Type 2 diabetes mellitus involves insulin resistance combined with a failure of pancreatic beta-cells to compensate for the increased insulin demand. Although insulin resistance is a feature of type 2 diabetes, a person can be severely insulin resistant without ever developing diabetes. Therefore, beta-cell failure, or beta-cell decompensation, is an essential feature of type 2 diabetes. The objective of this project is to identify genetic modifiers of diabetes susceptibility that are associated with beta-cell decompensation in type 2 diabetes. The approach is to combine genetics with gene array technology. We shall map mRNA abundance as a quantitative trait in a population of animals segregating for type 2 diabetes mellitus alleles. We have shown that BTBR-ob/ob mice, in stark contrast to C57BLI6-ob/ob mice, develop severe diabetes. We have shown that F2 mice generated from these two strains segregate diabetes susceptibility alleles. In the present studies, we propose to generate a (C57BL/6 x BTBR)-ob/ob F2 population. We will isolate RNA from their pancreatic islets and quantitate mRNA abundance using microarray technology. The mRNA values (gene expression traits) will be used as phenotypes for gene mapping. Using dimension reduction approaches (clustering and principal components), the gene expression traits will be transformed into superphenotypes in order to genetically map networks that are dysfunctional in type 2 diabetes mellitus and result in beta-cell decompensation.
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