title: β-Cell-Specific Glucocorticoid Reactivation Attenuates Inflammatory β-Cell Destruction.
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(tg/+) 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(tg/+) 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(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 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.
authors.affiliation: Molecular Metabolism Group, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute , Edinburgh , UK ; Division of Endocrinology and Metabolism, Department of Internal Medicine, Huashan Hospital, Shanghai Medical College, Fudan University , Shanghai , China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Molecular Metabolism Group, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute , Edinburgh , UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Turban
authors.affiliation: Molecular Metabolism Group, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute , Edinburgh , UK.
authors.forename: Roderick N
authors.initials: RN
authors.lastname: Carter
authors.affiliation: Aston Medical School, Aston University , Birmingham , UK.
authors.forename: Shakil
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Molecular Metabolism Group, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute , Edinburgh , UK.
authors.forename: Lynne
authors.initials: L
authors.lastname: Ramage
authors.affiliation: Endocrinology Unit, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute , Edinburgh , UK.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Webster
authors.affiliation: Endocrinology Unit, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute , Edinburgh , UK.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.affiliation: Endocrinology Unit, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute , Edinburgh , UK.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.affiliation: Molecular Metabolism Group, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute , Edinburgh , UK.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Morton
keywords: 11beta-hydrosteroid dehydrogenase type 1; anti-inflammatory agents; beta-cells; glucocorticoids; inflammation; insulin secretion; streptozotocin; type 1 diabetes