Irs2 deficient mice develop type2- like diabetes due to a reduction in β-cell mass and a failure of pancreatic islets to undergo compensatory hyperplasia in response to insulin resistance. In order to define the molecular mechanisms, we knocked down Irs2 gene expression in mouse MIN6 insulinoma cells. IRS2 suppression induced apoptotic cell death which was associated with an increase in expression of the BH3-only molecule Bim. Knockdown of Bim reduced apoptotic β-cell death induced by IRS2 suppression. In Irs2 deficient mice, Bim ablation restored β-cell mass, decreased the number of TUNEL positive cells and restored normal glucose tolerance after glucose challenge. FoxO1 mediates Bim up-regulation induced by IRS2 suppression and FoxO1 knockdown partially inhibits β-cell death induced by IRS2 suppression. These results suggest that Bim plays an important role in mediating the increase in β-cell apoptosis and the reduction in β-cell mass that occurs in IRS2-deficient diabetes.
- Received November 27, 2013.
- Accepted April 18, 2014.
- © 2014 by the American Diabetes Association.
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