Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes
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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 L; 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.
I: JCI Insight, Bind 3, Nr. 23, e93936, 2018, s. 1-16.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 L
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
Y1 - 2018
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.
U2 - 10.1172/jci.insight.93936
DO - 10.1172/jci.insight.93936
M3 - Journal article
C2 - 30518693
VL - 3
SP - 1
EP - 16
JO - JCI Insight
JF - JCI Insight
SN - 2379-3708
IS - 23
M1 - e93936
ER -
ID: 215565268