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β-Cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction

Lookup NU author(s): Professor Brian Walker

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2014 Liu, Turban, Carter, Ahmad, Ramage, Webster, Walker, Seckl and Morton. 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 ameliorated lipotoxic β-cell failure in transgenic mice overexpressing the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (MIP-HSD1tg/+ mice). Here, we tested the hypothesis that elevated β-cell 11beta-HSD1 protects against the β-cell destruction elicited by streptozotocin (STZ), a toxin that dose-dependently mimics aspects of inflammatory and autoimmune β-cell destruction. MIP-HSD1tg/+ mice exhibited an episodic protection from the severe hyperglycemia caused by a single high dose of STZ associated with higher and sustained β-cell survival, maintained β-cell replicative potential, higher plasma and islet insulin levels, reduced inflammatory macrophage infiltration and increased anti-inflammatory T regulatory cell content. MIP-HSD1tg/+ mice also completely resisted mild hyperglycemia and insulitis induced by multiple low-dose STZ administration. In vitro, MIP-HSD1tg/+ islets exhibited attenuated STZ-induced nitric oxide production, an effect reversed with a specific 11beta-HSD1 inhibitor. GC regeneration selectively within β-cells protects against inflammatory β-cell destruction, suggesting therapeutic targeting of 11beta-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation.


Publication metadata

Author(s): Liu X, Turban S, Carter RN, Ahmad S, Ramage L, Webster SP, Walker BR, Seckl JR, Morton NM

Publication type: Article

Publication status: Published

Journal: Frontiers in Endocrinology

Year: 2014

Volume: 5

Online publication date: 14/10/2014

Acceptance date: 01/01/1900

Date deposited: 22/12/2017

ISSN (electronic): 1664-2392

Publisher: Frontiers Research Foundation

URL: https://doi.org/10.3389/fendo.2014.00165

DOI: 10.3389/fendo.2014.00165


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