Sub-chronic stimulation of glucocorticoid receptor impairs and mineralocorticoid receptor protects cytosolic Ca2+ responses to glucose in pancreatic beta-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 assessment 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 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 beta-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 beta-cells against deteriorating glucocorticoid action via GR.
Koizumi
Masaru
M
Division of Integrative Physiology, Department of Physiology Department of Surgery, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.
Yada
Toshihiko
T
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003345:Corticosterone / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D015735:Mifepristone / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D013148:Spironolactone / Q000494:pharmacology
D007328:Insulin; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D015735:Mifepristone; D000450:Aldosterone; D037342:Pertussis Toxin; D005947:Glucose; D002118:Calcium; D003345:Corticosterone