Optimal Elevation of b-Cell 11b-Hydroxysteroid Dehydrogenase Type 1 Is a Compensatory Mechanism that Prevents High Fat Diet–Induced b-Cell Failure

Type 2 diabetes ultimately results from pancreatic b-cell failure. Abnormally elevated intracellular regeneration of glucocorti-coids by the enzyme 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) in fat or liver may underlie pathophysiological aspects of the metabolic syndrome. Elevated 11b-HSD1 is also found in pancreatic islets of obese/diabetic rodents and is hypothesized to suppress insulin secretion and promote diabetes. To define the direct impact of elevated pancreatic b-cell 11b-HSD1 on insulin secretion, we generated b-cell–specific, 11b-HSD1–overexpressing (MIP-HSD1) mice on a strain background prone to b-cell failure. Unexpectedly, MIP-HSD1tg/+ mice exhibited a reversal of high fat– induced b-cell failure through augmentation of the number and intrinsic function of small islets in association with induction of heat shock, protein kinase A, and extracellular signal–related kinase and p21 signaling pathways. 11b-HSD12/2 mice showe