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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.