CHARACTERIZATION OF INSULIN SECRETION IN NORMOGLYCEMIC INDIVIDUALS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。我们认为，与E23变异体（E/E）纯合子相比，KCNJ 11基因K23变异体（K/K）纯合子的血糖正常个体在葡萄糖升高时胰岛素分泌减少，当考虑到胰岛素敏感性时，这种效应将更加显著，并且最近描述的胰腺对葡萄糖敏感性的指数在K/K纯合子中将降低。其次，我们提出，类似的效果将观察到在个体杂合子的变异单倍型，包括外显子18沉默变异和内含子15变异的ABCC 8。我们提出了三个目标来解决这些假设。 1.犹他州家族的基因型成员，其先前已被表征为E23 K变体的ABCC 8变体。这些数据将使我们能够建立ABCC 8和KCNJ 11之间的单倍型，建立连锁不平衡的存在，并在家庭成员的口服葡萄糖耐量试验的基础上测试指标。 2.通过口服葡萄糖耐量试验（OGTT）和KCNJ 11基因型筛选180例年龄在30 - 50岁之间的个体，选择25例E/E和K/K基因型纯合且年龄、性别、糖尿病家族史和体脂匹配的个体。该目标将确定密码子23处的三种基因型之间的葡萄糖耐量差异：E/E、E/K和K/K，以及选择具有正常葡萄糖耐量的个体用于目标3。 3.比较25名E/E基因型个体和25名K/K基因型个体的胰岛素敏感性、胰岛素分泌（对葡萄糖的急性胰岛素反应）、对精氨酸的最大胰岛素反应、对分级葡萄糖输注的胰岛素反应和胰岛素分泌的最小模型指数。

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.