Skeletal muscle accounts for approximately 75% of glucose disposal in body and statins impair glucose metabolism. We aimed to investigate the effect of atorvastatin on glucose metabolism in C2C12 cells. Glucose metabolism and expression of glucose transporter 4 (GLUT4) and hexokinase II (HXKII) were measured following incubation with atorvastatin or pravastatin . Roles of cholesterol in atorvastatin-induced glucose metabolism impairment were investigated via adding cholesterol or mevalonic acid and confirmed by cholesterol depletion with methyl-β-cyclodextrin. Hypercholesterolemia mice induced by high fat diet (HFD) feeding, orally received atorvastatin (6 and 12 mg/kg) or pravastatin (12 mg/kg) for 22 days. Results showed that atorvastatin not pravastatin concentration-dependently impaired glucose consumption, glucose uptake and GLUT4 membrane translocation in C2C12 cells without affecting expression of HXKII or total GLUT4 protein. The atorvastatin-induced alterations were reversed by cholesterol or mevalonic acid. Cholesterol depletion exerted similar impact to atorvastatin, which could be alleviated by cholesterol supplement. Glucose consumption or GLUT4 translocation was positively associated with cellular cholesterol levels. In HFD mice, atorvastatin not pravastatin significantly increased blood glucose levels following glucose or insulin dose and decreased expression of membrane not total GLUT4 protein in muscle. Glucose exposure following glucose or insulin dose was negatively correlated to muscular free cholesterol concentration. Expression of membrane GLUT4 protein was positively related to free cholesterol in muscle. In conclusion, atorvastatin impaired glucose utilization in muscle cells partly via inhibiting GLUT4 membrane translocation due to inhibition of cholesterol synthesis by atorvastatin, at least, partly contributing to glucose intolerance in HFD mice.
The current study aimed to assess the effectiveness of pharmacological intervention with Platycodin D (PD), a critically active compound isolated from the roots of Platycodon grandiflorum, in mitigating cardiotoxicity in a murine model of type 2 diabetes-induced cardiac injury and in H9c2 cells in vitro. Following oral administration for 4 weeks, PD (2.5 mg/kg) significantly suppressed the elevation of fasting blood glucose (FBG) levels, improved dyslipidemia, and effectively inhibited the rise of the cardiac injury markers creatine kinase isoenzyme MB (CK-MB) and cardiac troponin T (cTnT). PD treatment could ameliorate energy metabolism disorders induced by impaired glucose uptake by activating AMPK protein expression in the DCM mouse model, thereby promoting the GLUT4 transporter and further activating autophagy-related proteins. Furthermore, in vitro experiments demonstrated that PD exerted a concentration-dependent increase in cell viability while also inhibiting palmitic acid and glucose (HG-PA)-stimulated H9c2 cytotoxicity and activating AMPK protein expression. Notably, the AMPK activator AICAR (1 mM) was observed to upregulate the expression of AMPK in H9c2 cells after high-glucose and -fat exposure. Meanwhile, we used AMPK inhibitor Compound C (20 μM) to investigate the effect of PD activation of AMPK on cells. In addition, the molecular docking approach was employed to dock PD with AMPK, revealing a binding energy of −8.2 kcal/mol and indicating a tight interaction between the components and the target. PD could reduce the expression of autophagy-related protein p62, reduce the accumulation of autophagy products, promote the flow of autophagy, and improve myocardial cell injury. In conclusion, it has been demonstrated that PD effectively inhibits cardiac injury-induced type 2 diabetes in mice and enhances energy metabolism in HG-PA-stimulated H9c2 cells by activating the AMPK signaling pathway. These findings collectively unveil the potential cardioprotective effects of PD via modulation of the AMPK signaling pathway.
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