specificity 87%, and predictive power 97%. Mean fasting blood glucose concentration was only just significantly higher in men with diabetes associated haplotypes than in men with no such haplotypes, but there was a substantial difference in blood glucose values two hours after glucose loading (10.4 and 6.4 mmol/l in men with diabetes associated HLA haplotypes and men with no such haplotypes, respectively (p < 0.0001)).
These findings support the hypothesis that specific HLA haplotypes exhibit a common genetic determinant for insulin dependent and non-insulin dependent diabetes. Furthermore, HLA is a major genetic determinant of glucose intolerance in elderly Finnish men. The belief that the HLA predisposition to diabetes is specific for insulin dependent diabetes mellitus is largely incorrect.
During the period 1989–1994, 462 cases of insulin-dependent diabetes mellitus were registered among children from Northern Ireland aged under 15 years. The estimated completeness of the register was 98.8% (95% confidence interval (CI) 97.7%, 99.9%). A standardised rate of 19.6 (95% CI 17.8, 21.4) per 100 000 person years was obtained, placing Northern Ireland near the top of the range of published incidence in the United Kingdom, with a rate close to that reported for Scotland. In an analysis based on 217 postcode sectors, areas with a high population density and the most material deprivation were observed to have the lowest incidence rates. After inclusion of population density in a Poisson regression analysis, the component of deprivation which was found to be most significant was household crowding. Relative to children living in areas of low population density, there was a reduced risk for children in medium (relative incidence 0.85 (95% confidence limits CI 0.67,1.09)) and high (0.62 (95% CI 0.48,0.80)) population density areas. Similarly, relative to children living in areas with low levels of household crowding, there was a reduced risk for children in medium (relative incidence 0.73 (95% CI 0.58,0.93)) and high (0.67 (95%CI 0.53,0.83)) levels of household crowding. Tests for space-time clustering at diagnosis and at birth were negative. A possible explanation for the differences in incidence rate observed in this study is that exposure to infections very early in childhood is a protective factor. Later infections may act as either initiators or promoters of diabetes, but the absence of space-time clustering suggests that no single specific infectious agent is responsible.
A nationwide study of childhood Type 1 (insulin-dependent) diabetes mellitus was established in 1986 in Finland, the country with the highest incidence of this disease worldwide. The aim of the project called "Childhood Diabetes in Finland" is to evaluate the role of genetic, environmental and immunological factors and particularly the interaction between genetic and environmental factors in the development of Type 1 diabetes. From September 1986 to April 1989, 801 families with a newly-diagnosed child aged 14 years or younger at the time of diagnosis were invited to participate in this study. The vast majority of the families agreed to participate in the comprehensive investigations of the study. HLA genotypes and haplotypes were determined in 757 families (95%). Our study also incorporates a prospective family study among non-diabetic siblings aged 3-19 years, and two case-control studies among the young-onset cases of Type 1 diabetes. During 1987-1989, the overall incidence of Type 1 diabetes was about 35.2 per 100,000 per year. It was higher in boys (38.4) than in girls (32.2). There was no clear geographic variation in incidence among the 12 provinces of Finland. Of the 1,014 cases during these 3 years only six cases were diagnosed before their first birthday. The incidence was high already in the age group 1-4-years old: 33.2 in boys and 29.5 in girls. Of the 801 families 90 (11.2%) were multiple case families, of which 66 had a parent with Type 1 diabetes at the time of diagnosis of the proband.(ABSTRACT TRUNCATED AT 250 WORDS)
It is merely necessary to delete or ignore irrelevant members and, in the remainder, to cross out any genotypes inconsistent with the tests. The probabilities for both individuals and for their descendants are then modified so that the various genotypes sum to one (Figs. 3 and 4). It may be helpful to specify the sexes by adding the traditional arrow and cross symbols to define sex; although irrelevant to the results, this makes documentation clearer. We have assumed, for simplicity, the approximate round numbers of an incidence of 1/1,600, and a carrier proportion of 1/20 as well as a most common affected allele which is assumed to represent three-quarters of the mutant alleles and is capable of definitive detection or exclusion on testing. These values are similar to those published for Scotland: heterozygote frequencies have been inferred from the homozygote frequency, although, because of heterogeneity, this will be an underestimate and the biasses are too complicated to justify the complication of unrounded numbers. As more alleles come to be within range of tests, they can be grouped together and combined for purposes of prediction so that the only changes needed to the diagram are those derived from the combined gene frequency of the group of testable alleles. A copy of the drawing program, in Macdraft, is available on receipt of a disk formatted for a Macintosh.
