BETA-CELL COMPENSATION FAMILIAL TYPE 2 DIABETES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。2型糖尿病(T2 DM)具有很强的遗传性，在同卵双胞胎中有近90%的一致性。正在进行的研究，包括我们实验室的研究，已经将假定的T2 DM易感性定位于广泛的染色体区域，但定位和识别复杂的疾病基因是一个艰巨的挑战。绘制T2 DM最终二分特征图的一种补充方法是检查在显性糖尿病发病之前的数量异常。我们和其他人已经证明，糖尿病前期胰岛素作用和胰岛素分泌缺陷是遗传的。我们最近发现，在胰岛素敏感性的背景下，胰岛素分泌指数具有高度的遗传性，而且该指数随着年龄的增长和2型糖尿病兄弟姐妹的后代中肥胖的增加而下降。我们假设，少量常见的隐性遗传变异会导致b细胞代偿功能受损，从而降低胰岛素敏感性，这在存在胰岛素抵抗时会导致2型糖尿病表型。

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. Type 2 diabetes (T2DM) is strongly inherited, with nearly 90% concordance in identical twins. Ongoing studies, including those of our laboratory, have localized putative T2DM susceptibility to broad chromosomal regions, but localization and identification of complex disease genes represents a difficult challenge. A complementary approach to mapping the final dichotomous trait of T2DM is to examine the quantitative abnormalities that precede the onset of overt diabetes. We and others have shown that prediabetic defects in insulin action and insulin secretion are inherited. We recently showed that an index of insulin secretion in the context of insulin sensitivity is highly heritable, and that this index falls with increasing age and obesity among offspring of a type 2 diabetic sibling pair. We hypothesize that a small number of common, recessive genetic variants result in impaired b-cell compensation to reduced insulin sensitivity which in the presence of insulin resistance results in the type 2 diabetic phenotype.