OBJECTIVE To investigate the therapeutic mechanisms of electroacupuncture at "Tianshu" (ST25) and "Sanyinjiao" (SP6) acupoints combined with metformin in the treatment of type 2 diabetes mellitus (T2DM) using serum non-targeted metabolomics.

METHODS Male SD rats were randomly divided into blank group, model group, metformin group, electroacupuncture group, and acupuncture-medicine combination (electroacupuncture combined with metformin) group. A type 2 diabetes model was established by high-fat diet combined with intraperitoneal injection of streptozotocin. The metformin group was treated with 250 mg ·kg^-1 metformin by gavage, the electroacupuncture group was treated with bilateral Tianshu and Sanyinjiao, the acupuncture-medicine combination group was treated with metformin by gavage combined with electroacupuncture, and the blank group and model group were treated with normal saline by gavage. All rats were treated 6 times a week for 7 weeks. After the intervention, the blood glucose level in the tail vein of the rats was measured using a blood glucose meter in the fasting state. The blood glucose levels of the rats were measured at 30, 60, 120, and 240 min after intraperitoneal injection of 50% glucose solution (4 mL·kg^-1) to evaluate glucose tolerance. The serum insulin level of the rats was detected by ELISA and the insulin resistance index was calculated. The blood biochemical parameters were measured by an automatic blood biochemical analyzer. HE staining was used to evaluate the pathological conditions of the liver and pancreatic tissues of the rats. Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) technology was used for mass spectrometry detection to identify differential metabolites, and MetaboAnalyst 5.0 was used for pathway enrichment analysis.

RESULTS Compared with the blank group, the fasting blood glucose, area under the glucose tolerance curve, and insulin resistance index of the model group rats were significantly increased (P < 0.001), blood TP and GLB were significantly decreased (P < 0.01), AST, ALT, and ALP were significantly increased (P < 0.05, P < 0.01, P < 0.001), and obvious inflammatory cell infiltration and pathological damage were observed in the liver and pancreas tissues; compared with the model group, the fasting blood glucose, area under the glucose tolerance curve, and insulin resistance index of the acupuncture-medicine combination group were significantly decreased (P < 0.05, P < 0.01, P < 0.001), blood ALP was significantly decreased (P < 0.01), TP and GLB were significantly increased (P < 0.05), and the pathological damage of the liver and pancreas was significantly improved. Serum metabolomics showed that the metabolic profiles of the groups were well distinguished. Compared with the blank group, the differential metabolites in the model group were enriched in histidine metabolism, thiamine metabolism, taurine and hypotaurine metabolism, ascorbic acid and aldehyde ester metabolism, valine, leucine and isoleucine biosynthesis pathways; compared with the model group, 237 metabolites such as 3-aminoadipic acid, 3-oxocyclobutanecarboxylic acid and phosphorylcholine in the acupuncture-medicine combination group were significantly reduced, and the pathways were enriched in histidine metabolism, linoleic acid metabolism, thiamine metabolism, taurine and hypotaurine metabolism, valine, leucine and isoleucine biosynthesis pathways.

CONCLUSION Electroacupuncture combined with metformin can effectively improve the glucose and lipid metabolism of T2DM rats, and its potential mechanism may be related to the regulation of amino acid metabolism.