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?-Cell-Specific Glucocorticoid Reactivation Attenuates Inflammatory ?-Cell Destruction.


ABSTRACT: Progression and severity of type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic ?-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 ?-cell insulin secretion at the high-doses employed clinically. In contrast, physiological-range elevation of GC action within ?-cells ameliorated lipotoxic ?-cell failure in transgenic mice overexpressing the intracellular enzyme 11?-hydroxysteroid dehydrogenase type 1 (MIP-HSD1(tg/+) mice). Here, we tested the hypothesis that elevated ?-cell 11beta-HSD1 protects against the ?-cell destruction elicited by streptozotocin (STZ), a toxin that dose-dependently mimics aspects of inflammatory and autoimmune ?-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 ?-cell survival, maintained ?-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 ?-cells protects against inflammatory ?-cell destruction, suggesting therapeutic targeting of 11beta-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation.

SUBMITTER: Liu X 

PROVIDER: S-EPMC4196588 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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β-Cell-Specific Glucocorticoid Reactivation Attenuates Inflammatory β-Cell Destruction.

Liu Xiaoxia X   Turban Sophie S   Carter Roderick N RN   Ahmad Shakil S   Ramage Lynne L   Webster Scott P SP   Walker Brian R BR   Seckl Jonathan R JR   Morton Nicholas M NM  

Frontiers in endocrinology 20141014


Progression and severity of type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic β-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 β-cell insulin secretion at the high-doses employed clinically. In contrast, physiological-range elevation of GC action within β-cells ame  ...[more]

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