Samples and data are analyzed from a longitudinal population study (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. The roles of obesity, serum insulin concentrations, impaired glucose regulation, occupational and leisure-time physical activity and diabetes in relatives are assessed. Findings on risk factors for diabetes are applied to a multicenter randomized clinical trial of prevention of type 2 diabetes that is currently in a long-term outcomes phase (the Diabetes Prevention Program Outcomes Study). Studies of the genetics of type 2 diabetes, obesity, and diabetes complications are described in other projects. 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. The DPPOS also began a genetics component to test whether genes with known or suspected effects on type 2 diabetes affected diabetes incidence in the DPP and interacted with study interventions. Treatment guidelines for diabetes have become increasingly stringent as most research shows that more aggressive intervention reduces risks for complications. Community data on the effect of these interventions is lacking. Changes in the pharmacologic treatment of diabetes, blood pressure and cholesterol in adults with diabetes were analyzed in the longitudinal population-based study of American Indians between 1975 and 2004. Major changes in community treatment patterns for diabetes and related conditions coincided with improvements in glycemia, blood pressure and cholesterol. In the Diabetes Prevention Program, metformin produced weight loss and delayed or prevented diabetes. We hypothesized that in the long-term extension of this randomized clinical trial (DPPOS), metformin would have a sustained weight loss effect that would be related to drug-taking adherence. During the DPPOS, the modest weight loss with metformin was durable through 10 years of treatment and was related to the degree of adherence to metformin. HbA1c is the standard measure of glycemic control for managing diabetes but not for diagnosis. Recently HbA1c was proposed for diagnosing diabetes if 6.5%, and at lower levels for identifying high risk persons for preventive interventions. We evaluated these proposals in the Diabetes Prevention Program (DPP) with long-term follow-up for 10 years after randomization (DPPOS). HbA1c at baseline predicted diabetes in all treatment groups. With HbA1c 6.5% as an alternate outcome, the incidence was reduced by 44% by metformin and 49% by lifestyle intervention during the DPP and by 38% by metformin and 29% by lifestyle during long-term follow-up. Unlike the primary findings based on the conventional diabetes definition, metformin and lifestyle were equivalent in preventing rise in HbA1c. The long-term health implications of these differences in treatment effects are unknown.

Project Start
Project End
Budget Start
Budget End
Support Year
45
Fiscal Year
2010
Total Cost
$211,322
Indirect Cost
City
State
Country
Zip Code
Muller, Yunhua L; Skelton, Graham; Piaggi, Paolo et al. (2018) Identification and functional analysis of a novel G310D variant in the insulin-like growth factor 1 receptor (IGF1R) gene associated with type 2 diabetes in American Indians. Diabetes Metab Res Rev 34:e2994
Hsueh, Wen-Chi; Bennett, Peter H; Esparza-Romero, Julian et al. (2018) Analysis of type 2 diabetes and obesity genetic variants in Mexican Pima Indians: Marked allelic differentiation among Amerindians at HLA. Ann Hum Genet 82:287-299
Vijayakumar, P; Wheelock, K M; Kobes, S et al. (2018) Secular changes in physical growth and obesity among southwestern American Indian children over four decades. Pediatr Obes 13:94-102
Tanamas, Stephanie K; Saulnier, Pierre-Jean; Hanson, Robert L et al. (2018) Serum lipids and mortality in an American Indian population: A longitudinal study. J Diabetes Complications 32:18-26
Tanamas, Stephanie K; Reddy, Sanil P; Chambers, Melissa A et al. (2018) Effect of severe obesity in childhood and adolescence on risk of type 2 diabetes in youth and early adulthood in an American Indian population. Pediatr Diabetes 19:622-629
Paddock, Ethan; Looker, Helen C; Piaggi, Paolo et al. (2018) One-Hour Plasma Glucose Compared With Two-Hour Plasma Glucose in Relation to Diabetic Retinopathy in American Indians. Diabetes Care 41:1212-1217
Paddock, Ethan; Hohenadel, Maximilian G; Piaggi, Paolo et al. (2017) One-hour and two-hour postload plasma glucose concentrations are comparable predictors of type 2 diabetes mellitus in Southwestern Native Americans. Diabetologia :
Vijayakumar, Pavithra; Nelson, Robert G; Hanson, Robert L et al. (2017) HbA1c and the Prediction of Type 2 Diabetes in Children and Adults. Diabetes Care 40:16-21
Piaggi, Paolo; Masindova, Ivica; Muller, Yunhua L et al. (2017) A Genome-Wide Association Study Using a Custom Genotyping Array Identifies Variants in GPR158 Associated With Reduced Energy Expenditure in American Indians. Diabetes 66:2284-2295
Grice, Brian A; Nelson, Robert G; Williams, Desmond E et al. (2017) Associations between persistent organic pollutants, type 2 diabetes, diabetic nephropathy and mortality. Occup Environ Med 74:521-527

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