The objective of this proposal is to develop new mouse models that more accurately reflect the pathophysiology underlying the most commonly occurring forms of type II diabetes (NIDDM) in humans. Since type II diabetes is multigenic in origin, such models are needed no only to identify individual diabetes genes and their products, but also to discover how such genes interact with other genes and with the environment to trigger clinical disease. Deleterious polygenes from two unrelated parental strain genomes, when combined in hybrid combinations, produce a reproducible and sever obesity-induced diabetes (""""""""diabesity""""""""). The parental strains selected are New Zealand Obese (NZO/Lt) and NON/Lt. Each strain exhibits subphenotypes of obesity and impaired glucose tolerance considered to be essential components in NIDDM etiopathogenesis. NON/Lt male mice, selected for impaired glucose tolerance associated with impaired pancreatic beta cell glucose responsiveness, develop moderate maturity-onset obesity but fail to progress into overt diabetes. NZO males develop juvenile-onset obesity, but only a percentage exceeds a threshold necessary for diabetes to develop. Combining both genomes results in a diabesity syndrome wherein virtually all F1 males transit from impaired glucose tolerance into diabetes. Distinct quantitative trait loci (QTL) from both progenitor strains independently affecting plasma glucose and insulin levels were identified. A dominant NZO diabetes QTL on Chromosome 1 was identified that affected not only adiposity development, but also interacted epistatically with a locus on Chromosome 15 tightly linked to the Peroxisome Proliferator-Activated Receptor alpha (PPAR alpha) gene. A series of 9 QTL locus-directed recombinant congenic stocks (RCS) has been created by inbreeding at second backcross to the NON-parental strain. Males from one RCS line containing both the NZO diabetes QTL on Chromosome 1 and 15 develop diabetes, whereas another line carrying the Chromosome 1 diabesity QTL, but lacking the NZO susceptibility QTL on Chromosome 15 is diabetes resistant. Gene array technology is proposed to identify metabolic changes in liver and regional fat depots from these genetically similar, but diabesity-divergent sublines. This will permit identification of the key metabolic events associated with impaired lipid and glucose homeostasis in liver and fat, and permit elucidation of the metabolic basis underlying the diabetogenic Chromosome 1/15 interaction. Collectively, these studies will permit genetic and metabolic characterization of key events in the transition from simple obesity to diabesity in thee novel mouse models.
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