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Glucocorticoids suppress GLP-1 secretion: possible contribution to their diabetogenic effects
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Karolinska Inst, Dept Clin Sci & Educ, Unit Diabet Res, SE-11883 Stockholm, Sweden.;Sodertalje Hosp, Dept Internal Med, SE-15286 Sodertalje, Sweden..
Karolinska Inst, Dept Clin Sci & Educ, Unit Diabet Res, SE-11883 Stockholm, Sweden..
Karolinska Inst, Dept Clin Sci & Educ, Unit Diabet Res, SE-11883 Stockholm, Sweden..
Karolinska Inst, Dept Clin Sci & Educ, Unit Diabet Res, SE-11883 Stockholm, Sweden.;Sodertalje Hosp, Dept Internal Med, SE-15286 Sodertalje, Sweden..
2015 (English)In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 129, no 5, 405-414 p.Article in journal (Refereed) Published
Abstract [en]

Evidence indicates that subtle abnormalities in GC (glucocorticoid) plasma concentrations and/or in tissue sensitivity to GCs are important in the metabolic syndrome, and it is generally agreed that GCs induce insulin resistance. In addition, it was recently reported that short-term exposure to GCs reduced the insulinotropic effects of the incretin GLP-1 (glucagon-like peptide 1). However, although defective GLP-1 secretion has been correlated with insulin resistance, potential direct effects of GCs on GLP-1-producing L-cell function in terms of GLP-1 secretion and apoptosis have not been studied in any greater detail. In the present study, we sought to determine whether GCs could exert direct effects on GLP-1-producing L-cells in terms of GLP-1 secretion and cell viability. We demonstrate that the GR (glucocorticoid receptor) is expressed in GLP-1-producing cells, where GR activation in response to dexamethasone induces SGK1 (serum-and glucocorticoid-inducible kinase 1) expression, but did not influence preproglucagon expression or cell viability. In addition, dexamethasone treatment of enteroendocrine GLUTag cells reduced GLP-1 secretion induced by glucose, 2-deoxy-D-glucose, fructose and potassium, whereas the secretory response to a phorbol ester was unaltered. Furthermore, in vivo administration of dexamethasone to rats reduced the circulating levels of GLP-1 concurrent with induction of insulin resistance and glucose intolerance. We can conclude that GR activation in GLP-1-producing cells will diminish the secretory responsiveness of these cells to subsequent carbohydrate stimulation. These effects may not only elucidate the pathogenesis of steroid diabetes, but could ultimately contribute to the identification of novel molecular targets for controlling incretin secretion.

Place, publisher, year, edition, pages
2015. Vol. 129, no 5, 405-414 p.
Keyword [en]
dexamethasone, glucagon-like peptide-1, glucocorticoids, insulin resistance
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-264061DOI: 10.1042/CS20140719ISI: 000361010900002PubMedID: 25853863OAI: oai:DiVA.org:uu-264061DiVA: diva2:858951
Available from: 2015-10-05 Created: 2015-10-05 Last updated: 2017-12-01Bibliographically approved

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Kappe, Camilla

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