Although most people with type 2 diabetes are obese, most obese people never develop diabetes. They are able to compensate for the insulin resistance that usually accompanies obesity by producing more insulin. We have replicated this obesity/diabetes dichotomy in mice by studying mouse strains that differ in diabetes susceptibility when made obese with the Leptin ( ob ) mutation; the C57BL/6 (B6) mice are resistant whereas the BTBR mice are susceptible. We have used this model system to search for genes that are causal for diabetes susceptibility. To find genes whose sequence variation leads to this phenotype, we have carried out positional cloning projects. To find genes that are responsive to genetic variation with respect to gene expression and are on pathways leading to diabetes, we have studied gene expression relative to gene variation; i.e., expression quantitative trait loci. We have used these data to generate network models, which incorporate gene loci, mRNA abundance, and other phenotypes. One of these networks is involved in the regulation of β-cell proliferation.