Overall Objective: to conduct a study of the safety and effects of treatment of obese, Hispanic adolescents at high risk for type 2 diabetes (T2D) with an insulin sensitizer. Overall Hypothesis: treatment of obese, Hispanic adolescents with pioglitazone, will result in enhanced insulin sensitivity, improved beta-cell function, normalization of glucose tolerance, improvements in cardiovascular disease (CVD) risk factors and atherosclerosis.
Specific Aims and Approach: i) to conduct a randomized double blind placebo controlled pilot study of the safety and effects of treatment of overweight, Hispanic adolescents with pioglitazone (30 mg/day) for 12 weeks, ii) to compare changes in insulin sensitivity, insulin secretion, beta-cell function (measured via the frequently sampled intravenous glucose tolerance test), body composition (via dual energy x-ray absorptiometry) body fat distribution (via magnetic resonance imaging), CVD risk factors (lipids, lipoproteins, blood pressure) and atherosclerosis (via intima media thickness of the common carotid artery and arterial stiffness) in Hispanic youth, before and after 12 weeks of treatment (30 mg/day) with pioglitazone + standard care (n = 20) or placebo + standard care (n =20). Forty, obese, Hispanic adolescents, with impaired glucose tolerance, a positive family history for type 2 diabetes, and exposed in utero to gestational diabetes will be recruited for the study and randomized to either treatment with pioglitazone or placebo. Rationale: T2D is recent health problem in obese youth specially in ethnic minorities. 28% of obese Hispanic adolescents with a family history of T2D have impaired glucose tolerance (IGT). In youth exposed to gestational diabetes in utero this value increases to 41%. Furthermore, 30% of obese Hispanic youth have the metabolic syndrome. Data from a current NIDDK longitudinal study provide compelling preliminary evidence to suggest that chronic insulin resistance coupled with poor insulin secretory response are the key events contributing to hyperglycemia in this population, while insulin resistance may be additionally responsible for the high prevalence of the metabolic syndrome. Health implications: Interventions aimed at improving insulin resistance in susceptible individuals may be an effective means of preventing both type 2 diabetes and early cardiovascular disease (CVD). The applicant's previous training, and the clinical & scientific expertise available at the host institution will facilitate the successful completion of the proposal.
