MOLECULAR GENETICS OF BETA CELL COMPENSATION IN FAMILIAL DIABETES

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。来自我们实验室和其他实验室的大量数据表明，2型糖尿病发病机制的一个关键因素是胰腺β细胞无法补偿胰岛素抵抗，这也是大多数典型2型糖尿病病例发生的原因。我们已经证明了胰岛素分泌的失败是高度遗传的，并且那些变得肥胖的家庭成员不能通过增加胰岛素分泌来补偿伴随肥胖而来的胰岛素抵抗。该提案将对白种人和非裔美国人这两个种族中的240人进行分类，并将这些人平均分为未来糖尿病高危人群（有2型糖尿病家族史）和疾病谱系正常的人群（对照组）。个体的胰岛素分泌和胰岛素敏感性将通过改良的静脉葡萄糖耐量试验进行鉴定，然后在高葡萄糖条件下使用精氨酸丸进行最大胰岛素刺激，以估计总胰腺β细胞分泌能力。这种表型分类将用于使用病例对照设计测试候选基因序列变异。候选基因将广泛地从β细胞生长和凋亡、胰岛素分泌和脂质积累（“脂肪毒性”）或“功能候选基因”的途径中选择，以及从家族性糖尿病类型中与胰岛素分泌相关的数量性状（“位置候选基因”）的位置中选择。序列变异和单核苷酸多态性分型采用本实验室标准技术进行。这些研究将为探索β细胞补偿胰岛素分泌的多基因贡献提供所需的人群，帮助整理β细胞功能（对葡萄糖的急性胰岛素反应）和质量缺陷（最大急性胰岛素反应）的贡献，并将探索对这些挑战的生理反应和潜在的基因型差异可能存在的种族差异。

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.