NEW MODELS FOR IDENTIFYING NIDDM POLYGENES

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The aim of this proposal is to establish the genetic basis for a new mouse model that may more accurately resemble the etiopathogenesis of non-insulin dependent diabetes mellitus (NIDDM) in humans. A mouse model of NIDDM should ideally combine both a genetic predisposition to development of obesity/insulin resistance with an intrinsic defect in pancreatic beta cell function. Both the NON/Lt strain, as well as the NZO/H1 strain, exhibit polygenic obesity. Both strains also exhibit intrinsic defects in pancreatic beta cell responsiveness to glucose challenge. NON/Lt mice progress only to impaired glucose tolerance, whereas hyperglycemia develops in some NZO/H1 males. Outcrossing of NZO females to NON males produces F1 progeny which all progressively develop obesity, but only F1 males develop maturity-onset hyperglycemia. Unlike other murine obesity-induced diabetes models, these F1 males are characterized by hypoinsulinemia rather than hyperinsulinemia. The aims of this proposal are to identify by F2 segregation analysis the chromosomal regions contributing Niddm susceptibility genes. The second aim is to establish polycongenic stocks of NON/Lt mice carrying NZO/Lt mice carrying NZO-derived susceptibility genes that will deviate the impaired glucose tolerance of NON mice to overt NIDDM. This will allow fine mapping of the Niddm genes, and test the hypothesis that beta cell defects characteristic of both the NON and NZO parental strains codominantly express to produce a more severe NIDDM syndrome. The final aim is to elucidate the genetic and endocrinologic basis for the male sex-limited nature of the NIDDM syndrome in this new mouse model. If genes controlling beta cell defects are identified, this new model will be important for testing and design of more effective pharmacologic agents for restoration of normal beta cell functions.