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Effects of chronic exposure of clonal β‐cells to elevated glucose and free fatty acids on incretin receptor gene expression and secretory responses to GIP and GLP ‐1
Author(s) -
Pathak V.,
Vasu S.,
Flatt P. R.,
Irwin N.
Publication year - 2014
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12227
Subject(s) - incretin , medicine , endocrinology , glucagon like peptide 1 , insulin , gastric inhibitory polypeptide , type 2 diabetes , receptor , biology , glucagon , diabetes mellitus , chemistry
Abstract Aim The incretin effect, mediated by glucose‐dependent insulinotropic polypeptide ( GIP ) and glucagon‐like peptide‐1 ( GLP ‐1), is impaired in type 2 diabetes. Methods This 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. Results Glucotoxic conditions (18 h) had no effect on GIP ‐ or GLP ‐1‐mediated insulinotropic responses. In contrast, 48 h glucotoxic culture impaired (p < 0.05 to p < 0.001) insulin release in response to GLP ‐1, and particularly GIP . Culture under lipotoxic conditions (18 h) impaired (p < 0.05 to p < 0.001) the insulin‐releasing effect of GIP , but was without effect on GLP ‐1. However, 48 h 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 (18 h) completely annulled the insulinotropic action of GIP , whereas GLP ‐1 effects were similar to control. However, when glucolipotoxic culture was extended to 48 h, 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 18 h 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. Conclusion The results indicate that impaired insulinotropic response to GIP and GLP ‐1 under diabetic milieu involves mechanisms beyond simple expression of respective receptors.