Cholesterol Accumulation In Skeletal Muscle: A Potential Novel Targetable Pathway In Insulin Resistance

Cholesterol is enriched in the skeletal muscle transverse tubule system, where translocation of GLUT4 glucose transporters takes place in response to insulin. We tested whether feeding mice a high fat diet (HFD), besides producing insulin resistance, increased TT cholesterol content and modified insulin‐induced glucose uptake. Male C57BL/6J mice were fed a normal or a HFD (60% fat) for 8 weeks. HFD‐fed mice displayed higher body weight and insulin resistance. Insulin‐stimulated glucose uptake in fibers from HFD‐fed mice was lower than in controls whereas cholesterol levels in triads from HFD‐fed mice were 30% higher. Pre‐incubation with Methyl‐β‐cyclodextrin (MβCD) reduced Akt phosphorylation and increased both basal and insulin‐induced glucose uptake in muscle fibers from controls or HFD‐fed mice. MβCD treatment restored normal glycemia and insulin sensitivity in HFD mice. Indinavir, a GLUT4 antagonist, inhibited the effects of MβCD. MβCD increased membrane GLUT4 content and elicited intracellular calcium signals inhibited by Dantrolene. Dantrolene also reduced MβCD‐mediated glucose uptake. These results provide a rationale for the clinical evaluation of cyclodextrins, as an approach to the treatment of insulin resistance and the control of diabetes. Grant Funding Source : ACT 1111, Fondecyt 3110105, 11130267, 11090301