Impaired cAMP Generation Contributes to Defective Glucose-Stimulated Insulin Secretion After Long-term Exposure to Palmitate

Chronic palmitate exposure impairs glucose-stimulated insulin secretion and other aspects of -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 -cells. Glucose stimulation of mouse and human -cells induced oscillations of the subplasma-membrane cAMP concentration, but after 48 h exposure to palmitate, most -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 -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.