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

Liu, Xiaoxia, Turban, Sophie, Carter, Roderick N., Ahmad, Shakil, Ramage, Lynne, Webster, Scott P., Walker, Brian R., Seckl, Jonathan R. and Morton, Nicholas M. (2014). β-cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction. Frontiers in Endocrinology, 5 ,

Abstract

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-HSD1<sup>tg/+</sup> 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-HSD1<sup>tg/+</sup> 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-HSD1<sup>tg/+</sup> mice also completely resisted mild hyperglycemia and insulitis induced by multiple low-dose STZ administration. In vitro, MIP-HSD1<sup>tg/+</sup> 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 DOI: https://doi.org/10.3389/fendo.2014.00165
Divisions: Aston Medical School
Additional Information: © 2014 Liu, Turban, Carter, Ahmad, Ramage, Webster, Walker, Seckl and Morton. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Funding: China Overseas Scholarship and Research Councils UK Fellowship. Supplementary Material: http://www.frontiersin.org/Journal/10.3389/fendo.2014.00165/abstract
Uncontrolled Keywords: 11beta-hydrosteroid dehydrogenase type 1,anti-inflammatory agents,beta-cells,glucocorticoids,inflammation,insulin secretion,streptozotocin,type 1 diabetes,Endocrinology, Diabetes and Metabolism
Full Text Link: http://journal. ... .00165/abstract
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2014-10-11
Authors: Liu, Xiaoxia
Turban, Sophie
Carter, Roderick N.
Ahmad, Shakil ( 0000-0002-9294-0475)
Ramage, Lynne
Webster, Scott P.
Walker, Brian R.
Seckl, Jonathan R.
Morton, Nicholas M.

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License: Creative Commons Attribution


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