Rare ginsenosides ameliorate lipid overload-induced myocardial insulin resistance via modulating metabolic flexibility

Abstract

Background: Rare ginsenosides are found in ginseng and notoginseng, two medicinal plants widely used in China for treatment of cardiovascular diseases and type 2 diabetes. However, their pharmacological studies regarding myocardial fuel metabolism and insulin signaling are not clear.

Purpose: To explore the effect of a rare ginsenoside-standardized extract (RGSE), derived from steamed notoginseng, on cardiac fuel metabolism and insulin signaling.

Study design: We used palmitic acid (PA) to treat H9c2 cells in vitro and high fat diet (HFD) to mice to induce insulin resistance in vivo.

Methods: In vitro, differentiated H9c2 cells were pretreated with RGSE, metformin, mildronate or dichloroacetate (DCA) and stimulated with PA. In vivo, mice were fed with HFD and received RGSE, metformin or DCA for 6 weeks. Protein expression was determined by Western blotting. Mitochondrial membrane potential (Δψm), glucose uptake and reactive oxygen species (ROS) production were measured by fluorescence labeling. Other assessments including oxygen consumption rate (OCR) were also performed.

Results: RGSE prevented PA-induced decrease in pyruvate dehydrogenase (PDH) activity and increase in carnitine palmitoyltransferase 1 (CPT1) expression, and ameliorated insulin-mediated glucose uptake and utilization in H9c2 cells. Metformin and mildronate exhibited similar effects. In vivo, RGSE counteracted HFD-induced increase in myocardial expression of p-PDH and CPT1 and ameliorated cardiac insulin signaling. Metformin and DCA also showed beneficial effects. Further study showed that RGSE decreased OCR and mitochondrial complex I activity in PA-treated H9c2 cells, reduced ROS production and relieved mitochondrial oxidative stress, thus decreased serine phosphorylation in IRS-1.

Conclusion: RGSE ameliorated myocardial insulin sensitivity under conditions of lipid overload, which was tightly associated with the decrease in mitochondrial oxidative stress via modulating glucose and fatty acid oxidation.

Keywords: Metabolic flexibility; Mitochondrial oxidative stress; Myocardial insulin resistance; Rare ginsenosides; Reactive oxygen species.