Combination therapy of metformin and morin attenuates insulin resistance, inflammation, and oxidative stress in skeletal muscle of high-fat diet-fed mice.

Lipid accumulation, inflammation, and oxidative stress are the most important causes of muscle insulin resistance. The aim of this study was to investigate the single and combined treatment effects of metformin (MET) and morin (MOR) on lipid accumulation, inflammation, and oxidative stress in the skeletal muscle of mice fed a high-fat diet. The mice were supplemented with MET (230 mg/kg diet), MOR (100 mg/kg diet), and MET + MOR for 9 weeks. Our results revealed that single treatment with MET or MOR, and with a stronger effect of MET + MOR combined treatment, reduced body weight gain, improved glucose intolerance and enhanced Akt phosphorylation in the muscle tissue. In addition, plasma and muscle triglyceride levels were decreased after treatment with MET and MOR. The expression of genes involved in macrophage infiltration and polarization and pro-inflammatory cytokines showed that MET + MOR combined treatment, significantly reduced inflammation in the muscle. Furthermore, combined treatment of MET + MOR with greater efficacy than the single treatment improved several oxidative stress markers in the muscle. Importantly, combined treatment of MET and MOR could increase the expression of nuclear factor erythroid 2-related factor 2, the master regulator of the antioxidant response. These findings suggest that combination of MET with MOR might ameliorate insulin resistance, inflammation, and oxidative stress in the skeletal muscle of mice fed high-fat diet.

Resveratrol as a potential protective compound against skeletal muscle insulin resistance.

The increasing prevalence of type 2 diabetes has become a major global problem. Insulin resistance has a central role in pathophysiology of type 2 diabetes. Skeletal muscle is responsible for the disposal of most of the glucose under conditions of insulin stimulation, and insulin resistance in skeletal muscle causes dysregulation of glucose homeostasis in the whole body. Despite the current pharmaceutical and non-pharmacological treatment strategies to combat diabetes, there is still a need for new therapeutic agents due to the limitations of the therapeutic agents. Meanwhile, plant polyphenols have attracted the attention of researchers for their use in the treatment of diabetes and have gained popularity. Resveratrol, a stilbenoid polyphenol, exists in various plant sources, and a growing body of evidence suggests its beneficial properties, including antidiabetic activities. The present review aimed to provide a summary of the role of resveratrol in insulin resistance in skeletal muscle and its related mechanisms. To achieve the objectives, by searching the PubMed, Scopus and Web of Science databases, we have summarized the results of all cell culture, animal, and human studies that have investigated the effects of resveratrol in different models on insulin resistance in skeletal muscle.

Combination therapy of metformin and p-coumaric acid mitigates metabolic dysfunction associated with obesity and nonalcoholic fatty liver disease in high-fat diet obese C57BL/6 mice.

Metformin (MET) has been demonstrated to have favorable impact on nonalcoholic fatty liver disease (NAFLD); however, the combined effect of this drug with p-coumaric acid (PCA) on liver steatosis is unclear. The aim of the current study was to evaluate the combined effects of MET and PCA on NAFLD in a high-fat diet (HFD)-induced NAFLD mouse model. The obese mice received MET (230 mg/kg), PCA (200 mg/kg) monotherapies, and MET combination with PCA in the diet for 10 weeks. Our results showed that the combination of MET and PCA markedly ameliorated weight gain and fat deposition in HFD fed mice. Furthermore, the combination of MET and PCA lowered liver triglyceride (TG) content which was accompanied by decreased expression of lipogenic and increased expression of ß-oxidation related genes and proteins. In addition, combination therapy of MET and PCA mitigated liver inflammation through inhibiting hepatic macrophage infiltration (F4/80), switching macrophage from M1 into M2 phenotype, and ameliorating nuclear factor-κB (NF-κB) activity in comparison with the monotherapy of MET or PCA. Furthermore, we found that MET and PCA combination therapy upregulated thermogenesis-related genes in BAT and sWAT. Combination therapy results in stimulating brown-like adipocyte (beige) formation in the sWAT of HFD mice. Taken together, these findings indicate that MET combined with PCA can improve NAFLD through decreasing lipid accumulation, inhibiting inflammation and inducing thermogenesis, and adipose tissue browning.