Impaired cAMP generation contributes to defective glucose-stimulated insulin secretion after long-term exposure to palmitate
2015 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 3, 904-915 p.Article in journal (Refereed) Published
Chronic palmitate exposure impairs glucose-stimulated insulin secretion and other aspects of β-cell function but the underlying mechanisms are not known. Using various live-cell fluorescence imaging approaches we show here that long-term palmitate treatment influences cAMP signaling in pancreatic β-cells. Glucose stimulation of mouse and human β-cells induced oscillations of the sub-plasma-membrane cAMP concentration but after 48 h exposure to palmitate, most β-cells failed to increase cAMP in response to glucose. In contrast, GLP-1-triggered cAMP formation and glucose- and depolarization-induced increases in cytoplasmic Ca2+ concentration were unaffected by the fatty acid treatment. Insulin secretion from control β-cells was pulsatile but the response deteriorated after long-term palmitate exposure. Palmitate-treated mouse islets showed reduced expression of adenylyl cyclase 9 and knockdown of this protein in insulinoma cells reduced the glucose-stimulated cAMP response and insulin secretion. We conclude that impaired glucose-induced generation of cAMP is an important determinant of defective insulin secretion after chronic palmitate exposure.
Place, publisher, year, edition, pages
2015. Vol. 64, no 3, 904-915 p.
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-192309DOI: 10.2337/db14-1036ISI: 000350235900031PubMedID: 25281428OAI: oai:DiVA.org:uu-192309DiVA: diva2:589354
FunderSwedish Research Council