Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism.

Hayashi, T; Hirshman, M F; Fujii, N; Habinowski, S A; Witters, L A; Goodyear, L J

doi:10.2337/diabetes.49.4.527

Cited by 447Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismNatural Antidiabetic Agents Studies

Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism.

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Hayashi, T, Hirshman, M F, Fujii, N, Habinowski, S A, Witters, L A, Goodyear, L J·2000·Diabetes

DOI 10.2337/diabetes.49.4.527

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Abstract

5'AMP-activated protein kinase (AMPK) can be activated in response to cellular fuel depletion and leads to switching off ATP-consuming pathways and switching on ATP-regenerating pathways in many cell types. We have hypothesized that AMPK is a central mediator of insulin-independent glucose transport, which enables fuel-depleted muscle cells to take up glucose for ATP regeneration under conditions of metabolic stress. To test this hypothesis, rat epitrochlearis muscles were isolated and incubated in vitro under several conditions that evoke metabolic stress accompanied by intracellular fuel depletion. Rates of glucose transport in the isolated muscles were increased by all of these conditions, including contraction (5-fold above basal), hypoxia (8-fold), 2,4-dinotrophenol (11-fold), rotenone (7-fold), and hyperosmolarity (8-fold). All of these stimuli simultaneously increased both alpha1 and alpha2 isoform-specific AMPK activity. There was close correlation between alpha1 (r2 = 0.72) and alpha2 (r2 = 0.67) AMPK activities and the rate of glucose transport, irrespective of the metabolic stress used, all of which compromised muscle fuel status as judged by ATP, phosphocreatine, and glycogen content. 5-Aminoimidazole-4-carboxamide ribonucleoside, a pharmacological AMPK activator that is metabolized to an AMP-mimetic ZMP, also increased both glucose transport and AMPK activity but did not change fuel status. Insulin stimulated glucose transport by 6.5-fold above basal but did not affect AMPK activity. These results suggest that the activation of AMPK may be a common mechanism leading to insulin-independent glucose transport in skeletal muscle under conditions of metabolic stress.

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Exercise training is a well-known AMPK activator in skeletal muscle of rodents and humans.
“Exercise training is a well-known AMPK activator in the skeletal muscle of rodents and humans26-28.”
From Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence (2024) · cites this paper as [26]
AMPK α1 activity is increased during high intensity muscle contractions equivalent to >100% VO2 Max.
“Both AMPK α1 and α2 are activated during exercise; however, α1 activity appears to be increased during high intensity muscle contractions, which are equivalent to >100% maximal oxygen consumption (VO2 Max; measure of maximal exercise capacity) [59,62,63].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [63]
Both AMPK α1 and α2 are activated during exercise.
“Both AMPK α1 and α2 are activated during exercise; however, α1 activity appears to be increased during high intensity muscle contractions, which are equivalent to >100% maximal oxygen consumption (VO2 Max; measure of maximal exercise capacity) [59,62,63].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [63]

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Authors: Hayashi, T., Hirshman, M. F., Fujii, N., Habinowski, S. A., Witters, L. A., & Goodyear, L. J.
Affiliations: Brigham and Women's Hospital (US)
ORCID: Hayashi, T
Hirshman, M F
Fujii, N
Goodyear, L J
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2000-04-01
Volume: 49
Issue: 4
Pages: 527-531
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diabetes.49.4.527
OpenAlex: W2106324494
Cited by: 447
References: 0
Citations by year: 2026: 1 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 4 · 2021: 3 · 2020: 6 · 2019: 4 · 2018: 10 · 2017: 19 · 2016: 20 · 2015: 23 · 2014: 12 · 2013: 23 · 2012: 24
FWCI: 10.36
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Diabetes (publishedVersion)
PubMed (publishedVersion)
Funders: Joslin Diabetes Center
Manpei Suzuki Diabetes Foundation
Japan Society for the Promotion of Science
National Institute of Diabetes and Digestive and Kidney Diseases (DK375712)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR45670, AR-42238, R01AR045670)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords: AMPK, insulin-independent glucose transport, metabolic stress, skeletal muscle, fuel depletion, ATP regeneration, hypoxia, rotenone, 2,4-dinitrophenol, hyperosmolarity, AMPK isoforms
MeSH terms: Adenosine Monophosphate, Adenosine Triphosphate, Animals, Biological Transport, Creatine, Enzyme Activation, Glucose, Kinetics, Male, Muscle Contraction, Osmolar Concentration, Phosphocreatine, Protein Kinases, Rotenone, Stress, Physiological, Uncoupling Agents, Rats, Sprague-Dawley, Muscle, Skeletal, 2,4-Dinitrophenol, Rats

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Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism.

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