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¹ Division of Integrative Physiology, Department of Physiology² Department of Surgery, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan

(Correspondence should be addressed to T Yada; Email: tyada{at}jichi.ac.jp)

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 β-cells. However, longer term direct effects of glucocorticoids on β-cells remain to be established. In this study, single β-cells isolated from rat islets were treated with glucocorticoids, mineralocorticoids, and their receptor agonists/antagonists for 3 days in culture, followed by assessment of the β-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 β-cells was suppressed. Simultaneous administration of RU-486, a glucocorticoid receptor (GR) antagonist, prevented this suppression. RU-486 by itself promoted the β-cell [Ca²⁺]_i response to glucose. Conversely, dexamethasone (1000 ng/ml), a highly selective GR agonist, impaired β-cell [Ca²⁺]_i responses to glucose. A mineralocorticoid receptor (MR) antagonist spironolactone, co-administered with corticosterone, further depressed [Ca²⁺]_i responses to glucose, while an MR 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 corticosterone impairs β-cell [Ca²⁺]_i responses to glucose. This effect is mediated by GR and attenuated partially by simultaneous MR stimulation by corticosterone. The results show a novel function of MR to protect islet β-cells against deteriorating glucocorticoid action via GR.