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 8

Decanoyl-l-carnitine impairs insulin-stimulated glucose uptake in rat skeletal muscle and plasma membrane GLUT4 translocation in L6 myotubes.

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Decanoyl-l-carnitine impairs insulin-stimulated glucose uptake in rat sk...
(A) Uptake of 2-deoxyglucose (2DG) in isolated rat EDL muscle treated with 0.15 mM decanoyl-l-carnitine or vehicle (ethanol) under basal and insulin-stimulated conditions. (B) Representative immunoblots for Akt phosphorylation (Ser473 and Thr308), total Akt (t-Akt), GLUT4, and HKII from EDL muscle treated as in (A). Quantification of p-Akt Ser473 (C), p-Akt Thr308 (D), total Akt (E), GLUT4 (F), and HKII (G). (H) Representative immunofluorescence images showing surface GLUT4 in GLUT4-myc overexpressing L6 myotubes treated with 0.4 mM decanoyl-l-carnitine or ethanol under basal or insulin-stimulated conditions. Scale bar = 200 μm. (I) Quantification of surface GLUT4-myc levels in L6 myotubes shown in (H). Experiments using GLUT4-myc overexpressing L6 myotubes were repeated twice, confirming consistent results. n = 12 for EDL muscle 2DG uptake and immunoblots and for L6 cell assays. Data are means ± SEM. (A and C–G) Two-way ANOVA was performed, using a repeated-measures design. (I) A nonrepeated measures design was used, followed by Bonferroni-Šidák post hoc test when appropriate. $$P < 0.01, $$$P < 0.001, $$$$P < 0.0001.