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-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.
Highlights
Type 1 diabetes is a chronic disease characterized by inflammatory β-cell destruction secondary to an initial autoimmune targeting of the islets [1]
HYPERGLYCEMIA We began by administering a high-dose of STZ (180 mg/kg body weight) known to completely ablate β-cell function [16]
Circulating corticosterone levels were markedly elevated by high STZ, but to a similar degree in KsJ and MIP-HSD1tg/+ mice, supporting a role for local β-cell GC regeneration as the underlying driver of genotype-specific effects
Summary
Type 1 diabetes is a chronic disease characterized by inflammatory β-cell destruction secondary to an initial autoimmune targeting of the islets [1]. Pro-inflammatory cytokines derived from macrophages and damaged β-cells further suppress β-cell function in part through induction of nitric oxide production [3, 4]. As type 1 diabetes progresses, pro-inflammatory cytokines inhibit β-cell regeneration, stimulate peripheral insulin resistance and maintain insulitis [1]. Glucocorticoids (GCs) are used clinically due to their potent anti-inflammatory and immunosuppressive effects [5] but were excluded as a treatment for type 1 diabetes and in transplant protocols [6] because they promoted peripheral insulin resistance and suppressed β-cell function at the high-doses employed [7,8,9]. Exposure of normal mouse islets to GCs can improve aspects of secretory function through suppression of inflammatory signaling [10]. Transgenic mice with modest β-cell-specific elevation of the intracellular GC regenerating enzyme 11β-hydroxysteroid dehydrogenase (HSD11b1; 11betaHSD1; MIP-HSD1 mice) exhibited protection from lipotoxic βcell failure in vivo as a result of increased islet number, arising from a post-developmental effect, and function, due to enhanced secretory capacity and cell survival signaling [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
