Effects of chronic exposure of clonal b- cells to elevated glucose and free fatty acids on incretin receptor gene expression and secretory responses to GIP and GLP-1

AimThe incretin effect, mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is impaired in type 2 diabetes. MethodsThis study examines the effects of prolonged exposure to elevated glucose and free fatty acids in clonal BRIN BD11 cells on GIP and GLP-1 action. ResultsGlucotoxic conditions (18h) had no effect on GIP- or GLP-1-mediated insulinotropic responses. In contrast, 48h glucotoxic culture impaired (p<0.05 to p<0.001) insulin release in response to GLP-1, and particularly GIP. Culture under lipotoxic conditions (18h) impaired (p<0.05 to p<0.001) the insulin-releasing effect of GIP, but was without effect on GLP-1. However, 48h lipotoxic culture compromised both GIP (p<0.05 to p<0.001) and GLP-1 (p<0.05 to p<0.01) insulin-releasing actions. Glucolipotoxic culture (18h) completely annulled the insulinotropic action of GIP, whereas GLP-1 effects were similar to control. However, when glucolipotoxic culture was extended to 48h, both GIP- and GLP-1-mediated effects were (p<0.05 to p<0.001) impaired. Assessment of cell viability, number and insulin content revealed detrimental (p<0.05 to p<0.001) effects under all culture conditions, barring 18h glucotoxic and lipotoxic culture. Finally, GIP-R gene and protein expression was increased (p<0.05 to p<0.01) under glucotoxic culture, with decreased (p<0.05 to p<0.001) expression following glucolipotoxic culture. GLP-1-R gene expression followed a similar trend, but protein levels were generally reduced under all culture conditions. ConclusionThe results indicate that impaired insulinotropic response to GIP and GLP-1 under diabetic milieu involves mechanisms beyond simple expression of respective receptors.