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 10

Etomoxir enhances insulin-stimulated glucose uptake in mouse skeletal muscle.

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Etomoxir enhances insulin-stimulated glucose uptake in mouse skeletal mu...
(A and B) Uptake of 2-deoxyglucose (2DG) in mouse EDL (A) and soleus (B) muscles in response to submaximal (Submax) or maximal (Max) insulin (Ins) stimulation, with or without etomoxir. (C) Representative immunoblots showing phosphorylation of Akt (Thr308, Ser473) and total Akt in EDL and soleus muscle samples treated as in (A and B). (D–F) Quantification of p-Akt Thr308 (D), p-Akt Ser473 (E), and total Akt (F) in EDL muscle. (G–I) Quantification of p-Akt Thr308 (G), p-Akt Ser473 (H), and total Akt (I) in soleus muscle. n = 4-10 per group. Data are presented as means ± SEM. (A, B, and D–I) Two-way repeated-measures ANOVA was used, followed by Tukey’s post hoc test when appropriate. $$P < 0.01, $$$$P < 0.0001 vs. corresponding basal. ME, main effect.