Intermittent ischemia/reperfusion as a potent insulin-sensitizing intervention via blood flow enhancement and muscle decanoyl-l-carnitine suppression
Kohei Kido, Janne R. Hingst, Johan Onslev, Kim A. Sjøberg, Jesper B. Birk, Nicolas O. Eskesen, Tongzhu Zhou, Kentaro Kawanaka, Jesper F. Havelund, Nils J. Færgeman, Ylva Hellsten, Jørgen F.P. Wojtaszewski, Rasmus Kjøbsted
Kohei Kido, Janne R. Hingst, Johan Onslev, Kim A. Sjøberg, Jesper B. Birk, Nicolas O. Eskesen, Tongzhu Zhou, Kentaro Kawanaka, Jesper F. Havelund, Nils J. Færgeman, Ylva Hellsten, Jørgen F.P. Wojtaszewski, Rasmus Kjøbsted
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Research Article Metabolism Muscle biology

Intermittent ischemia/reperfusion as a potent insulin-sensitizing intervention via blood flow enhancement and muscle decanoyl-l-carnitine suppression

Abstract

A single bout of exercise improves muscle insulin sensitivity for up to 48 hours via AMPK. Limb ischemia activates AMPK in muscle, and subsequent reperfusion enhances insulin-stimulated vasodilation, potentially eliciting a more pronounced exercise effect with reduced workload. 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.

Authors

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

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Figure 2

IIR-70%EX and 70%/95%EX enhance AMPK activation and glycogen consumption compared with 70%EX.

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IIR-70%EX and 70%/95%EX enhance AMPK activation and glycogen consumption...
(A and B) Leg glucose uptake during each exercise trial and the change in (Δ) glucose uptake between the rested and exercised leg. Pre- and immediately postexercise muscle glycogen content (C), AMPK activities(E, G, and I), ACC Ser221 phosphorylation(K), and TBC1D1 Ser237 phosphorylation (M). (D, F, H, J, L, and N) Change (Δ) in muscle glycogen content, AMPK activities, ACC Ser221, and TBC1D1 Ser237 phosphorylation from rest to exercise. (O) Representative immunoblot band images. n = 8 in the 70%EX and 70%EX + ischemia groups; n = 7 in the 70%/95%EX group. Data are means ± SEM. (A, C, E, G, I, K, and M) Comparisons between 70%EX and 70%EX + ischemia were performed using 2-way repeated-measures ANOVA; when a significant interaction was detected, post hoc Bonferroni-Šidák tests were applied. For 70%/95%EX, the exercise effect was evaluated using a paired (2-tailed) Student’s t test. (B, D, F, H, J, L, and N) One-way repeated-measures ANOVA was used, followed by Tukey’s post hoc test when significance was found. *P< 0.05, **P< 0.01, ***P < 0.001, and ****P< 0.0001 vs. rest within each trial; #P < 0.05, ##P < 0.01, ###P < 0.001, and ####P < 0.0001 vs. 70%EX within either rested or exercised leg. LLM, lean leg mass.