Glucose-dependent insulinotropic
polypeptide (GIP) is a
peptide hormone that is released postprandially from the small intestine and acts in concert with
glucagon-like peptide (GLP)-1 to potentiate
glucose-induced insulin secretion from the pancreatic beta-cell. 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 that 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. This hypothesis was tested using a strain of diabetic fatty Zucker rats. The obese rats displayed basal GIP levels similar to the control animals; however, they were unresponsive to a GIP infusion (4 pmol.min(-1). kg(-1)), whereas the lean animals displayed a significant reduction in
blood glucose (GIP levels, 50% control after 60 min, P < 0.05) as well as a significant increase in circulating
insulin. GIP also potently stimulated first-phase insulin 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 control area under the curve [AUC]) from lean animals. GIP yielded no significant effect in the Vancouver diabetic fatty Zucker (VDF) rat pancreases, whereas
GLP-1 elicited an eightfold increase of insulin secretion from the perfused VDF pancreas. Islets from lean animals subjected to static incubations with GIP showed a 2.2-fold increase in cAMP, whereas GIP failed to increase islet cAMP in the VDF islets. Finally, the expression of both
GIP receptor mRNA and
protein was decreased in islets from VDF rats. These data suggest that the decreased effectiveness of GIP in the VDF rat and in
type 2 diabetes may be a result of a decreased receptor expression in the islet.