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.