Non insulin dependent diabetes mellitus (NIDDM) is a major health problem which affects an estimated 5-10 percent of the American population. Although NIDDM is highly heritable in humans, its inheritance does not follow simple Mendelian laws and is, therefore, thought to be caused by the simultaneous action of many genes. Because such polygenic inheritance is still very difficult to unravel, single gene mutant models offer significant advantages for gene identification and for detailed physiological studies. Five recently cloned single gene obesity mutations in mouse have provided exciting new insights into the etiology of obesity. In contrast, identification of NIDDM genes is delayed, because single gene mouse mutations for NIDDM are lacking. We have identified a new mouse model for maturity onset NIDDM, which apparently is due to a recessive single gene mutation, that has provisionally been named sugar baby (sub). The Tallyho-sub/sub mouse stock is characterized by glucose intolerance, hyperinsulinemia, chronic hyperglycemia, and increased body weight. We have carried out a preliminary outcross to a nondiabetic, nonobese mouse strain to map the sub diabetes mutation. In this cross, in addition to the sub locus which determines plasma glucose levels, we were able to map a second locus, nicknamed 'brother of sub' (bos), which controls body weight. We also found evidence that the two loci interact epistatically, i.e. homozygosity at the bos locus is necessary for sub/sub mice to become diabetic. In contrast, homozygous bos/bos mice without the sub gene do not become diabetic. Based on our preliminary results, we hypothesize that the Tallyho strain carries a major obesity susceptibility allele (bos) that interacts with the sub mutation to produce the obese/diabetic phenotype of Tallyho-sub/sub mice. To test this hypothesis, we propose to carry out two specific aims. a.) to construct separate congenic lines of mice that carry either the bos and sub genes individually or in combination on a common genetic background and to use these lines to generate fine structure genetic maps for bos and sub in order to positionally clone these genes. b.) to physiologically characterize the Tallyho strain and the congenic lines and test the hypothesis that the sub gene can interact with obesity mutations other than bos to cause diabetes. At the successful conclusion of this work, we will have identified two new genes, bos and sub, that constitute an epistatic genetic system involved in the etiology of type II diabetes. Additionally, through examination of the mutations individually and in combination in a common genetic background, we will gain a better understanding of the pathways and physiological abnormalities that are necessary to cause diabetes.
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