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ResearchIn-Press PreviewMetabolismMuscle biology Open Access | 10.1172/JCI183567

Intermittent ischemia-reperfusion as a potent insulin-sensitizing intervention via blood flow enhancement and muscle Decanoyl-L-carnitine suppression

Kohei Kido,1 Janne R. Hingst,1 Johan Onslev,1 Kim A. Sjøberg,1 Jesper B. Birk,1 Nicolas O. Eskesen,1 Tongzhu Zhou,2 Kentaro Kawanaka,2 Jesper F. Havelund,3 Nils J. Færgeman,3 Ylva Hellsten,4 Jørgen F.P. Wojtaszewski,1 and Rasmus Kjøbsted1

1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

Find articles by Kido, K. in: PubMed | Google Scholar |

1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

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1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

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1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

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1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

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1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

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1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

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1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

Find articles by Kawanaka, K. in: PubMed | Google Scholar

1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

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1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

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1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

Find articles by Hellsten, Y. in: PubMed | Google Scholar

1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

Find articles by Wojtaszewski, J. in: PubMed | Google Scholar

1The August Krogh Section for Molecular Physiology, Department of Nutrition,, University of Copenhagen, Copenhagen, Denmark

2Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan

3Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanal, University of Southern Denmark, Odense, Denmark

4The August Krogh Section for Human Physiology, Department of Nutrition, Exe, University of Copenhagen, Copenhagen, Denmark

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Published September 2, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI183567.
Copyright © 2025, Kido et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 2, 2025 - Version history
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Abstract

A single bout of exercise improves muscle insulin sensitivity for up to 48 hours via the AMP-activated protein kinase (AMPK). Limb ischemia activates AMPK in muscle, and subsequent reperfusion enhances insulin-stimulated vasodilation, potentially eliciting a more pronounced exercise effect with reduced workload. Here, we investigated the combined effect of upper leg intermittent ischemia-reperfusion (IIR) and continuous knee-extension exercise on muscle insulin sensitivity regulation. We found that IIR-exercise potentiated AMPK activation and muscle insulin sensitivity. The potentiating effect of IIR-exercise on muscle insulin sensitivity was associated with increased insulin-stimulated blood flow in parallel with enhanced phosphorylation of endothelial nitric oxide synthase. Metabolomics analyses demonstrated a suppression of muscle medium-chain acylcarnitines during IIR-exercise, which correlated with insulin sensitivity and was consistent with findings in isolated rat muscle treated with Decanoyl-L-carnitine. Collectively, combining IIR with low-to-moderate intensity exercise may represent a promising intervention to effectively enhance muscle insulin sensitivity. This approach could offer potential for mitigating muscle insulin resistance in clinical settings and among individuals with lower physical activity levels.

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