This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Considerable data from our laboratory and others suggests that a key element in the pathogenesis of type 2 diabetes is the failure of the pancreatic beta-cell to compensate for the insulin resistance that also precedes most cases of typical type 2 diabetes. We have shown that this failure of insulin secretion is highly heritable, and that members of families who become obese fail to compensate for the insulin resistance that accompanies that obesity by increasing insulin secretion. This proposal will type 240 individuals in each of two ethnic groups, Caucasians and African Americans, and will divide these individuals equally between those at high risk for future diabetes (family history of type 2 diabetes) and those who will show a normal spectrum of disease (controls). Individuals will be characterized for insulin secretion and insulin sensitivity using a modified intravenous glucose tolerance test followed by a maximum insulin stimulation using an arginine bolus at high glucose to estimate total pancreatic beta-cell secretory capacity. This phenotypic classification will be used to test candidate gene sequence variation using a case control design. Candidate genes will be broadly chosen from pathways of beta-cell growth and apoptosis, insulin secretion, and lipid accumulation ('lipotoxicity'), or 'functional candidates', and from locations where quantitative traits related to insulin secretion have been mapped in familial diabetes kindreds ('positional candidates'). Sequence variation and single nucleotide polymorphism typing will be conducted using techniques standard in our laboratory. These studies will provide the population needed to explore the polygenic contributions to beta-cell compensation for insulin secretion, help sort out the contributions of beta-cell functional (acute insulin response to glucose) and mass defects (maximum acute insulin response), and will explore possible ethnic differences in both the physiological response to these challenges and the underlying genotypic differences.
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