title: Impaired cAMP generation contributes to defective glucose-stimulated insulin secretion after long-term exposure to palmitate.
abstract: 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 subplasma-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.
authors.affiliation: Binzhou Medical University, Yantai, Shandong, China Department of Medical Cell Biology, Uppsala University Biomedical Centre, Uppsala, Sweden.
authors.forename: Geng
authors.initials: G
authors.lastname: Tian
authors.affiliation: Department of Medical Cell Biology, Uppsala University Biomedical Centre, Uppsala, Sweden.
authors.forename: E-ri Maria
authors.initials: ER
authors.lastname: Sol
authors.affiliation: Department of Medical Cell Biology, Uppsala University Biomedical Centre, Uppsala, Sweden.
authors.forename: Yunjian
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Medical Cell Biology, Uppsala University Biomedical Centre, Uppsala, Sweden.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Shuai
authors.affiliation: Department of Medical Cell Biology, Uppsala University Biomedical Centre, Uppsala, Sweden anders.tengholm@mcb.uu.se.
authors.forename: Anders
authors.initials: A
authors.lastname: Tengholm
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D019308:Palmitic Acid / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D019308:Palmitic Acid; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D005947:Glucose; D002118:Calcium