MOLECULAR GENETICS OF BETA CELL COMPENSATION IN FAMILIAL DIABETES

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。来自我们实验室和其他人的大量数据表明，2型糖尿病发病机制中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型糖尿病病例的原因。我们已经证明，这种胰岛素分泌的失败是高度遗传的，并且肥胖的家庭成员无法通过增加胰岛素分泌来补偿伴随肥胖的胰岛素抵抗。该提案将在两个种族群体（高加索人和非洲裔美国人）中各分型240人，并将这些人平均分为未来糖尿病高风险（2型糖尿病家族史）和正常疾病谱（对照组）。将使用改良的静脉内葡萄糖耐量试验表征个体的胰岛素分泌和胰岛素敏感性，随后使用高葡萄糖下的精氨酸推注进行最大胰岛素刺激，以估计总胰腺β细胞分泌能力。该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。候选基因将广泛地选自β细胞生长和细胞凋亡、胰岛素分泌和脂质积累（“脂毒性”）的途径，或“功能性候选基因”，以及选自与胰岛素分泌相关的数量性状已在家族性糖尿病激酶中定位的位置（“位置性候选基因”）。序列变异和单核苷酸多态性分型将按照本实验室的技术标准进行。这些研究将提供探索多基因对β细胞胰岛素分泌补偿的贡献所需的人群，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基因型差异的可能种族差异。

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.