β-cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction.
Progression and severity of Type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic β-cell damage. Glucocorticoids are highly effective anti-inflammatory agents but have been precluded in type 1 diabetes and in islet transplantation protocols bec...
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2014-10-01
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Online Access: | http://journal.frontiersin.org/Journal/10.3389/fendo.2014.00165/full |
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doaj-f37813837557492185d79e100a8e017a2020-11-24T22:53:44ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922014-10-01510.3389/fendo.2014.00165111482β-cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction.XiaoXia eLiu0Sophie eTurban1Roderick N Carter2Shakil eAhmad3Lynne eRamage4Scott P Webster5Brian R Walker6Jonathan eSeckl7Nicholas Michael Morton8University of EdinburghUniversity of EdinburghUniversity of EdinburghAston UniversityUniversity of EdinburghUniversity of EdinburghUniversity of EdinburghUniversity of EdinburghUniversity of EdinburghProgression and severity of Type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic β-cell damage. Glucocorticoids 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 glucocorticoid 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 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. Glucocorticoid regeneration selectively within β-cells protects against inflammatory β-cell destruction, suggesting therapeutic targeting of 11β-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation.http://journal.frontiersin.org/Journal/10.3389/fendo.2014.00165/fullAnti-Inflammatory AgentsGlucocorticoidsInflammationStreptozocintype 1 diabetesinsulin secretion |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
XiaoXia eLiu Sophie eTurban Roderick N Carter Shakil eAhmad Lynne eRamage Scott P Webster Brian R Walker Jonathan eSeckl Nicholas Michael Morton |
spellingShingle |
XiaoXia eLiu Sophie eTurban Roderick N Carter Shakil eAhmad Lynne eRamage Scott P Webster Brian R Walker Jonathan eSeckl Nicholas Michael Morton β-cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction. Frontiers in Endocrinology Anti-Inflammatory Agents Glucocorticoids Inflammation Streptozocin type 1 diabetes insulin secretion |
author_facet |
XiaoXia eLiu Sophie eTurban Roderick N Carter Shakil eAhmad Lynne eRamage Scott P Webster Brian R Walker Jonathan eSeckl Nicholas Michael Morton |
author_sort |
XiaoXia eLiu |
title |
β-cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction. |
title_short |
β-cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction. |
title_full |
β-cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction. |
title_fullStr |
β-cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction. |
title_full_unstemmed |
β-cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction. |
title_sort |
β-cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction. |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Endocrinology |
issn |
1664-2392 |
publishDate |
2014-10-01 |
description |
Progression and severity of Type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic β-cell damage. Glucocorticoids 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 glucocorticoid 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 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. Glucocorticoid regeneration selectively within β-cells protects against inflammatory β-cell destruction, suggesting therapeutic targeting of 11β-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation. |
topic |
Anti-Inflammatory Agents Glucocorticoids Inflammation Streptozocin type 1 diabetes insulin secretion |
url |
http://journal.frontiersin.org/Journal/10.3389/fendo.2014.00165/full |
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