Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes

Emilie Bahne, Emily W.L. Sun, Richard Young, Morten Hansen, David P. Sonne, Jakob S. Hansen, Ulrich Rohde, Alice P. Liou, Margaret L. Jackson, Dayan de Fontgalland, Philippa Rabbitt, Paul Hollington, Luigi Sposato, Steven Due, David A. Wattchow, Jens F. Rehfeld, Jens J. Holst, Damien J. Keating, Tina Vilsbøll, Filip K. Knop

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

BACKGROUND: Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS: Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS: Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS: Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose-lowering effect and mode of action. TRIAL REGISTRATION: NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074). FUNDING: This study received grants from the A.P. Møller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc.

LanguageEnglish
JournalJCI Insight
Volume3
Issue number23
Early online date6 Dec 2018
DOIs
Publication statusPublished - 6 Dec 2018

Keywords

  • Diabetes
  • Endocrinology
  • Metabolism

Cite this

Bahne, Emilie ; Sun, Emily W.L. ; Young, Richard ; Hansen, Morten ; Sonne, David P. ; Hansen, Jakob S. ; Rohde, Ulrich ; Liou, Alice P. ; Jackson, Margaret L. ; de Fontgalland, Dayan ; Rabbitt, Philippa ; Hollington, Paul ; Sposato, Luigi ; Due, Steven ; Wattchow, David A. ; Rehfeld, Jens F. ; Holst, Jens J. ; Keating, Damien J. ; Vilsbøll, Tina ; Knop, Filip K. / Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes. In: JCI Insight. 2018 ; Vol. 3, No. 23.
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abstract = "BACKGROUND: Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS: Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS: Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS: Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose-lowering effect and mode of action. TRIAL REGISTRATION: NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074). FUNDING: This study received grants from the A.P. M{\o}ller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc.",
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author = "Emilie Bahne and Sun, {Emily W.L.} and Richard Young and Morten Hansen and Sonne, {David P.} and Hansen, {Jakob S.} and Ulrich Rohde and Liou, {Alice P.} and Jackson, {Margaret L.} and {de Fontgalland}, Dayan and Philippa Rabbitt and Paul Hollington and Luigi Sposato and Steven Due and Wattchow, {David A.} and Rehfeld, {Jens F.} and Holst, {Jens J.} and Keating, {Damien J.} and Tina Vilsb{\o}ll and Knop, {Filip K.}",
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Bahne, E, Sun, EWL, Young, R, Hansen, M, Sonne, DP, Hansen, JS, Rohde, U, Liou, AP, Jackson, ML, de Fontgalland, D, Rabbitt, P, Hollington, P, Sposato, L, Due, S, Wattchow, DA, Rehfeld, JF, Holst, JJ, Keating, DJ, Vilsbøll, T & Knop, FK 2018, 'Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes', JCI Insight, vol. 3, no. 23. https://doi.org/10.1172/jci.insight.93936

Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes. / Bahne, Emilie; Sun, Emily W.L.; Young, Richard; Hansen, Morten; Sonne, David P.; Hansen, Jakob S.; Rohde, Ulrich; Liou, Alice P.; Jackson, Margaret L.; de Fontgalland, Dayan; Rabbitt, Philippa; Hollington, Paul; Sposato, Luigi; Due, Steven; Wattchow, David A.; Rehfeld, Jens F.; Holst, Jens J.; Keating, Damien J.; Vilsbøll, Tina; Knop, Filip K.

In: JCI Insight, Vol. 3, No. 23, 06.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes

AU - Bahne, Emilie

AU - Sun, Emily W.L.

AU - Young, Richard

AU - Hansen, Morten

AU - Sonne, David P.

AU - Hansen, Jakob S.

AU - Rohde, Ulrich

AU - Liou, Alice P.

AU - Jackson, Margaret L.

AU - de Fontgalland, Dayan

AU - Rabbitt, Philippa

AU - Hollington, Paul

AU - Sposato, Luigi

AU - Due, Steven

AU - Wattchow, David A.

AU - Rehfeld, Jens F.

AU - Holst, Jens J.

AU - Keating, Damien J.

AU - Vilsbøll, Tina

AU - Knop, Filip K.

PY - 2018/12/6

Y1 - 2018/12/6

N2 - BACKGROUND: Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS: Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS: Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS: Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose-lowering effect and mode of action. TRIAL REGISTRATION: NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074). FUNDING: This study received grants from the A.P. Møller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc.

AB - BACKGROUND: Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS: Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS: Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS: Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose-lowering effect and mode of action. TRIAL REGISTRATION: NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074). FUNDING: This study received grants from the A.P. Møller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc.

KW - Diabetes

KW - Endocrinology

KW - Metabolism

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U2 - 10.1172/jci.insight.93936

DO - 10.1172/jci.insight.93936

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JO - JCI Insight

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