UPLC-Q/TOF-MS-Based Serum Metabolomics Reveals Hypoglycemic Effects of , and Their Combination on High-Fat-Diet-Induced Diabetes in KK-Ay Mice.

Diabetes is a worldwide severe health issue which causes various complications. This study aimed to evaluate the hypoglycemic effects of (RG), (CC) alone and their combination on high-fat-diet-induced diabetes in mice via biochemical assays and UPLC-Q/TOF-MS-based serum metabolomic analysis. Diabetic KK-Ay mice were induced by high-fat diet and treated for eight weeks, separately with RG, CC and their combination and the positive control drug metformin. Administration of RG and CC alone, and their combination could decrease the fasting blood glucose level, ameliorate the tolerance of glucose, and recover the levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in sera of diabetic mice. Orthogonal partial least squares discriminant analysis (OPLS-DA) on serum metabolomes revealed that 79 ESI⁺ and 76 ESI metabolites were changed by diabetes mellitus (DM) compared to the normal control. Heatmaps on these diabetes-related metabolites showed that CC and RG/CC were clustered closer with the normal control, indicating that they had the better antidiabetic effects at the metabolite level. Fifteen of the differential metabolites in DM serum were annotated and their related metabolic pathways were lipid metabolism. These data suggested that RG and CC alone and in combination treatment had the antidiabetic activity in lowering glycemia and improving lipid metabolism. UPLC-Q/TOF-MS-based metabolomics shed light on the differential metabolite effects of RG and CC in DM treatment. However, it should be noted that some differential metabolites were possibly generated or not detected due to our groupwise run order, which possibly contributed to or covered the group difference in our experiment. They need to be further discriminated in the future work.