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Excessive glucocorticoid exposure has been shown to be deleterious for pancreatic beta-cell function and insulin release. However, glucocorticoids at physiological levels are essential for many homeostatic processes, including glycemic control. We show that corticosterone and cortisol and their less active precursors 11-dehydrocorticosterone (11-DHC) and cortisone suppress voltage-dependent Ca(2+) channel function and Ca(2+) fluxes in rodent as well as in human beta-cells. However, insulin secretion, maximal ATP/ADP responses to glucose, and beta-cell identity were all unaffected. Further examination revealed the upregulation of parallel amplifying cAMP signals and an increase in the number of membrane-docked insulin secretory granules. Effects of 11-DHC could be prevented by lipotoxicity and were associated with paracrine regulation of glucocorticoid activity because global deletion of 11beta-hydroxysteroid dehydrogenase type 1 normalized Ca(2+) and cAMP responses. Thus, we have identified an enzymatically amplified feedback loop whereby glucocorticoids boost cAMP to maintain insulin secretion in the face of perturbed ionic signals. Failure of this protective mechanism may contribute to diabetes in states of glucocorticoid excess, such as Cushing syndrome, which are associated with frank dyslipidemia.

Original publication




Journal article



Publication Date





278 - 290


11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics/metabolism Animals Biomarkers/metabolism Calcium Channels/chemistry/metabolism *Calcium Signaling Cell Differentiation Corticosterone/analogs & derivatives/*metabolism Cortisone/metabolism Cyclic AMP/metabolism Glucocorticoids/*metabolism Glucose/metabolism Humans Hydrocortisone/*metabolism Insulin/genetics/*metabolism Insulin Secretion Insulin-Secreting Cells/cytology/*metabolism Kinetics Mice, Inbred Strains Mice, Knockout Tissue Culture Techniques