OBJECTIVE To investigate the effects of curcumin and astragalus total saponins(AC) on blood glucose regulation and liver protection in a rat model of type 2 diabetes mellitus(T2DM), and to elucidate the underlying mechanism through gut microbiota and serum metabolomics.

METHODS Twenty-four male SD rats were randomly assigned to a normal control group(n=6) and a modeling group(n=18). T2DM model was induced by feeding the modeling group a high-fat diet for 4 weeks, followed by tail-vein injection of streptozotocin. Successfully modeled rats were further randomized into 3 groups: model group, AC group, and metformin(MET) group. After 10 weeks of treatment, an oral glucose tolerance test(OGTT) and an insulin tolerance test(ITT) were performed to calculate the area under the blood glucose curve(AUC) and the insulin tolerance test constant(K-ITT). At the end of 12 weeks, biochemical parameters, including fasting plasma glucose(FPG), aspartate aminotransferase(AST), alanine aminotransferase(ALT), total bilirubin(TBIL), and direct bilirubin(DBIL) were measured. Liver histopathology was assessed using HE staining. Combined with 16S rRNA sequencing and untargeted metabolomics technology, the potential mechanisms by which AC ameliorated glucose metabolic disorder and alleviated liver injury was explored.

RESULTS AC intervention significantly reduced the levels of FPG, liver-function enzymes(AST and ALT), and bilirubin concentrations(TBIL and DBIL) in T2DM rats(all P<0.05). ITT results revealed that the AC group exhibited significantly higher K value and markedly lower AUC(all P<0.05), and its effect on improving insulin sensitivity was comparable to that of MET. HE staining of liver tissues revealed that AC markedly alleviated hepatocyte injury, inflammatory infiltration, and fibrosis lesions. Furthermore, 16S rRNA sequencing results demonstrated that AC effectively regulated gut microbiota dysbiosis, significantly increased the relative abundance of short-chain fatty acid(SCFAs)-producing bacteria(such as Limosilactobacillus and Ruminococcus)(P<0.05), and reduced the abundance of Unclassified_f_Prevotellaceae(P<0.05). Untargeted metabolomics analysis identified that AC significantly reversed 73 differential metabolites in the model group, predominantly involved in alanine-aspartate-glutamate metabolism, and steroid hormone biosynthesis pathways.

CONCLUSION AC markedly improves glucose metabolic disorders and liver dysfunction in T2DM rats, and its mechanism was closely related to the restoration of gut microbiota balance and modulation of metabolic pathways in the organism. This study reveales the potential regulatory pathway by which AC modulates intestinal microecology to further affect hepatic metabolic function, providing new insights for the treatment of T2DM and its hepatic complications.