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.
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