MOLECULAR GENETICS OF BETA CELL COMPENSATION IN FAMILIAL DIABETES

家族性糖尿病中β细胞代偿的分子遗传学

• 批准号: 7377664
• 负责人: Steven C Elbein
• 金额: $ 0.13万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7377664
• 关键词: MOLECULAR; GENETICS; BETA; CELL; COMPENSATION

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.

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。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。来自我们实验室和其他实验室的大量数据表明，2型糖尿病发病机理的关键因素是胰腺β细胞的失败，无法补偿大多数典型2型糖尿病病例之前的胰岛素抵抗。我们已经表明，这种胰岛素分泌的失败是高度遗传的，肥胖的家庭成员未能通过增加胰岛素分泌而弥补肥胖伴随的胰岛素抵抗。该提议将在两个族裔中的高加索人和非裔美国人中的每个群体中的每个群体中键入240个人，并将这些人平均分配给有未来糖尿病风险的人（2型糖尿病的家族史）和将表现出正常疾病（控制）的人。使用改良的静脉内葡萄糖耐受性测试，将对个体进行胰岛素分泌和胰岛素敏感性的特征，然后使用高葡萄糖的精氨酸注入最大的胰岛素刺激，以估算总胰腺β-细胞分泌能力。这种表型分类将使用案例控制设计来测试候选基因序列变化。候选基因将从β细胞生长和凋亡，胰岛素分泌和脂质积累（“脂毒性”）或“功能性候选者”以及与胰岛素分泌有关的定量性状映射在家族性糖尿病中（Kinderal diabetes chinderdsedsreds（“”位置候选的位置）。序列变异和单核苷酸多态性分型将使用我们的实验室中的技术标准进行。这些研究将为探索胰岛素分泌的β细胞补偿的多基因贡献提供所需的人群，有助于解决β细胞功能（急性胰岛素对葡萄糖的反应）和质量缺陷（最大急性胰岛素反应）的贡献，并将在对这些挑战性差异和下层基因类别的物理学反应中探索可能的种族差异。