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). Knowledge of diabetes risk factors coming from this and other studies led to the hypothesis that type 2 diabetes could be prevented or delayed in adults at high short-term risk. This hypothesis was confirmed in the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial in which many of the participants and investigators in this project participated. We are now in a long-term follow-up phase, the Diabetes Prevention Program Outcomes Study (DPPOS), to assess long-term success with weight loss, reduction in the incidence of diabetes, and effects on diabetes complications. This study is reported in DK075078 (Prevention of type 2 diabetes). Environmental exposure to arsenic has been implicated as contributing to the risk of type 2 diabetes in other populations. We, therefore, examined effects of urinary concentrations of arsenic species on incident diabetes in a case-control study nested within the longitudinal population study. One-hundred-fifty nondiabetic subjects 25 years old who subsequently developed type 2 diabetes were matched for year of examination and sex to 150 controls who remained nondiabetic for 10 years. There was no significant linear association between urinary arsenic concentration and development of diabetes, but in a post-hoc analysis, persons in the top 3 quartiles of urinary arsenic concentration had 2.14 times the incidence of diabetes as those in the lowest quartile. Therefore, modestly elevated exposure to inorganic arsenic may predict type 2 diabetes in Southwestern American Indians. Larger studies that include measures of speciated arsenic are required for confirmation. We performed another nested case-control study to examine the relationship between serum concentrations of persistent organic pollutants (POPs). The case-control study included 300 persons without diabetes at baseline (median age=24 years);149 subjects subsequently developed diabetes (cases) and 151 remained non-diabetic during 10 years of follow-up (controls). POPs 37 polychlorinated biphenyls (PCBs) and 9 persistent pesticides (PSTs) were measured in serum collected in 1969-1974. Diabetes was diagnosed clinically or by a 2-hour oral glucose test. Odd ratios for diabetes were computed with logistic regression analysis for total PCBs (sum of the 37 congeners), the individual PCB congeners, and individual PSTs. Three of the POPs, PCB66, PCB151, and PCB195, were weakly but positively associated with development of diabetes. In this nested case-control study, we also measured 25-hydroxyergocalciferol 25(OH)D2, 25-hydroxycholecalciferol 25(OH)D3, and vitamin D binding protein. Half of the study participants (82 cases, 68 controls) were 25(OH)D deficient. Median 25(OH)D3 was 18 ng/ml in cases and 20 ng/ml in controls;25(OH)D2 was detectable in 12% of cases and 20% of controls. Odds ratio (OR) for incident diabetes in those with detectable vs. undetectable 25(OH)D2 was 0.50 (95% CI, 0.26-0.98) after adjustment for potential confounders. 25(OH) and vitamin D binding protein were not associated with incident diabetes. Detectable 25(OH)D2, derived from dietary sources, was associated with half the rate of incident type 2 diabetes in this population. Whether this finding is attributable to a direct beneficial effect of 25(OH)D2 or to a protective effect of a healthier diet in general remains to be determined. Other findings related to kidney complications of diabetes are reported in DK069062 (Epidemiology, pathophysiology and treatment of diabetic nephropathy).

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
Wheelock, Kevin M; Sinha, Madhumita; Knowler, William C et al. (2016) Metabolic Risk Factors and Type 2 Diabetes Incidence in American Indian Children. J Clin Endocrinol Metab 101:1437-44
Wheelock, K M; Fufaa, G D; Nelson, R G et al. (2016) Cardiometabolic risk profile based on body mass index in American Indian children and adolescents. Pediatr Obes :
Muller, Yunhua L; Piaggi, Paolo; Hanson, Robert L et al. (2015) A cis-eQTL in PFKFB2 is associated with diabetic nephropathy, adiposity and insulin secretion in American Indians. Hum Mol Genet 24:2985-96
Baier, Leslie J; Muller, Yunhua Li; Remedi, Maria Sara et al. (2015) ABCC8 R1420H loss-of-function variant in a Southwest American Indian community: association with increased birth weight and doubled risk of type 2 diabetes. Diabetes :
Muller, Yunhua L; Hanson, Robert L; Wiessner, Gregory et al. (2015) Assessing FOXO1A as a potential susceptibility locus for type 2 diabetes and obesity in American Indians. Obesity (Silver Spring) 23:1960-5
Chang, Douglas C; Piaggi, Paolo; Hanson, Robert L et al. (2015) Use of a High-Density Protein Microarray to Identify Autoantibodies in Subjects with Type 2 Diabetes Mellitus and an HLA Background Associated with Reduced Insulin Secretion. PLoS One 10:e0143551
Thearle, Marie S; Votruba, Susanne B; Piaggi, Paolo et al. (2015) The effect of differing patterns of childhood body mass index gain on adult physiology in American Indians. Obesity (Silver Spring) 23:1872-80
Votruba, Susanne B; Thearle, Marie S; Piaggi, Paolo et al. (2014) Weight maintenance from young adult weight predicts better health outcomes. Obesity (Silver Spring) 22:2361-9
Nair, Anup K; Muller, Yunhua Li; McLean, Nellie A et al. (2014) Variants associated with type 2 diabetes identified by the transethnic meta-analysis study: assessment in American Indians and evidence for a new signal in LPP. Diabetologia :
del Rosario, Melissa C; Ossowski, Vicky; Knowler, William C et al. (2014) Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: an analysis of genome-wide DNA methylation. Metabolism 63:654-60

Showing the most recent 10 out of 38 publications