This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Aaboe, K. Articles by Krarup, T. Search for Related Content PubMed PubMed Citation Articles by Aaboe, K. Articles by Krarup, T. Related Collections Diabetes and Insulin

K_ATP Channel Closure Ameliorates the Impaired Insulinotropic Effect of Glucose-Dependent Insulinotropic Polypeptide in Patients with Type 2 Diabetes

Department of Internal Medicine F (K.A., F.K.K., T.V., T.K.), Gentofte Hospital, University of Copenhagen, 2900 Copenhagen, Denmark; Department of Biomedical Sciences (K.A., C.F.D., J.J.H.), Panum Institute, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Endocrinology (S.M.), Hvidovre Hospital, University of Copenhagen, 2650 Copenhagen, Denmark; Department of Clinical Pharmacology (U.S.), University of Århus, 8000 Århus, Denmark; and Statistician (A.V.) 2920 Charlottenlund, Denmark

Address all correspondence and requests for reprints to: Kasper Aaboe, M.D., Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Niels Andersens Vej 65, Hellerup DK-2900, Denmark. E-mail: Kasper{at}dadlnet.dk.

Objective: The reduced incretin effect in subjects with type 2 diabetes is accompanied by a severely impaired insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP). The K_ATP channels of the β-cell appear to be essential for the function of GIP in mice, and mutations in the gene encoding these channels have been linked to the development of type 2 diabetes. With this study we therefore aimed at clarifying the role of K_ATP channel malfunction in the impaired function of GIP.

Research Design and Methods: We examined 12 subjects with type 2 diabetes using a 2-h (15 mM) hyperglycemic clamp on 4 separate days with concomitant infusion of one of the following: GIP; GIP + 10 mg sulfonylurea (SU, glipizide) taken orally 1 h before the clamp; saline + 10 mg SU; or saline alone. Blood was sampled to measure plasma concentrations of glucose, intact GIP, insulin, C-peptide, and glucagon.

Results: Compared to the results of GIP alone, SU alone, or those results added together, coadministration of GIP and SU resulted in a more-than-additive increase in the peripheral insulin (P = 0.002) and C-peptide (P = 0.028) responses and furthermore, a more-than-additive increase in total (P = 0.01), early (P = 0.02), and late-phase (P = 0.02) insulin secretion.

Conclusion: We have demonstrated that inhibiting the K_ATP channels of the diabetic β-cell acutely using SU significantly increases both the peripheral insulin response to GIP and GIP-induced insulin secretion, indicating an ameliorated insulinotropic effect of GIP.