We operate three clinical centers of the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial of diabetes prevention in high-risk, but nondiabetic, adults. Nationally, the DPP enrolled 3,234 volunteers who received standard lifestyle recommendations and were randomly assigned to one of three interventions: intensive lifestyle with the aim of losing and maintaining 7% weight loss and achieving > 150 minutes per week of moderate intensity physical activity, metformin therapy with 850 mg twice per day, or placebo. The development of diabetes in the lifestyle intervention and metformin-treated groups were reduced by 58% and 31%, respectively, compared with the placebo group, during the first three years of treatment and follow-up. Many important issues remained unanswered, however. Specifically, whether the decrease in the development of diabetes can be sustained is unknown. Moreover, determining whether the delay or prevention of diabetes will translate into a decrease in retinopathy, nephropathy, neuropathy, and cardiovascular disease, all of which require more years to develop than the DPP period of study, is critical to establish the true impact of the DPP on public health. This long-term follow-up study of the DPP, the DPPOS, addresses these issues. Several findings were reported this fiscal year. H. pylori infection. The association between H. pylori infection and risk of incident diabetes was evaluated in adults in a nested casecontrol study conducted among 421 adults with newly diagnosed diabetes and 421 matched controls. We examined the association between serological status of H. pylori at baseline and risk of incident diabetes over a mean follow-up period of 2.6 years. Using data from the baseline visit of the DPP, we also examined the cross-sectional association between presence of H. pylori antibodies and insulin sensitivity, insulin secretion and the disposition index-like measure after a 75-g oral glucose tolerance test (OGTT). At baseline, H. pylori antibodies were present in 40% of participants who developed diabetes and 39% of controls. There was no association between exposure to H. pylori and incident diabetes (odds ratio OR of 1.04 (95% CI, 0.77 to 1.40). In cross-sectional analyses, H. pylori seropositivity was not significantly associated with insulin sensitivity and secretion estimated from the OGTT. In adults at high risk for diabetes, H. pylori seropositivity was not associated with risk of developing diabetes. MODY genes and response to interventions. Variation in genes that cause maturity-onset diabetes of the young (MODY) has been associated with diabetes incidence and glycemic traits. We determined if genetic variation in MODY genes leads to differential responses to insulin-sensitizing interventions. After 1 year, the minor allele of rs3212185 (HNF4A) was associated with improved b-cell function in the metformin and lifestyle groups but not the placebo group; the minor allele of rs6719578 (NEUROD1) was associated with an increase in insulin secretion in the metformin group but not in the placebo and lifestyle groups. Genetic variation among MODY genes may influence response to insulin-sensitizing interventions. Genes affecting serum lipid levels. We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program. We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein HDL and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with prediabetes. Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits. Summary of metformin effects in the Diabetes Prevention Program. The largest and longest clinical trial of metformin for the prevention of diabetes is the Diabetes Prevention Program/ Diabetes Prevention Program Outcomes Study (DPP/DPPOS). We summarized data from the DPP/DPPOS, focusing on metformin for diabetes prevention, as well as its long-term glycemic and cardiometabolic effects and safety in people at high-risk of developing diabetes. After an average follow-up of 2.8 years, metformin reduced the incidence of diabetes by 31% compared with placebo, with a greater effect in those who were more obese, had a higher fasting glucose or a history of gestational diabetes. The DPPOS addressed the longer-term effects of metformin, showing a risk reduction of 18% over 10 and 15 years post-randomization. Metformin treatment for diabetes prevention was estimated to be cost-saving. At 15 years, lack of progression to diabetes was associated with a 28% lower risk of microvascular complications across treatment arms, a reduction that was no different among treatment groups. Recent findings suggest metformin may reduce atherosclerosis development in men. Long-term follow-up, currently underway in the DPP/DPPOS, is now evaluating metformins potential role, when started early in the spectrum of dysglycemia, on later-stage comorbidities, including cardiovascular disease and cancer. Other. Based on the DPP experience, the principal investigator gave advice on the development of a new clinical trial of preventing diabetes in Latino youth.

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6
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2017
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U.S. National Inst Diabetes/Digst/Kidney
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de Groot, Mary; Marrero, David; Mele, Lisa et al. (2018) Depressive Symptoms, Antidepressant Medication Use, and Inflammatory Markers in the Diabetes Prevention Program. Psychosom Med 80:167-173
Herman, William H; Pan, Qing; Edelstein, Sharon L et al. (2017) Impact of Lifestyle and Metformin Interventions on the Risk of Progression to Diabetes and Regression to Normal Glucose Regulation in Overweight or Obese People With Impaired Glucose Regulation. Diabetes Care 40:1668-1677
Billings, Liana K; Jablonski, Kathleen A; Warner, A Sofia et al. (2017) Variation in Maturity-Onset Diabetes of the Young Genes Influence Response to Interventions for Diabetes Prevention. J Clin Endocrinol Metab 102:2678-2689
Mercader, Josep M; Liao, Rachel G; Bell, Avery D et al. (2017) A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes. Diabetes 66:2903-2914
Aroda, Vanita R; Knowler, William C; Crandall, Jill P et al. (2017) Metformin for diabetes prevention: insights gained from the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study. Diabetologia 60:1601-1611
Sylvetsky, Allison C; Edelstein, Sharon L; Walford, Geoffrey et al. (2017) A High-Carbohydrate, High-Fiber, Low-Fat Diet Results in Weight Loss among Adults at High Risk of Type 2 Diabetes. J Nutr 147:2060-2066
Soltero, Erica G; Konopken, Yolanda P; Olson, Micah L et al. (2017) Preventing diabetes in obese Latino youth with prediabetes: a study protocol for a randomized controlled trial. BMC Public Health 17:261
Alzahrani, Saud; Nelson, Jason; Moss, Steven F et al. (2017) H. pylori seroprevalence and risk of diabetes: An ancillary case-control study nested in the diabetes prevention program. J Diabetes Complications 31:1515-1520
McCaffery, Jeanne M; Jablonski, Kathleen A; Franks, Paul W et al. (2017) Replication of the Association of BDNF and MC4R Variants With Dietary Intake in the Diabetes Prevention Program. Psychosom Med 79:224-233
Perreault, L; Pan, Q; Aroda, V R et al. (2017) Exploring residual risk for diabetes and microvascular disease in the Diabetes Prevention Program Outcomes Study (DPPOS). Diabet Med 34:1747-1755

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