KATP channel closure ameliorates the impaired insulinotropic effect of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

J Clin Endocrinol Metab. 2009 Feb;94(2):603-8. doi: 10.1210/jc.2008-1731. Epub 2008 Dec 2.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Dose-Response Relationship, Drug
  • Female
  • Gastric Inhibitory Polypeptide / administration & dosage
  • Gastric Inhibitory Polypeptide / pharmacology*
  • Glucagon / blood
  • Glucose Clamp Technique
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacology
  • Infusion Pumps
  • Insulin / metabolism*
  • Insulin Resistance / physiology
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology*
  • KATP Channels / metabolism*
  • KATP Channels / physiology
  • Male
  • Middle Aged
  • Sulfonylurea Compounds / administration & dosage
  • Sulfonylurea Compounds / pharmacology


  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • KATP Channels
  • Sulfonylurea Compounds
  • Gastric Inhibitory Polypeptide
  • Glucagon