Non-insulin-dependent diabetes mellitus (NIDDM) is a disorder of glucose homeostasis characterized by impaired insulin action (insulin resistance) and impaired insulin production. It is widely held that genetic factors play a key role in the development of insulin resistance and NIDDM. Insulin resistance is inherited in as a non-Mendelian trait, the pathogenesis of which likely involves genetic heterogeneity and polygenic inheritance. We are interested in dissecting the genetic components of insulin resistance using mouse and human genetic models. Using genetic crosses between mice with mutations of the insulin receptor (IR) and IR substrate-1 (IRS-1) genes, we have generated a diabetic mouse strain (the NIDDM mouse) in which the pathogenesis of diabetes closely mirrors the pathogenesis of human diabetes. The relative roles of insulin resistance and insulin deficiency in the genetics of diabetes are being dissected by way of further crosses between strains carrying mutations in genes important for insulin action and beta cell development or insulin secretion. We hope to learn from these investigations whether insulin resistance and insulin deficiency share a common etiology, and which genes govern these complex metabolic events. An important offshoot of this area of research is the identification of modifier genes, i.e., alleles that determine the different susceptibility of different mouse strains to insulin resistance and/or beta cell failure. Insulin and IGF-1 receptors (IGF-1R) play important and complementary roles in embryonic growth and development. These roles have been addressed by crossing mice with mutations in both genes. The experiments indicate that IGF-1Rs are important for embryonic growth in mid-gestation, whereas IRs play a more important role in late gestation. Interestingly, IGF-2, and not insulin, is the ligand that mediates the growth-promoting actions of IRs in embryonic life. We are extending these observations to understand the role of the two receptors in determining the growth rate of embryonic pancreas, and how this may affect beta cell mass and the ability of beta cells to grow in post-natal life.
