CHARACTERIZATION OF INSULIN SECRETION IN NORMOGLYCEMIC INDIVIDUALS

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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. We propose that euglycemic individuals homozygous for the K23 variant (K/K) of the KCNJ11 gene will show decreased insulin secretion in response to rising glucose when compared with individuals homozygous for the E23 variant (E/E), that this effect will be more significant when accounting for insulin sensitivity, and that recently described indexes of pancreatic sensitivity to glucose will be decreased in K/K homozygotes. Secondarily, we propose that a similar effect will be observed in individuals heterozygous for the variant haplotype comprising the exon 18 silent variant and the intron 15 variant of ABCC8. We propose three aims to address these hypotheses. 1. Genotype members of Utah families who have been previously characterized for the ABCC8 variants for the E23K variant. These data will allow us to establish haplotypes between ABCC8 and KCNJ11, to establish the existence of linkage disequilibrium, and to test indexes based on oral glucose tolerance tests in family members. 2. Screen 180 individuals who are between the ages of 30 and 50 years by oral glucose tolerance test (OGTT) and KCNJ11 genotype to select 25 individuals who are homozygous for the E/E and K/K genotypes and matched on age, gender, family history of diabetes, and body fat. This aim will determine glucose tolerance differences between the three genotypes at codon 23: E/E, E/K, and K/K, as well as selecting individuals with normal glucose tolerance for aim 3. 3. Compare insulin sensitivity, insulin secretion (acute insulin response to glucose), maximum insulin response to arginine, insulin response to graded glucose infusion, and minimal model indexes of insulin secretion in 25 individuals with the E/E genotype and 25 individuals with the K/K genotype.