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 1

IIR potentiates the insulin-sensitizing effect of a single bout of exercise.

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IIR potentiates the insulin-sensitizing effect of a single bout of exerc...
(A) Schematic of the human study. Participants performed a 1-legged knee extension exercise under 1 of the following regimens in a randomized crossover design: 70%EX, 70%EX + ischemia, or 70%/95%EX. After a 3-hour rest, a 2-hour hyperinsulinemic-euglycemic clamp was performed, with biopsy and blood sampling collected from rested and exercised legs. (B–H) Results from the insulin clamp: average leg glucose uptake (B), prior exercise-induced change in leg glucose uptake (Δ) (C), average leg blood flow (D), prior exercise-induced change in blood flow (Δ) (E), average blood glucose A-V difference (F), prior exercise-induced change in A–V glucose difference (Δ) (G), and whole-body glucose clearance (H). Sample sizes were as follows: n = 8 for 70%EX and 70%EX + ischemia; n = 7 for 70%/95%EX. Data are presented as means ± SEM. (B, D, and F) Comparisons between 70%EX and 70%EX + ischemia were made with 2-way repeated-measures ANOVA; significant interactions were followed by Bonferroni-Šidák post hoc tests. For 70%/95%EX, the exercise effect was evaluated using a paired (2-tailed) Student’s t test. (C, E, and G) One-way repeated-measures ANOVA was used, followed by Tukey’s post hoc test when significant. (H) Analysis was conducted using 2-way repeated-measures ANOVA to assess main effects. **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. rest within trial; #P < 0.05, ##P < 0.01 vs. 70%EX within rest or exercise leg; †P < 0.05 vs. 70%EX + ischemia. Δ, change in; Ex, exercise; Ins, insulin; ME, main effect; LLM, lean leg mass.