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. Type 2 diabetes mellitus is one of the most common inherited diseases in man with an estimated prevalence in Caucasian populations of 8-10%. Current evidence suggests that the common forms of type 2 diabetes result from a number of predisposing genes, ech of which contributes modestly to the development of diabetes as well as aging and the environment. Type 2 diabetes is characterized by insulin resistance and beta cell dysfunction. Therefore, candidate genes for type 2 diabetes include those involved with insulin secretion. Genes known to affect insulin secretion and/or pancreatic development include pancreatic duodenal homeobox factor-1 (PDX-1), Beta2/NeuroD, insulin receptor substrate-2 (IRS-2) and the beta-3-adrenergic receptor (beta3AR). Functional mutations have been identified in these genes (PDX-1Asp76Asn, BETA2/NeuroD Ala45Thr, IRS2 Gly1057Asp, or beta3AR Trp64Arg) which have the potential to alter the function of the protein, thereby, individually or in combination, effecting insulin secretion. In this study, we propose to characterize insulin secretion in prospectively recruited age-gender- and BMI-matched nondiabetic subjects with either one or two of the following variants, PDX-1 Asp76Asn, BETA2/NeuroD Ala45Thr, IRS2 Gly1057Asp, or beta3AR Trp64Arg, using the frequently sampled intravenous glucose tolerance test (FSIGTT) and insulin oscillation studies and to determine if having two variants in genes related to beta cell function have additive effects on insulin secretion.
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