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Restoration of the insulinotropic effect of glucose-dependent insulinotropic polypeptide contributes to the antidiabetic effect of dipeptidyl peptidase-4 inhibitors

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Authors:
  • Aaboe, K. ;
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    unknown
  • Akram, S. ;
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    unknown
  • Deacon, C. F. ;
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    Endocrinology and Metabolism, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet
  • Holst, J. J. ;
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    Orcid logo0000-0001-6853-3805
    Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet
  • Madsbad, S. ;
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    Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
  • Krarup, T.
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    unknown
DOI:
10.1111/dom.12395
Abstract:
AIMS: To examine whether 12 weeks of treatment with a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, influences the insulin secretion induced by glucose, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during a hyperglycaemic clamp in patients with type 2 diabetes (T2DM). METHODS: A randomized, double-blind, placebo-controlled study was conducted over 12 weeks, during which 25 patients with T2DM completed treatment with either sitagliptin (100 mg once daily) or placebo as add-on therapy to metformin [sitagliptin group (n = 12): mean ± standard error of the mean (s.e.m.) age 54 ± 2.5 years, mean ± s.e.m. HbA1c 7.8 ± 0.2%; placebo group (n = 13): mean ± s.e.m. age: 57 ± 3.0 years, mean ± s.e.m. HbA1c 7.9 ± 0.2 %]. In weeks 1 and 12, the patients underwent three 2-h 15-mM hyperglycaemic clamp experiments with infusion of either saline, GLP-1 or GIP. β-cell function was evaluated according to first-phase, second-phase, incremental and total insulin and C-peptide responses. RESULTS: In the sitagliptin group, the mean HbA1c concentration was significantly reduced by 0.9% (p = 0.01). The total β-cell response during GIP infusion improved significantly from week 1 to week 12, both within the sitagliptin group (p = 0.004) and when compared with the placebo group (p = 0.04). The total β-cell response during GLP-1 infusion was significantly higher (p = 0.001) when compared with saline and GIP infusion, but with no improvement from week 1 to week 12. No significant changes in β-cell function occurred in the placebo group. CONCLUSIONS: Treatment with the DPP-4 inhibitor sitagliptin over 12 weeks in patients with T2DM partially restored the lost insulinotropic effect of GIP, whereas the preserved insulinotropic effect of GLP-1 was not further improved. A gradual enhancement of the insulinotropic effect of GIP, therefore, possibly contributes to the antidiabetic actions of DPP-4 inhibitors.
Type:
Journal article
Language:
English
Published in:
Diabetes, Obesity and Metabolism, 2015, Vol 17, Issue 1, p. 74-81
Keywords:
Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
Main Research Area:
Medical science
Publication Status:
Published
Review type:
Peer Review
Submission year:
2015
Scientific Level:
Scientific
ID:
271183521

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