Glucocorticoids are widely used in clinical practice, while the chronic administration at a high dose often leads to the progression of steroid-induced diabetes. This hyperglycemic state results mainly from the suppression of insulin secretion due to pancreatic β-cell dysfunction and the increment of systemic insulin resistance. However, the mechanisms which underlie glucocorticoid action on expression and secretion of insulin in pancreatic β-cells have not been clarified. The aim of this study is to elucidate the effects of glucocorticoid on insulin synthesis and secretion in pancreatic β-cells. Insulin gene expression was significantly increased in 30nM of dexamethasone and decreased in 300 and 3000 nM of dexamethasone. These changes in the expression were canceled by RU486, a GR antagonist, at any concentrations of dexamethasone. Meanwhile, insulin and proinsulin secretion were significantly reduced at any concentrations of dexamethasone. Interestingly, the proinsulin/insulin ratio was significantly decreased at 30 nM, and increased at 300 and 3000 nM. The changes were completely restored by RU486 at 30 nM of dexamethasone, while the reduction of insulin and proinsulin secretion by 300 or 3000 nM of dexamethasone was not released by RU486. In addition, similar results were obtained in experiments using knockdown of GR expression. Interestingly, the short-term induction of insulin secretion by membrane depolarization treated with 30 mM of KCl was rather enhanced by 3000 nM of dexamethasone, and this enhancement was not canceled by RU486.

In conclusion, glucocorticoid regulates insulin gene expressions via the genomic pathway containing GR in pancreatic β-cells, while particularly high-dose glucocorticoid regulates insulin secretion principally via non-genomic pathway. Since the proinsulin/insulin ratio increased under chronic administration of high-dose glucocorticoid, it was assumed that the non-genomic pathway was involved in insulin processing.


T. Murashima: None. T. Kondo: None. K. Kondo: None. N. Morita: None. A. Kitahara: None. Y. Sumitani: None. K. Takahashi: None. T. Tanaka: None. T. Hosaka: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Ono Pharmaceutical Co., Ltd. H. Ishida: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Kowa pharmaceutical Co. Ltd., MSD, Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho.


Japan Ministry of Education, Culture, Sports, Science and Technology

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