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 beta-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 beta-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.
Keywords: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Infusion Pumps; Insulin; Insulin Resistance; Ion Channel Gating; KATP Channels; Male; Middle Aged; Sulfonylurea Compounds