TY - UNPB

T1 - Reducing the mitochondrial oxidative burden alleviates lipid-induced insulin resistance in human skeletal muscle

AU - Fiorenza, Matteo

AU - Onslev, Johan

AU - Henríquez-Olguín, Carlos

AU - Jensen, Thomas Elbenhardt

AU - Wojtaszewski, Jørgen

AU - Hostrup, Morten

AU - Bangsbo, Jens

N1 - (Preprint)

PY - 2023/4/12

Y1 - 2023/4/12

N2 - Pre-clinical models indicate a causative nexus between mitochondrial oxidative stress and insulin resistance. However, the pathophysiological significance of this mechanism in humans remains unproven. Herein, we employed an invasive in vivo mechanistic approach in humans to manipulate mitochondrial redox state while assessing insulin action. To this end, we combined intravenous infusion of a lipid overload with intake of a mitochondria-targeted antioxidant (mtAO) in conjunction with insulin clamp studies. During lipid overload, insulin-stimulated muscle glucose uptake, as determined by the femoral arteriovenous balance technique, was increased by mtAO. At the muscle molecular level, mtAO did not affect canonical insulin signaling but enhanced insulin-stimulated GLUT4 translocation while decreasing the mitochondrial oxidative burden under lipid oversupply. Ex vivo studies revealed that mtAO ameliorated features of mitochondrial bioenergetics, including diminished mitochondrial H2O2 emission, in muscle fibres exposed to high intracellular lipid levels. These findings implicate mitochondrial oxidants in the development of lipid-induced insulin resistance in humans.

AB - Pre-clinical models indicate a causative nexus between mitochondrial oxidative stress and insulin resistance. However, the pathophysiological significance of this mechanism in humans remains unproven. Herein, we employed an invasive in vivo mechanistic approach in humans to manipulate mitochondrial redox state while assessing insulin action. To this end, we combined intravenous infusion of a lipid overload with intake of a mitochondria-targeted antioxidant (mtAO) in conjunction with insulin clamp studies. During lipid overload, insulin-stimulated muscle glucose uptake, as determined by the femoral arteriovenous balance technique, was increased by mtAO. At the muscle molecular level, mtAO did not affect canonical insulin signaling but enhanced insulin-stimulated GLUT4 translocation while decreasing the mitochondrial oxidative burden under lipid oversupply. Ex vivo studies revealed that mtAO ameliorated features of mitochondrial bioenergetics, including diminished mitochondrial H2O2 emission, in muscle fibres exposed to high intracellular lipid levels. These findings implicate mitochondrial oxidants in the development of lipid-induced insulin resistance in humans.

U2 - 10.1101/2023.04.10.535538

DO - 10.1101/2023.04.10.535538

M3 - Preprint

SP - 1

EP - 39

BT - Reducing the mitochondrial oxidative burden alleviates lipid-induced insulin resistance in human skeletal muscle

PB - bioRxiv

ER -