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

Kasper Aaboe; Filip Krag Knop; Tina Vilsboll; Aage Vølund; Ulf Simonsen; Carolyn F. Deacon; Sten Madsbad; Jens Juul Holst; Thure Krarup

doi:10.1210/jc.2008-1731

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

Kasper Aaboe, Filip Krag Knop, Tina Vilsboll, Aage Vølund, Ulf Simonsen, Carolyn F. Deacon, Sten Madsbad, Jens Juul Holst, Thure Krarup

42 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	94
Issue number	2
Pages (from-to)	603-8
Number of pages	6
ISSN	0021-972X
DOIs	https://doi.org/10.1210/jc.2008-1731
Publication status	Published - 2008

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10.1210/jc.2008-1731

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Aaboe, K., Knop, F. K., Vilsboll, T., Vølund, A., Simonsen, U., Deacon, C. F., Madsbad, S., Holst, J. J., & Krarup, T. (2008). KATP channel closure ameliorates the impaired insulinotropic effect of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism, 94(2), 603-8. https://doi.org/10.1210/jc.2008-1731

KATP channel closure ameliorates the impaired insulinotropic effect of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. / Aaboe, Kasper; Knop, Filip Krag; Vilsboll, Tina et al.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 94, No. 2, 2008, p. 603-8.

Research output: Contribution to journal › Journal article › Research › peer-review

Aaboe, K, Knop, FK, Vilsboll, T, Vølund, A, Simonsen, U, Deacon, CF , Madsbad, S , Holst, JJ & Krarup, T 2008, 'KATP channel closure ameliorates the impaired insulinotropic effect of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes', Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 2, pp. 603-8. https://doi.org/10.1210/jc.2008-1731

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

abstract = "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.",

author = "Kasper Aaboe and Knop, {Filip Krag} and Tina Vilsboll and Aage V{\o}lund and Ulf Simonsen and Deacon, {Carolyn F.} and Sten Madsbad and Holst, {Jens Juul} and Thure Krarup",

note = "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",

year = "2008",

doi = "10.1210/jc.2008-1731",

language = "English",

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T1 - KATP channel closure ameliorates the impaired insulinotropic effect of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

AU - Aaboe, Kasper

AU - Knop, Filip Krag

AU - Vilsboll, Tina

AU - Vølund, Aage

AU - Simonsen, Ulf

AU - Deacon, Carolyn F.

AU - Madsbad, Sten

AU - Holst, Jens Juul

AU - Krarup, Thure

N1 - 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

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1210/jc.2008-1731

DO - 10.1210/jc.2008-1731

M3 - Journal article

C2 - 19050053

SN - 0021-972X

VL - 94

SP - 603

EP - 608

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 2

ER -

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

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