Sub-chronic stimulation of glucocorticoid receptor impairs and mineralocorticoid receptor protects cytosolic Ca2+ responses to glucose in pancreatic β-cells

The development of diabetes associated with stress, obesity, and metabolic syndrome involves elevated plasma glucocorticoid levels. It has been shown that short-term (< 1 day) exposure to glucocorticoids reduces insulin secretion from pancreatic islets by affecting several steps of glucose signaling in beta-cells. However, longer term direct effects of glucocorticoids on beta-cells remain to be established. In this study, single beta-cells isolated from rat islets were treated with glucocorticoids, mineralocorticoids, and their receptor agonists/antagonists for 3 days in culture, followed by assesment of the beta-cell responsiveness to glucose by measuring cytosolic Ca2+ concentration ([Ca2+](i)) using fura-2. Following treatment with corticosterone at 10-500 ng/ml for 3 days, the first-phase [Ca2+](i) response to 8.3 mM glucose in beta-cells was suppressed. Simultaneous administration of RU-486, a glucocorticoid receptor (GR) antagonist, prevented this suppression. RU-486 by itself promoted the beta-cell [Ca2+](i) response to glucose. Conversely, dexamethasone (1000 ng/ml), a highly selective GR agonist, impaired beta-cell [Ca2+](i) responses to glucose. A nuncralocorticoid receptor (MR) antagonist spironolactone, co-administered with corticosterone, further depressed [Ca2+], responses to glucose, while in MP, ligand aldosterone attenuated the corticosterone inhibition of [Ca2+](i) responses. Neither spironolactone nor aldosterone by itself affected [Ca2+](i) responses. These results indicate that long-term treatment with orticosterone impairs beta-cell [Ca2+](i) responses to glucose. This effect is mediated by GR, and attenuated partially by simultaneous NIP, stimulation by corticosterone. The results show a novel function of MR to protect islet beta-cells against deteriorating glucocorticoid action via GR.