Objective

2

To investigate the mechanism of

Xuanshen

（

Scrophulariae Radix

）-

Cangzhu

（

Atractylodis Rhizoma

）combined with metformin in the treatment of type 2 diabetes mellitus（T2DM）.

Methods

2

SD rats were randomly divided into a blank group，model group，control group，and treatment group.Except for the blank group，all other groups were induced with a high-fat diet combined with streptozotocin（STZ）to establish a T2DM model.The control group was administered 200 mg/kg metformin suspension by gavage，while the treatment group received 630 mg/kg

Xuanshen-Cangzhu

suspension and 200 mg/kg metformin suspension by gavage.The model and blank groups received distilled water by gavage，all once daily. After six weeks，the rats were fasted overnight for 12 hours and anesthetized with chloral hydrate.Blood was collected from the abdominal aorta，and serum was separated.Biochemical parameters［fasting blood glucose（FBG），postprandial 2-hour blood glucose（PBG），alanine aminotransferase（ALT），aspartate aminotransferase（AST），blood urea nitrogen（BUN），triglycerides（TG），total cholesterol（TC），high-density lipoprotein cholesterol（HDL-C），low-density lipoprotein cholesterol（LDL-C），fasting serum insulin （FINS），and glycated serum protein（GSP）］，nuclear factor-kappa B（NF-κB），and NLR family pyrin domain containing 3 （NLRP3），were measured and compared.Differential metabolites were screened using liquid chromatography-mass spectrometry （LC-MS）untargeted metabolomics，and metabolic pathway enrichment analysis was performed.

Results

2

Compared with the blank group，the model group exhibited lower body weight（

P

<

0.05），higher food and water intake（

P

<

0.05），and increased FBG，PBG，and GSP levels（

P

<

0.01）.Compared with the model group，the treatment group showed reduced food and water intake （

P

<

0.05）and increased body weight（

P

<

0.05）.C

ompared with the control group，the treatment group had higher body weight and lower FBG（

P

<

0.05）.Both the control and treatment groups exhibited lower FBG，PBG，and GSP levels than the model group （

P

<

0.05）.The treatment group had lower FBG and GSP levels than the control group，but the difference was not statistically significant（

P

>

0.05），whereas PBG was significantly lower in the treatment group than in the control group（

P

<

0.05）.The FINS level in the model group was lower than in the blank group（

P

<

0.01）.Compared with the model group，the control group showed a downward trend in FINS（

P

<

0.05），while the treatment group exhibited an upward trend（

P

<

0.05），with a statistically significant difference between the control and treatment groups（

P

<

0.05）.Compared with the blank group， the model group had higher ALT and BUN levels（

P

<

0.05）.Compared with the model group，the ALT and BUN levels in the control and treatment groups showed no significant improvement（

P

>

0.05），though the treatment group exhibited a downward trend in ALT and BUN compared with the control group（

P

<

0.05）.Compared with the blank group，the model group showed higher serum NF-κB and NLRP3 levels（

P

<

0.01）.Compared with the model group，the control group showed lower NF-κB and NLRP3 levels，but the difference was not statistically significant（

P

>

0.05），whereas the treatment group exhibited significantly lower NF-κB and NLRP3 levels than the model group（

P

<

0.01）.Serum NLRP3 levels were positively correlated with NF-κB levels and PBG levels but negatively correlated with FINS levels.A total of 36 differential metabolites were identified as biomarkers related to the therapeutic mechanism of

Xuanshen-Cangzhu

combined with metformin for T2DM，including 10 upregulated and 26 downregulated m

etabolites，most of which belonged to amino acids.The metabolic pathways involved in the treatment were related to D-glutamine and D-glutamate metabolism，with L-glutamate as a differential metabolite within the pathway.

Conclusion

2

The biological mechanism of

Xuanshen-Cangzhu

combined with metformin in treating T2DM rats involves regulating the expression of genes in the D-glutamine and D-glutamate metabolic pathways， thereby maintaining the dynamic balance of the glutamine-glutamate cycle， inhibiting NF-κB/NLRP3 pathway activation， reducing inflammation， improving insulin sensitivity， and regulating glucose and lipid metabolism disorders.