CHARACTERIZATION OF INSULIN SECRETION IN NORMOGLYCEMIC INDIVIDUALS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。我们提出，与E23基因纯合的个体（E/E）相比，KCNJ11基因K23变体（K/K）的正糖个体在血糖升高时胰岛素分泌减少，考虑到胰岛素敏感性，这种影响将更为显著，并且最近描述的胰腺对葡萄糖敏感性指标在K/K纯合个体中会降低。其次，我们提出在包含ABCC8外显子18沉默变体和内含子15变体的变异单倍型杂合的个体中也会观察到类似的效应。我们提出三个目标来解决这些假设。1. 犹他州家族成员的基因型谁已被表征为ABCC8变体的E23K变体。这些数据将使我们能够建立ABCC8和KCNJ11之间的单倍型，确定连锁不平衡的存在，以及基于家庭成员口服葡萄糖耐量试验的指标。2. 采用口服糖耐量试验（OGTT）和KCNJ11基因型筛查180例年龄在30 ~ 50岁之间的个体，筛选出E/E和K/K基因型纯合且年龄、性别、糖尿病家族史、体脂匹配的个体25例。该目的将确定密码子23 E/E、E/K和K/K三种基因型之间的糖耐量差异，并选择糖耐量正常的个体进行目的3。3. 比较25例E/E基因型患者和25例K/K基因型患者的胰岛素敏感性、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标。

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.