From July 1, 1977 to July 1, 1986, 3,503 incident cases of Type 1 (insulin-dependent) diabetes mellitus were registered in the Swedish childhood diabetes study. Using data from this register and from a case-referent study, including all incident Type 1 diabetic children in Sweden during one year and, for each patient, two referent children matched according to age, sex and county, we have studied the associations between Type 1 diabetes and familial Type 1 and Type 2 (non-insulin-dependent) diabetes, thyroid, adrenal, allergic, rheumatic, heart and bowel disease. The mean annual incidence per 100,000 during the nine year period was 25.1 for boys and 23.5 for girls. In 8.5% of the patients, one parent had Type 1 diabetes, 73% of whom were fathers. Fifty-six of the patients (1.7%) had a parent with Type 2 diabetes. The prevalence of parental Type 1 diabetes tended to be higher in patients with younger age at onset; whereas, the opposite was found for patients with parental Type 2 diabetes. In the case-referent study, the age-adjusted odds ratio for Type 1 diabetes when a first and/or second degree relative had Type 1 diabetes was 5.5 (95% confidence limits 4.0-7.7), and in accordance with the findings of the case register, the odds ratio tended to be highest in patients with the youngest age at onset. Season at onset of the patients was not associated with parental Type 1 diabetes. The odds ratio for Type 1 diabetes was significantly increased 3.3 (95% confidence limits: 2.3-4.6) when Type 2 diabetes was reported in relatives (three generations).(ABSTRACT TRUNCATED AT 250 WORDS)
During the period 1989-1994, 462 cases of insulin-dependent diabetes mellitus were registered among children from Northern Ireland aged under 15 years. The estimated completeness of the register was 98.8% (95% confidence interval (CI) 97.7%, 99.9%). A standardised rate of 19.6 (95% CI 17.8, 21.4) per 100 000 person years was obtained, placing Northern Ireland near the top of the range of published incidence in the United Kingdom, with a rate close to that reported for Scotland. In an analysis based on 217 postcode sectors, areas with a high population density and the most material deprivation were observed to have the lowest incidence rates. After inclusion of population density in a Poisson regression analysis, the component of deprivation which was found to be most significant was household crowding. Relative to children living in areas of low population density, there was a reduced risk for children in medium (relative incidence 0.85 (95% confidence limits CI 0.67, 1.09)) and high (0.62 (95% CI 0.48,0.80)) population density areas. Similarly, relative to children living in areas with low levels of household crowding, there was a reduced risk for children in medium (relative incidence 0.73 (95% CI 0.58,0.93)) and high (0.67 (95% CI 0.53, 0.83)) levels of household crowding. Tests for space-time clustering at diagnosis and at birth were negative. A possible explanation for the differences in incidence rate observed in this study is that exposure to infections very early in childhood is a protective factor. Later infections may act as either initiators or promoters of diabetes, but the absence of space-time clustering suggests that no single specific infectious agent is responsible.
We review the strategy used to identify a susceptibility locus (IDDM2) for type 1 (insulin dependent) diabetes mellitus. As type 1 diabetes is becoming the paradigm for dissecting multifactorial disease genetics, the approach described provides important general guidelines for positional cloning of human disease polygenes. Main topics include: (a) historical conspectus of the mapping and identification of IDDM2--a critical survey of the work leading up to the conclusion that IDDM2 most likely corresponds to allelic variation at the insulin gene minisatellite (VNTR) locus; (b) the nature of allelic (length and sequence) variation at the VNTR locus; (c) gene interactions and disease pathogenesis; (d) mechanism of action of the INS VNTR in type 1 diabetes--insulin gene expression, parent-of-origin effects (genomic imprinting); and (e) summary and future prospects--alleles of the insulin VNTR that are protective for type 1 diabetes appear to encode susceptibility to type 2 diabetes.