In young Hispanic women who developed gestational diabetes mellitus (GDM) during pregnancy, we have identified relatively early-onset and progressive loss of insulin secretion that precedes and predicts the development of type 2 diabetes mellitus (T2DM). The defect in insulin secretion appears to be caused or worsened by insulin resistance and it is highly heritable in families of GDM probands. Based on these observations, we hypothesize that there are genetic determinants of the defect in insulin secretion that leads to T2DM in these young women. We have extensive experience with the performance of detailed phenotyping to quantify insulin secretion and insulin resistance in large cohorts of Hispanic Americans, including one large family-based cohort. We also have access to a large number of large families with a GDM proband. Accordingly, we propose to search for genetic determinants of the beta-cell defect that we have identified, using detailed phenotyping combined with candidate gene and genome-wide QTL linkage analysis. The present application is focused on the recruitment and phenotyping of Mexican American women with GDM and their siblings and first cousins (i.e., families enriched with the B-cell defect) and of matched control women who maintained normal glucose tolerance during pregnancy (robust B-cell function). All of these individuals will have detailed studies of B-cell function, insulin sensitivity and body composition. Additional family members will provide DNA for assessment of identity-by-descent and for future construction of haplotypes in GDM probands and matched controls. Studies of selected candidate genes for GDM and T2DM will be conducted during this award period. Support for a genome-wide scan will be sought separately and will be followed by fine mapping and association studies of positional candidate regions and genes. Ultimately, the results of this project will be crucial in attaining our long-term goals of (a) understanding the fundamental cause(s) of T2DM in young Hispanic Americans and (b) developing strategies to predict and prevent that disease at relatively early stages in its evolution.
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