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


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.


CONCLUSIONS
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.
Aaboe
Kasper
K
Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Niels Andersens Vej 65, Hellerup DK-2900, Denmark. Kasper@dadlnet.dk
Knop
Filip Krag
FK
Vilsboll
Tina
T
Vølund
Aage
A
Simonsen
Ulf
U
Deacon
Carolyn Fiona
CF
Madsbad
Sten
S
Holst
Jens Juul
JJ
Krarup
Thure
T
D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage / Q000494:pharmacology*; D005934:Glucagon / Q000097:blood; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D007260:Infusion Pumps; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D054086:KATP Channels / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D054086:KATP Channels; D013453:Sulfonylurea Compounds; D005749:Gastric Inhibitory Polypeptide; D005934:Glucagon