The objective of this proposal is to identify genetic factors in a mouse model that predispose individuals to type 2 diabetes. The project will focus on defining the genetics of diet-induced insulin resistance and hyperglycemia which are characteristic of the C57BL/6J (BL/6) mouse. The segregation of insulin resistance, hyperinsulinemia, hyperglycemia and obesity on a high fat, high simple carbohydrate diet will be analyzed in crosses between diabetes susceptible C57BL/6J and resistant A/J mice utilizing backcrosses, recombinant inbred (RI) and recombinant congenics (RC) of these strains. We will examine whether the loci which result in each manifestation of this disease segregate traits on the BL/6 genome will be determined by their strain distribution pattern in at least 14 BXA and 19 AXB RI strains by comparison with previously typed genetic markers and additional markers to be characterized. Restriction fragment length variants (RFLV) will be determined for both disease candidate loci and evenly spaced genetic markers throughout genome in order to enhance the probability of identifying a genetic locus. Similarly, evenly spaced RFLV markers will be typed in 25 RC strains. Finally, DNA from appropriate backcross mice will be analyzed to confirm the identification of candidate genetic loci. These studies will determine the feasibility of reverse genetic approaches to cloning of """"""""diabetagenic"""""""" gene(s) in the mouse and identity possible candidate loci for human genetic linkage studies.
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