Glucocorticoids directly inhibit insulin biosynthesis via the glucocorticoid receptor in pancreatic β-cells

Abstract

Glucocorticoids induce hyperglycemia by promoting hepatic gluconeogenesis and impairing insulin sensitivity in peripheral tissues. However, their direct effects on pancreatic β-cells remained poorly understood. This study investigated whether glucocorticoids directly impair insulin biosynthesis in pancreatic β-cells, using both in vivo and in vitro models. In vivo, male C57BL/6J mice were treated with vehicle, corticosterone, or dexamethasone in drinking water for two weeks. Pancreatic β-cell line MIN6 cells were treated with and without a glucocorticoid receptor (GR) antagonist RU-486 or a JNK inhibitor SP600125. GR knockdown was also performed using siRNA. In vivo, dexamethasone, but not corticosterone, induced hyperglycemia and insulin resistance, while both corticosterone and dexamethasone reduced high-quality insulin granules and suppressed the expression of insulin biosynthesis-related genes in pancreatic islets. In vitro, dexamethasone decreased the expression of Ins1, Ins2, Pdx1, and Mafa, and significantly reduced glucose-stimulated insulin secretion (GSIS). RU-486, SP600125, or GR knockdown ameliorated these impairments. Electron microscopy showed the reduction of insulin granule density in dexamethasone-treated cells, which was preserved by GR or JNK inhibition. Glucocorticoids directly suppress insulin biosynthesis in pancreatic β-cells via GR signaling despite preserved or enhanced glucose-stimulated insulin secretion in vivo. It is likely that inhibition of GR/JNK signaling may represent a potential strategy to protect β-cells from steroid-induced dysfunction.