Statins impair glucose uptake in human cells

Abstract

ObjectiveConsidering the increasing number of clinical observations indicating hyperglycemic effects of statins, this study was designed to measure the influence of statins on the uptake of glucose analogs by human cells derived from liver, adipose tissue, and skeletal muscle.DesignFlow cytometry and scintillation counting were used to measure the uptake of fluorescently labeled or tritiated glucose analogs by differentiated visceral preadipocytes, skeletal muscle cells, skeletal muscle myoblasts, and contact-inhibited human hepatocellular carcinoma cells. A bioinformatics approach was used to predict the structure of human glucose transporter 1 (GLUT1) and to identify the presence of putative cholesterol-binding (cholesterol recognition/interaction amino acid consensus (CRAC)) motifs within this transporter. Mutagenesis of CRAC motifs in SLC2A1 gene and limited proteolysis of membrane GLUT1 were used to determine the molecular effects of statins.ResultsStatins significantly inhibit the uptake of glucose analogs in all cell types. Similar effects are induced by methyl-β-cyclodextrin, which removes membrane cholesterol. Statin effects can be rescued by addition of mevalonic acid, or supplementation with exogenous cholesterol. Limited proteolysis of GLUT1 and mutagenesis of CRAC motifs revealed that statins induce conformational changes in GLUTs.ConclusionsStatins impair glucose uptake by cells involved in regulation of glucose homeostasis by inducing cholesterol-dependent conformational changes in GLUTs. This molecular mechanism might explain hyperglycemic effects of statins observed in clinical trials.

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

“…Huang et al found that the combination of pitavastatin and paclitaxel can significantly decrease the glycolytic rate in renal carcinoma [47]. Nowis et al reported that statins impaired glucose uptake in human cells derived from the liver [48]. These findings suggest that Sim may also be effective in inhibiting glycolysis and may be a potential agent to help improve glycolysis-mediated Sora resistance.…”

Statins and their increased risk of inducing diabetes

“…decreased Ca 2+ -and glucose-stimulated pancreatic b cell insulin secretion [7,47] NA NA + Impaired energy production in the form of ATP via pancreatic b cell mitochondrial dysfunction [50] NA NA + Inhibition of insulin signaling [37,47,51,52] NA NA NA Statin-related reduced tissue insulin sensitivity Reduced GLUT4 expression by adipocytes [7,50,[55][56][57][58] + -+ Reduced plasma membrane cholesterol content ! impaired GLUT1 functionality in the adipocytes, skeletal myocytes and hepatocytes [61] + N A + Increased IL-1b expression by macrophages ! NLRP3 inflammasome activation !…”

“…Different lipophilic statins were associated with reduced glucose analogs uptake by various cell types, including visceral adipocytes, skeletal myocytes, and differentiated hepatoma cells [61]. This effect was associated with a statin-induced reduction in plasma membrane cholesterol content.…”

“…This effect was associated with a statin-induced reduction in plasma membrane cholesterol content. The latter may play a key role in the function of transmembrane proteins involved in glucose homeostasis, including the GLUT1 [61].…”

Association of statin therapy with incidence of Type 2 diabetes among US Veterans

“…-Several potential biologic mechanisms have been proposed including inhibition of glucose uptake [26]. Studies have demonstrated that simvastatin can rapidly and reversibly block insulin secretion in single-islet cultures [27] and cell cultures [28].…”