The pancreatic beta cell is the body's only source of insulin. The failure or destruction of the beta cell results in type 2 and type 1 diabetes respectively. We identified a novel regulator of insulin expression in the pancreatic beta cell wit a whole genome RNA interference screen. Interestingly, this gene appears to be highly enriched in the beta cell versus non-islet tissues, making it an attractive candidate.
The first aim of this R03 proposes to study the mouse knockout of this gene. Specifically, insulin expression, glucose tolerance, insulin tolerance, and insulin secretion will be measured in mice lacking beta cell expression of this gene.
The second aim asks if knockdown of the human homolog of this gene in human islets also affects insulin expression and insulin secretion. To do this, small hairpin RNAs targeting this gene will be delivered into human islets using adenovirus. Then, insulin promoter activity and glucose stimulated insulin secretion will be measured. The goal of this application is to provide critical in vivo data to support an R01 application on the detailed mechanism of this gene in beta cell function.
Diabetes incidence continues to rise in the US and worldwide. The failure of the pancreatic beta cell lies at the heart of diabetes. This application calls for te in vivo study of a novel gene that positively regulates insulin production in beta cells.
|Lee, Jessica; Pappalardo, Zachary; Chopra, Deeksha Gambhir et al. (2018) A Genetic Interaction Map of Insulin Production Identifies Mfi as an Inhibitor of Mitochondrial Fission. Endocrinology 159:3321-3330|