Defective glucose-dependent insulinotropic polypeptide receptor expressionin diabetic fatty Zucker rats

Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone tha t is released postprandially from the small intestine and acts in concert w ith glucagon-like peptide (GLP)-1 to potentiate glucose-induced insulin sec retion from the pancreatic B-cen. In type 2 diabetes, there is a decreased responsiveness of the pancreas to GIP; however, the insulin response to GLP -1 remains intact. The Literature suggests that the ineffectiveness of GIP in type 2 diabetes may be a result of chronic homologous desensitization of the GIP receptor. Yet, there has been no conclusive evidence suggesting th at GIP levels are elevated in diabetes. The hypothesis of the present study is that one cause of decreased responsiveness to GIP in type 2 diabetes is an inappropriate expression of the GIP receptor in the pancreatic islet. T his hypothesis was tested using a strain of diabetic fatty Zucker rats. The obese rats displayed basal GIP levels similar to the control animals; howe ver, they mere unresponsive to a GIP infusion (4 pmol.min(-1) kg(-1)), wher eas the lean animals displayed a significant reduction in blood glucose (GI P levels, 50% control after 60 min, P < 0.05) as well as a significant incr ease in circulating insulin. GIP also potently stimulated first-phase insul in secretion from isolated perifused islets (10.3 +/- 3.0 x basal), and GIP and GLP-1 potentiated insulin secretion from the perfused pancreas (6 x co ntrol area under the curve [AUC]) from lean animals. GIP yielded no signifi cant effect in the Vancouver diabetic fatty Zucker (VDF) rat pancreases, wh ereas GLP-1 elicited an eightfold increase of insulin secretion from the pe rfused VDF pancreas. Islets from lean animals subjected to static incubatio ns with GIP showed a 2.2-fold increase in cAMP, whereas GIP failed to incre ase islet cAMP in the VDF islets. Finally, the expression of both GIP recep tor mRNA and protein was decreased in islets from VDF rats. These data sugg est that the decreased effectiveness of GIP in the VDF rat and in type 2 di abetes may be a result of a decreased receptor expression in the islet.