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Cited by 806Metabolism, Diabetes, and CancerDiabetes Treatment and ManagementNatural Antidiabetic Agents Studies

Metformin Increases AMP-Activated Protein Kinase Activity in Skeletal Muscle of Subjects With Type 2 Diabetes

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Musi, Nicolas, Hirshman, Michael F., Nygren, Jonas, Svanfeldt, Monika, Bavenholm, Peter, Rooyackers, Olav, Zhou, Gaochao, Williamson, Joanne M. +5 more·2002·Diabetes
DOI 10.2337/diabetes.51.7.2074
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Abstract

Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK α2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK α2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK α2.

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  • Metformin diminishes hepatic glucose output due to glycogenolysis/gluconeogenesis and enhances glucose uptake into peripheral tissues by activating AMPK-α2.

    “It not only diminishes hepatic glucose output due to glycogenolysis/gluconeogenesis342 but it also enhances glucose uptake into peripheral tissues, such as skeletal muscle, by activating 5′-adenosine monophosphate-activated protein kinase (AMPK-α2).343”

    From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [343]

    Citation 343 is attached to the peripheral-uptake and AMPK-α2 clause, not the hepatic-output clause cited to 342. The Abstract and Discussion (pages unavailable in our copy) report increased skeletal-muscle AMPK-α2 activity alongside enhanced glucose disposal after metformin treatment in subjects with type 2 diabetes. They suggest AMPK-α2 activation may mediate the effect, but do not establish the claim’s definite causal wording, “by activating.” (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • AMPK is a critical regulator of glucose and fat metabolism in skeletal muscle during exercise.

    “Furthermore, AMPK is a critical regulator of glucose and fat metabolism in skeletal muscle during exercise (38,45).”

    From Signaling Specificity of Interleukin-6 Action on Glucose and Lipid Metabolism in Skeletal Muscle (2006) · cites this paper as [45]

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Authors
Musi, N., Hirshman, M. F., Nygren, J., Svanfeldt, M., Bavenholm, P., Rooyackers, O., Zhou, G., Williamson, J. M., Ljunqvist, O., Efendic, S., Moller, D. E., Thorell, A., & Goodyear, L. J.
Affiliations
  • Brigham and Women's Hospital (US)
  • Karolinska Institutet (SE)
  • Department of Surgery, Huddinge University Hospital, Huddinge, Sweden
  • Division of Medicine, Karolinska Hospital and Institute, Stockholm, Sweden
  • Department of Anesthesiology and Intensive Care, Huddinge University Hospital, Huddinge, Sweden
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • Division of Molecular Medicine, Karolinska Hospital and Institute, Stockholm, Sweden
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2002-07-01
Volume
51
Issue
7
Pages
2074-2081
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.51.7.2074
OpenAlex
W2122649002
Cited by
806
References
67
Citations by year
2026: 11 · 2025: 18 · 2024: 21 · 2023: 34 · 2022: 39 · 2021: 37 · 2020: 27 · 2019: 41 · 2018: 38 · 2017: 28 · 2016: 42 · 2015: 35 · 2014: 48 · 2013: 49 · 2012: 37
FWCI
8.58
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Diabetes Association
  • Brigham and Women's Hospital
  • National Institutes of Health
  • Medical Research Council
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR45670, R01AR045670)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords
metformin, AMPK, AMPKα2, type 2 diabetes, skeletal muscle, glucose disposal, acetyl-CoA carboxylase 2, muscle glycogen, hepatic glucose production, Thr172 phosphorylation
MeSH terms
Blood Glucose, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Female, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Insulin, Kinetics, Lipids, Male, Metformin, Middle Aged, Multienzyme Complexes, Time Factors, Protein Serine-Threonine Kinases, Muscle, Skeletal, AMP-Activated Protein Kinases

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