The genetic basis of type 2 diabetes mellitus has been shown to be complex. This is not surprising given the large number of tissues that are engaged in regulating glucose metabolism: liver, muscle, fat, endocrine pancreas, the gut, and the brain. Alterations in numerous genes that affect pancreatic beta cell function and hepatic carbohydrate metabolism (all of the known MODY genes) can produce carbohydrate intolerance and hyperglycemia. Mutations in adipocytes can confer diabetes susceptibility, such as leptin deficiency, or diabetes resistance, as is the case in perilipin deficiency. Thus, loss of function mutations can provide both susceptibility to and protection from diabetes. Much more remains to be discovered about the complex relationships between the genome and the soma that regulate carbohydrate metabolism. To this end, we have utilized the existence of genetic modifiers of the obesity/diabetes syndrome of leptin receptor (Lepr) deficiency to identify novel diabetes genes. We have generated and characterized a novel diabetes phenotype of LEPR-null mice on the FVB strain. Obese LEPR-deficient mice of the FVB strain develop persistent hyperglycemia and concomitant hyperinsulinemia due to massive pancreatic beta cell mass expansion. This apparent resistance of the FVB mouse's beta cell to glucotoxicity is a genetically determined trait controlled by one major locus on mouse Chromosome 5 and we will provide evidence in support of this statement. Moreover, we will provide an experimental strategy to isolate and identify the genetic variants that confer resistance or susceptibility to glucotoxicity in the beta cell. We have three specific aims: 1. Identify a major locus (Modbl) that regulates the pancreatic beta cell response to hyperglycemia. 2. Define a critical genetic interval for Modbl at subcentimorgan resolution. 3. Identify the Modbl gene and the sequence variants that control beta cell responses to hyperglycemia.
|Effective start/end date||6/1/03 → 7/31/13|
- Endocrinology, Diabetes and Metabolism
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