| First Author | Liu X | Year | 2014 |
| Journal | Front Endocrinol (Lausanne) | Volume | 5 |
| Pages | 165 | PubMed ID | 25352830 |
| Mgi Jnum | J:289828 | Mgi Id | MGI:6433962 |
| Doi | 10.3389/fendo.2014.00165 | Citation | Liu X, et al. (2014) beta-Cell-Specific Glucocorticoid Reactivation Attenuates Inflammatory beta-Cell Destruction. Front Endocrinol (Lausanne) 5:165 |
| abstractText | Progression and severity of type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic beta-cell damage. Glucocorticoids (GCs) are highly effective anti-inflammatory agents but have been precluded in type 1 diabetes and in islet transplantation protocols because they exacerbated insulin resistance and suppressed beta-cell insulin secretion at the high-doses employed clinically. In contrast, physiological-range elevation of GC action within beta-cells ameliorated lipotoxic beta-cell failure in transgenic mice overexpressing the intracellular enzyme 11beta-hydroxysteroid dehydrogenase type 1 (MIP-HSD1(tg/+) mice). Here, we tested the hypothesis that elevated beta-cell 11beta-HSD1 protects against the beta-cell destruction elicited by streptozotocin (STZ), a toxin that dose-dependently mimics aspects of inflammatory and autoimmune beta-cell destruction. MIP-HSD1(tg/+) mice exhibited an episodic protection from the severe hyperglycemia caused by a single high dose of STZ associated with higher and sustained beta-cell survival, maintained beta-cell replicative potential, higher plasma and islet insulin levels, reduced inflammatory macrophage infiltration and increased anti-inflammatory T regulatory cell content. MIP-HSD1(tg/+) mice also completely resisted mild hyperglycemia and insulitis induced by multiple low-dose STZ administration. In vitro, MIP-HSD1(tg/+) islets exhibited attenuated STZ-induced nitric oxide production, an effect reversed with a specific 11beta-HSD1 inhibitor. GC regeneration selectively within beta-cells protects against inflammatory beta-cell destruction, suggesting therapeutic targeting of 11beta-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation. |
