Glucocorticoids Reprogram Beta Cell Signaling to Preserve Insulin Secretion

NHF Fine, CL Doig, YS Elhassan, NC Vierra, P Marchetti, Marco Bugliani, R Nano, L Piemonti, GA Rutter, DA Jacobson, GG Lavery, DJ Hodson

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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. Here, we show that corticosterone and cortisol and their less active precursors, 11-dehydrocorticosterone (11-DHC) and cortisone, suppress voltage-dependent Ca2+ channel function and Ca2+ fluxes in rodent as well as 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, since global deletion of 11β-hydroxysteroid dehydrogenase type 1 normalized Ca2+ 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's syndrome, which are associated with frank dyslipidemia. © 2017 by the American Diabetes Association.
Original languageEnglish
Pages (from-to)278-290
Number of pages13
Issue number2
Publication statusPublished - 2018

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    Fine, NHF., Doig, CL., Elhassan, YS., Vierra, NC., Marchetti, P., Bugliani, M., Nano, R., Piemonti, L., Rutter, GA., Jacobson, DA., Lavery, GG., & Hodson, DJ. (2018). Glucocorticoids Reprogram Beta Cell Signaling to Preserve Insulin Secretion. Diabetes, 67(2), 278-290.