Epidemiology of Type 2 Diabetes Mellitus in the Gila River Indian Community

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Samples and data are analyzed from a longitudinal population study conducted from 1965 to 2007 that allows study of the risk factors and effects of diabetes mellitus. Risk factors for obesity, hypertension, and nephropathy are also studied, along with the relationships of these diseases to diabetes and their effects on development of vascular complications and mortality. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. These findings are reported in DK069028 (Genetic epidemiology of diabetes and obesity) and DK069094 (Genetic epidemiology of diabetic complications). Findings related to kidney complications of diabetes are reported in DK069062 (Epidemiology, pathophysiology and treatment of diabetic nephropathy). Here we summarize other findings published this fiscal year from this study and from other studies of the epidemiology of type 2 diabetes and obesity. One-hour plasma glucose in the glucose tolerance test. It has been proposed that the one-hour plasma glucose (1-h PG) during the oral glucose tolerance test (OGTT) is an accurate predictor of type 2 diabetes and can be used instead of the two-hour glucose (2-h PG). This could have the advantage of making the test shorter and more acceptable to patients. We performed a meta-analysis to determine the optimum cutoff of 1-h PG for detection of type 2 diabetes using 2-h PG as the gold standard. Data from this study were included among 15 studies with 35,551 participants from multiple ethnic groups (53.8% Caucasian) and 2,705 newly detected cases of diabetes based on 2-h PG during OGTT. We excluded cases identified only by elevated fasting plasma glucose and/or HbA1c. We determined the optimal 1-h PG threshold and its accuracy at this cutoff for detection of diabetes (2-h PG 11.1 mmol/L) using a mixed linear effects regression model with different weights to sensitivity/specificity (2/3, 1/2, and 1/3). Three cutoffs of 1-h PG, at 10.6 mmol/L, 11.6 mmol/L, and 12.5 mmol/L, had sensitivities of 0.95, 0.92, and 0.87 and specificities of 0.86, 0.91, and 0.94 at weights 2/3, 1/2, and 1/3, respectively. The cutoff of 11.6 mmol/L (95% CI 10.6, 12.6) had a sensitivity of 0.92 (0.87, 0.95), specificity of 0.91 (0.88, 0.93), area under the curve 0.939 (95% confidence region for sensitivity at a given specificity: 0.904, 0.946), and a positive predictive value of 45%. In conclusion, the 1-h PG of 11.6 mmol/L during OGTT has a good sensitivity and specificity for detecting type 2 diabetes as conventionally defined by the 2-h PG. Genetics of obesity. Studies of the genetics of obesity, diabetes, and its complications in this study population are included in other reports. In one example of the ongoing effort to identify the genetic variation that contributes to obesity in American Indians, known Bardet-Biedl syndrome (BBS) genes were analyzed for an effect on BMI and leptin signaling in participants in the Gila River Indian Community study. Potentially deleterious variants (Combined Annotation Dependent Depletion score > 20) in BBS genes were identified in whole-exome sequence data from 6,851 American Indians informative for BMI. Common variants (detected in 10 individuals) were analyzed for association with BMI; rare variants (detected in < 10 individuals) were analyzed for mean BMI of carriers. Functional assessment of variants' effect on signal transducer and activator of transcription 3 (STAT3) activity was performed in vitro. Potentially functional variants in BBS genes in American Indians are reported. However, functional evidence supporting a causal role for BBS9 in obesity is inconclusive. Refined typing of the HLA system. While the samples and data from the Pima Indians of the Gila River Indian Community have been included in many international HLA workshops and conferences and have been the focus of numerous population reports and the source of novel alleles at the classical HLA loci, they have not been studied for the non-classical loci. In order to expand our HLA-disease association studies, we typed over 300 whole genome sequences from full Pima heritage members, controlled for first degree relationship, and employed recently developed computer algorithms to resolve HLA alleles. Both classical-HLA-A, -B, and -C- and non-classical- HLA-E, -F, -G, -J, -L, -W, -Y, -DPA2, -DPB2, -DMA, -DMB, -DOA, -DRB2, -DRB9, TAP1- loci were typed at the 4-field level of resolution. We present allele and selected haplotype frequencies, test the genotype distributions for population structure, discuss the issues that are created for tests of Hardy-Weinberg equilibrium over the four sample spaces of high resolution HLA typing, and address the implications for the evolution of non-classical pseudogenes that are no longer expressed in a phenotype subject to natural selection. Epidemiology and pathophysiology of diabetic kidney disease (DKD). Prospective studies in informative populations are crucial to increasing our knowledge of disease. We published a review of a half century of studies in an American Indian population that transformed our understanding of kidney disease in type 2 diabetes, now recognized as the leading cause of kidney failure worldwide. Serial examinations conducted for many years that included the collection of data and samples across multiple domains captured an unprecedented volume of clinical, physiologic, morphometric, genomic, and transcriptomic data. This work permitted us to extensively characterize the course and determinants of diabetic kidney disease, its pathophysiologic underpinnings, and important secular trends of urgent concern to populations worldwide, including the emergence of youth-onset type 2 diabetes and its effect on development of diabetic kidney disease in midlife. By combining these data using the tools of integrative biology, we are developing new mechanistic insights into the development and progression of diabetic kidney disease in type 2 diabetes. These insights have already contributed to the identification and successful therapeutic targeting of a novel pathway in DKD. We anticipate that this work will continue to expand our understanding of this complex disease and influence its management in the coming years.