Glucose-Dependent Insulinotropic Hormone Potentiates the Hypoglycemic Effect of Glibenclamide in Healthy Volunteers: Evidence for an Effect on Insulin Extraction1

Glucose-dependent insulinotropic hormone (GIP) is an intestinal hormone considered to be an important mediator of the incretin effect, i.e. the augmented insulin release observed in response to orally, compared with iv, administered glucose, despite isoglycemic glucose profiles. Stimulation of beta-cell secretion of insulin by GIP is seen both in vitro and in vivo at permissive extracellular glucose concentrations (> 6 mmol/L). It has also been claimed that part of the incretin effect is due to decreased insulin extraction. We now show that an infusion of GIP in healthy volunteers in whom blood glucose levels were maintained at 5 mmol/L, increased glibenclamide-stimulated levels of plasma insulin without significantly changing the C peptide profile. The increased plasma insulin levels necessitated extra glucose infusion to maintain euglycemia, demonstrating the biological significance of the elevated insulin levels. Infusion of GIP alone caused neither glucose changes nor elevation of C peptide or insulin levels. Hence, our results show that at a blood glucose concentration of 5 mmol/L, GIP augments the increase in plasma insulin levels stimulated by glibenclamide, possibly acting through a mechanism involving decreased insulin extraction in the liver or peripheral tissues, thus increasing insulin availability.