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Glucocorticoids reprogram beta cell signaling to preserve insulin secretion

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Title: Glucocorticoids reprogram beta cell signaling to preserve insulin secretion
Authors: Fine, NHF
Doig, CL
Elhassan, YS
Vierra, NC
Marchetti, P
Bugliani, M
Nano, R
Piemonti, L
Rutter, GA
Jacobson, DA
Lavery, GG
Hodson, DJ
Item Type: Journal Article
Abstract: 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.
Issue Date: 4-Dec-2017
Date of Acceptance: 16-Nov-2017
URI: http://hdl.handle.net/10044/1/55491
DOI: https://dx.doi.org/10.2337/db16-1356
ISSN: 0012-1797
Publisher: American Diabetes Association
Start Page: 278
End Page: 290
Journal / Book Title: Diabetes
Volume: 67
Issue: 2
Copyright Statement: © 2017 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. Source Database: pubmed
Sponsor/Funder: Diabetes UK
Medical Research Council (MRC)
European Foundation for the Study of Diabetes
Funder's Grant Number: 15821
MC_PC_14100
N/A
Keywords: 11 Medical And Health Sciences
Endocrinology & Metabolism
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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