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Two weeks of metformin treatment induces AMPK-dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle

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@article{e78fa167fd274452994ba6aae3163a40,
title = "Two weeks of metformin treatment induces AMPK-dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle",
abstract = "Metformin-induced activation of the 5'-AMP-activated protein kinase (AMPK) has been associated with enhanced glucose uptake in skeletal muscle, but so far no direct causality has been examined. We hypothesized that an effect of in vivo metformin treatment on glucose uptake in mouse skeletal muscles is dependent on AMPK signaling. Oral doses of metformin or saline treatment were given to muscle-specific kinase dead (KD) AMPKα2 mice and wild-type (WT) littermates either once or chronically for 2 wk. Soleus and extensor digitorum longus muscles were used for measurements of glucose transport and Western blot analyses. Chronic treatment with metformin enhanced insulin-stimulated glucose uptake in soleus muscles of WT (∼45{\%}, P < 0.01) but not of AMPK KD mice. Insulin signaling at the level of Akt protein expression or Thr(308) and Ser(473) phosphorylation was not changed by metformin treatment. Insulin signaling at the level of Akt and TBC1D4 protein expression as well as Akt Thr(308)/Ser(473) and TBC1D4 Thr(642)/Ser(711) phosphorylation were not changed by metformin treatment. Also, protein expressions of Rab4, GLUT4, and hexokinase II were unaltered after treatment. The acute metformin treatment did not affect glucose uptake in muscle of either of the genotypes. In conclusion, we provide novel evidence for a role of AMPK in potentiating the effect of insulin on glucose uptake in soleus muscle in response to chronic metformin treatment.",
keywords = "AMP-Activated Protein Kinases, Animals, Biological Transport, Female, Glucose, Glucose Transporter Type 4, Insulin, Metformin, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muscle, Skeletal, Time Factors",
author = "Kristensen, {Jonas M{\o}ller} and Treebak, {Jonas T} and Peter Schjerling and Laurie Goodyear and Wojtaszewski, {J{\o}rgen F P}",
note = "Copyright {\circledC} 2014 the American Physiological Society.",
year = "2014",
month = "5",
day = "15",
doi = "10.1152/ajpendo.00417.2013",
language = "English",
volume = "306",
pages = "E1099--109",
journal = "A J P: Endocrinology and Metabolism (Online)",
issn = "1522-1555",
publisher = "American Physiological Society",
number = "10",

}

RIS

TY - JOUR

T1 - Two weeks of metformin treatment induces AMPK-dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle

AU - Kristensen, Jonas Møller

AU - Treebak, Jonas T

AU - Schjerling, Peter

AU - Goodyear, Laurie

AU - Wojtaszewski, Jørgen F P

N1 - Copyright © 2014 the American Physiological Society.

PY - 2014/5/15

Y1 - 2014/5/15

N2 - Metformin-induced activation of the 5'-AMP-activated protein kinase (AMPK) has been associated with enhanced glucose uptake in skeletal muscle, but so far no direct causality has been examined. We hypothesized that an effect of in vivo metformin treatment on glucose uptake in mouse skeletal muscles is dependent on AMPK signaling. Oral doses of metformin or saline treatment were given to muscle-specific kinase dead (KD) AMPKα2 mice and wild-type (WT) littermates either once or chronically for 2 wk. Soleus and extensor digitorum longus muscles were used for measurements of glucose transport and Western blot analyses. Chronic treatment with metformin enhanced insulin-stimulated glucose uptake in soleus muscles of WT (∼45%, P < 0.01) but not of AMPK KD mice. Insulin signaling at the level of Akt protein expression or Thr(308) and Ser(473) phosphorylation was not changed by metformin treatment. Insulin signaling at the level of Akt and TBC1D4 protein expression as well as Akt Thr(308)/Ser(473) and TBC1D4 Thr(642)/Ser(711) phosphorylation were not changed by metformin treatment. Also, protein expressions of Rab4, GLUT4, and hexokinase II were unaltered after treatment. The acute metformin treatment did not affect glucose uptake in muscle of either of the genotypes. In conclusion, we provide novel evidence for a role of AMPK in potentiating the effect of insulin on glucose uptake in soleus muscle in response to chronic metformin treatment.

AB - Metformin-induced activation of the 5'-AMP-activated protein kinase (AMPK) has been associated with enhanced glucose uptake in skeletal muscle, but so far no direct causality has been examined. We hypothesized that an effect of in vivo metformin treatment on glucose uptake in mouse skeletal muscles is dependent on AMPK signaling. Oral doses of metformin or saline treatment were given to muscle-specific kinase dead (KD) AMPKα2 mice and wild-type (WT) littermates either once or chronically for 2 wk. Soleus and extensor digitorum longus muscles were used for measurements of glucose transport and Western blot analyses. Chronic treatment with metformin enhanced insulin-stimulated glucose uptake in soleus muscles of WT (∼45%, P < 0.01) but not of AMPK KD mice. Insulin signaling at the level of Akt protein expression or Thr(308) and Ser(473) phosphorylation was not changed by metformin treatment. Insulin signaling at the level of Akt and TBC1D4 protein expression as well as Akt Thr(308)/Ser(473) and TBC1D4 Thr(642)/Ser(711) phosphorylation were not changed by metformin treatment. Also, protein expressions of Rab4, GLUT4, and hexokinase II were unaltered after treatment. The acute metformin treatment did not affect glucose uptake in muscle of either of the genotypes. In conclusion, we provide novel evidence for a role of AMPK in potentiating the effect of insulin on glucose uptake in soleus muscle in response to chronic metformin treatment.

KW - AMP-Activated Protein Kinases

KW - Animals

KW - Biological Transport

KW - Female

KW - Glucose

KW - Glucose Transporter Type 4

KW - Insulin

KW - Metformin

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Muscle, Skeletal

KW - Time Factors

U2 - 10.1152/ajpendo.00417.2013

DO - 10.1152/ajpendo.00417.2013

M3 - Journal article

VL - 306

SP - E1099-109

JO - A J P: Endocrinology and Metabolism (Online)

JF - A J P: Endocrinology and Metabolism (Online)

SN - 1522-1555

IS - 10

ER -

ID: 44835006