title: 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.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  The results indicate that impaired insulinotropic response to GIP and GLP-1 under diabetic milieu involves mechanisms beyond simple expression of respective receptors.
authors.affiliation: SAAD Centre for Pharmacy Diabetes, University of Ulster, Coleraine, UK.
authors.forename: V
authors.initials: V
authors.lastname: Pathak
authors.forename: S
authors.initials: S
authors.lastname: Vasu
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
authors.forename: N
authors.initials: N
authors.lastname: Irwin
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism* / Q000494:pharmacology; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D015870:Gene Expression; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D054795:Incretins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D054795:Incretins; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; C041086:gastric inhibitory polypeptide receptor; D005947:Glucose
keywords: diabetes; glucagon-like peptide-1 (GLP-1); glucose-dependent insulinotropic polypeptide (GIP); insulin release