| First Author | Turban S | Year | 2012 |
| Journal | Diabetes | Volume | 61 |
| Issue | 3 | Pages | 642-52 |
| PubMed ID | 22315313 | Mgi Jnum | J:196749 |
| Mgi Id | MGI:5489845 | Doi | 10.2337/db11-1054 |
| Citation | Turban S, et al. (2012) Optimal elevation of beta-cell 11beta-hydroxysteroid dehydrogenase type 1 is a compensatory mechanism that prevents high-fat diet-induced beta-cell failure. Diabetes 61(3):642-52 |
| abstractText | Type 2 diabetes ultimately results from pancreatic beta-cell failure. Abnormally elevated intracellular regeneration of glucocorticoids by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in fat or liver may underlie pathophysiological aspects of the metabolic syndrome. Elevated 11beta-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 beta-cell 11beta-HSD1 on insulin secretion, we generated beta-cell-specific, 11beta-HSD1-overexpressing (MIP-HSD1) mice on a strain background prone to beta-cell failure. Unexpectedly, MIP-HSD1(tg/+) mice exhibited a reversal of high fat-induced beta-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. 11beta-HSD1(-/-) mice showed mild beta-cell impairment that was offset by improved glucose tolerance. The benefit of higher beta-cell 11beta-HSD1 exhibited a threshold because homozygous MIP-HSD1(tg/tg) mice and diabetic Lep(db/db) mice with markedly elevated beta-cell 11beta-HSD1 levels had impaired basal beta-cell function. Optimal elevation of beta-cell 11beta-HSD1 represents a novel biological mechanism supporting compensatory insulin hypersecretion rather than exacerbating metabolic disease. These findings have immediate significance for current therapeutic strategies for type 2 diabetes. |
