Methyl‐β‐cyclodextrin increases GLUT4‐mediated glucose transport in skeletal muscle fibers from insulin resistant mice

Abstract

Insulin stimulates glucose uptake in skeletal muscle fibers by promoting the translocation of Glut4 glucose transporters to the transverse tubule (TT) system. Cholesterol is highly enriched in TT, raising the possibility that modifying TT cholesterol content may affect insulin‐induced glucose transport. By feeding mice a high fat diet (HFD), we increased TT cholesterol content and modified insulin‐induced glucose uptake. Male C57BL/6J mice were fed a normal or a HFD for 8 weeks. Cholesterol levels in triads from HFD‐fed mice were 30% higher than in controls whereas insulin‐stimulated glucose uptake in fibers from HFD‐fed mice was lower than in controls. In FDB muscle, pre‐incubation with low doses of Methyl‐β‐cyclodextrin (MβCD), reported to extract membrane cholesterol, decreased Akt phosphorylation without altering the activity of AMPK, and increased both basal and insulin‐induced glucose uptake in muscle fibers from controls or HFD‐fed mice. MβCD restored insulin sensitivity in HFD‐fed mice, even after Akt or CaMKII inhibition and increased membrane GLUT4 content. Indinavir, a GLUT4 antagonist, inhibited the effect of MβCD. Our findings suggest that TT cholesterol content has a critical role in GLUT4 translocation and glucose transport and that partial cholesterol removal from muscle fibers may be a strategy to improve insulin resistance. Supported by ACT1111 and FONDECYT 3110105.