Overall Goal: Our major objective is to examine the role of metabolic factors in the development of insulin resistance and progression to beta- cell failure, and type 2 diabetes during puberty in Hispanic American adolescents. Rationale: The pubertal transition is a time during which rapid and dynamic changes occur in various metabolic systems, including insulin resistance. However, there is almost a complete lack of longitudinal studies on metabolic changes during puberty, especially among high risk ethnic groups, and especially with a focus on diabetes risk. Because of the unique metabolic events associated with the pubertal transition, the mechanism of insulin resistance and type 2 diabetes during adolescence cannot be inferred from adult studies.
Specific Aims & Approach: We will recruit a cohort of non-diabetic Hispanic American adolescents who are obese and have at least one first degree relative with type 2 diabetes for a longitudinal study. We will examine the time course of changes in insulin action, insulin secretion, beta-cell function, visceral versus subcutaneous abdominal fat, cardiovascular fitness, and endocrine factors using the most advanced clinical research techniques possible within the confines of a cohort study in adolescents. The patterns of change in these variables will be examined in those who progress to develop type 2 diabetes, versus those who do not. The application is based on compelling cross-sectional and longitudinal evidence from ongoing NIH supported cohort studies in children, young women and adults that support our hypothesis, and an extensive network of clinics providing diabetes care for Hispanic Americans from whom unaffected relatives will be recruited. Hypothesis: Our unifying hypothesis is that the progression to type 2 diabetes will be characterized by a sustained increase in insulin resistance, and a gradual deterioration in insulin secretion relative to the degree of insulin resistance, indicating a failure of beta-cell function. These events will be rapidly accelerated and confounded by puberty-related increases in insulin resistance, and requisite hypersecretion of insulin, as well as a puberty related increases in visceral fat and decreases in cardiovascular fitness that will further compound the puberty-related rise in insulin resistance. Summary: This study will establish the fundamental mechanism of type 2 diabetes in Hispanic adolescents and will clarify the role of body fat, physical activity and endocrine factors in relation to insulin resistance during puberty and progression to type 2 diabetes.
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