Abstract
Beside their beneficial effects on cardiovascular events, statins are thought to contribute to insulin resistance and type-2 diabetes. It is not known whether these effects are long-term events from statin-treatment or already triggered with the first statin-intake. Skeletal muscle is considered the main site for insulin-stimulated glucose uptake and therefore, a primary target for insulin resistance in the human body. We analyzed localization and expression of proteins related to GLUT4 mediated glucose uptake via AMPKα or AKT in human skeletal muscle tissue from patients with statin-intake >6 months and in primary human myotubes after 96 h statin treatment. The ratio for AMPKα activity significantly increased in human skeletal muscle cells treated with statins for long- and short-term. Furthermore, the insulin-stimulated counterpart, AKT, significantly decreased in activity and protein level, while GSK3ß and mTOR protein expression reduced in statin-treated primary human myotubes, only. However, GLUT4 was normally distributed whereas CAV3 was internalized from plasma membrane around the nucleus in statin-treated primary human myotubes. Statin-treatment activates AMPKα-dependent glucose uptake and remains active after long-term statin treatment. Permanent blocking of its insulin-dependent counterpart AKT activation may lead to metabolic inflexibility and insulin resistance in the long run and may be a direct consequence of statin-treatment.
Highlights
Publisher’s Note: MDPI stays neutralStatins, the most widely used cholesterol-reducing drugs worldwide, have been associated with type 2 diabetes mellitus (T2DM)
The GSK3ß levels (Figure 3a,c–i), inhibited by phosphorylated AKT, as well as those of mTOR (Figure 3a,c–i), which is relevant for GSK3ß activation, were both decreased under simvastatin. mTOR levels decreased after treatment with rosuvastatin in the non-stimulated group
Becoming pAKT/AKT ratio decreased by 65% for simvastatin and increased by 92% for rosuvastatin evident from clinical studies that diabetes is a risk factor in statin-treated patients [7,11]
Summary
The most widely used cholesterol-reducing drugs worldwide, have been associated with type 2 diabetes mellitus (T2DM). In patients with insulin resistance and T2DM, GLUT4 translocation to the membrane is disturbed and glucose uptake is reduced in skeletal muscle [15–18]. Sanvee et al and Seshadri et al report on impaired insulin signaling, reduced glucose uptake, and higher amounts of fatty acids after chronic and short-term statin treatment in vitro and in vivo in rodents [19,20]. In primary human muscle cells, we showed that two statins, simvastatin and rosuvastatin, alter fatty-acid metabolism as well as glucose related events. We wondered whether the molecular changes in skeletal muscle glucose metabolism in statin patients is a long-term effect or is detectable shortly after first treatment and whether data reported from non-human muscle are translatable to the human situation. Primary human skeletal muscle cells are an optimal model for studying metabolic events and signal transduction under defined conditions, controlling for any influence on glucose and fatty acid metabolism, i.e., glucose uptake. GLUT4 is normally distributed whereas CAV3 tends so localize more intracellular in statin-treated primary muscle cells
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