Anti-Qi-deficiency Type Diabetes Effect Of Different Active Ingredients Of Ginseng And Its Underlying Mechanism Exploration

Diabetes is a metabolic disease characterized by chronic hyperglycemia.As its incidence continues to increase,diabetes and its complications have become one of the major public health problems in this century,seriously affecting human health.At present,insulin injection and oral hypoglycemic drugs are the main methods of prevention and treatment of diabetes.These methods cannot prevent the progression of the disease and cause common side effects such as hypoglycemia.Therefore,there is an urgent need to find new methods for the prevention and treatment of diabetes.Traditional Chinese medicine(TCM)has the characteristics of multi-component,multitarget,mild effect,etc.It can regulate the disease state as a whole and has certain advantages in the treatment of diabetes.The combination of disease and syndrome animal model of Qi-deficiency diabetes not only reflects the Qi-deficiency syndrome of traditional Chinese medicine,but also has the pathological characteristics of diabetes in modern medicine.It is an ideal experimental animal model for studying the prevention and treatment of diabetes by TCM.As the "king of herbs",ginseng has a history of more than 2,000 years of medicinal use in China.It has been proved to have a certain intervention effect on both diabetes and qi deficiency syndrome.However,the efficacy and related mechanisms of ginseng in the treatment of Qi-deficiency diabetes are still unclear.Based on this,this paper studied the pharmacodynamics and mechanism of different active components of ginseng on Qi-deficiency diabetic rats from the aspects of pathophysiology,metabolomics,and gut microbiome,and further analyzed the correlation between serum medicinal chemistry and PK-PD.The material basis and potential mechanism of the combined use of ginseng total saponins and total polysaccharide components in anti-Qi-deficiency diabetes were explored,and a new basis for further development and utilization of ginseng was provided.1.The establishment and evaluation of Qi-deficiency diabetes rat modelAt present,the establishment method and evaluation system of the animal model of Qi-deficiency diabetes are not perfect.The establishment of a reliable and accurate animal model is an important basis for the research on the efficacy and action mechanism of TCM.In this chapter,a high-fat and high-sugar diet feeding combined with exhaustive swimming and low-dose streptozotocin induction was used to establish Qi-deficiency diabetes rat model,and from various aspects such as pathophysiology,metabolomics and intestinal flora to evaluate the characteristics of model.The results showed that compared with the blank group,the Qi-deficiency diabetic rats had reduced hair gloss,higgling,lethargy,loose stools,decreased appetite,swimming endurance,energy metabolism,immune function and blood routine indexes were significantly reduced(p < 0.05),oxidative stress injury was significantly aggravated(p < 0.05).At the same time,there are also symptoms of diabetes such as hyperglycemia,hyperlipidemia and insulin resistance.Compared with diabetic rats,the levels of swimming endurance,RBC,HCT,HGB,LDH,ATP,Ig M and SOD activity in Qideficiency diabetic rats were significantly decreased(p < 0.05),and MDA levels were significantly increased(p < 0.05),however,there were no significant differences in the levels of FBG,TC,TG and INS(p > 0.05).The metabolomics results showed that there were significant differences in the metabolic profiles between the type 2 diabetic rats and the Qi-deficiency diabetic rats.The 32 biomarkers associated with the Qideficiency diabetic rats not only covered the biomarkers related to diabetes and Qideficiency,but also the relative content changes of biomarkers in Qi-deficiency diabetic rats were more significant.The results of intestinal flora showed that compared with the blank group,the abundances of Firmicutes,Bacteroidetes,Lactobacillus and Oscillobacter were significantly reduced in Qi-deficiency diabetic rats,while Actinobacteria,Bifidobacterium,Turicibacter and Allobaculum abundances were significantly increased(p < 0.05).Compared with type 2 diabetic rats,the abundances of Actinobacteria,Bifidobacterium and Allobaculum were significantly increased in Qideficiency diabetic rats,while Bacteroidetes and Lactobacillus were significantly decreased(p < 0.05).The results showed that the Qi-deficiency diabetic rat model successfully simulated the dual pathophysiological states of qi-deficiency syndrome and type 2 diabetes,and had more severe pathological damage than the type 2 diabetic rats,and the disease-combined model was successfully established.At the same time,there are significant differences in the metabolic profile and intestinal flora composition between Qi-deficiency diabetic rats and type 2 diabetic rats.Based on the pathophysiology-metabolic characteristics-gut flora evaluation system,the rat model of qi-deficiency diabetes can be systematically and comprehensively evaluated.2.Efficacy evaluation of different active ingredients of ginseng in anti-Qideficiency diabetic ratsIn order to accurately evaluate the efficacy of different ginseng active ingredients in anti-Qi-deficiency diabetes,this chapter was based on the Qi-deficiency diabetes rat model,with metformin as the positive drug(ME),and investigated the total polysaccharide(GP),total saponins(GS),water extract Changes in pathophysiology of qi-deficiency diabetic rats after intervention with GE(GE)and saponin plus polysaccharide(1:1)mixture(GPS).The results showed that the intervention effects of each administration group on Qi-deficiency diabetic rats were manifested in different aspects.The positive drug metformin can significantly reduce blood glucose,blood lipid levels and improve glucose tolerance in rats(p < 0.05),but its regulating effect on qi deficiency-related indicators is significantly weaker than that of each ginseng group.GP showed certain advantages in regulating the related indicators of qi-deficiency syndrome,especially in improving swimming endurance and enhancing immune function,but there was no significant difference in the regulation of LDH,FBG,INS,glucose tolerance and TC.GS can significantly improve swimming time,blood routine indexes,thymus index,MDA,glucose tolerance,TC and TG levels in rats,but has no significant regulatory effect on spleen index,Ig M,Ig G,LDH,SOD and FBG.GPS has the most significant effect in regulating blood routine,energy metabolism and oxidative stress damage,and can significantly enhance immune function,reduce hyperglycemia,improve glucose tolerance,and reduce INS,TC and TG levels(p < 0.05).On the whole,GE has the weakest effect,GP plays a key role in regulating qi-deficiency-related indicators,GS plays a major role in regulating blood sugar and blood lipids,and GPS has a good regulating effect on the pathological changes of qi-deficiency diabetes mellitus with outstanding effect.The above results show that ginseng is more beneficial to improve the pathological damage of Qi-deficiency diabetic rats as a whole,and the combined use of saponins and polysaccharides has a certain synergistic effect.The mechanism may be related to the therapeutic effects of polysaccharides and saponins through multiple pathways and multiple targets.3.Effects of different active ingredients of ginseng on serum metabolites in Qi-deficiency diabetic ratsSerum metabolomics and lipidomics based on UPLC-Q-TOF/MS technology were used to investigate the effects of GS,GP and GPS on serum metabolites in Qideficiency diabetic rats o explore the potential mechanism of the synergistic effect of the combined use of saponins and polysaccharides.The results showed that the active ingredients of ginseng can significantly reduce the content of bile acids,eicosanoids,cresols and retinoids,improve the content of amino acids,unsaturated fatty acids,indoles and improve lipid metabolism disorders.At the same time,different active ingredients of ginseng have different regulating effects on metabolites and lipid disorders in Qi-deficiency diabetic rats.The intervention effect of GS and GPS on serum metabolites was more obvious than that of GP,and GPS had the most significant effect,and improved the most types of differential metabolites.It can be seen that the degree of regulation on the relative content of metabolites and lipids is greater than that of GP and GS.The results show that different active ingredients of ginseng can exert anti-Qi-deficiency diabetes effects by regulating serum metabolites and lipid metabolism disorders,and their mechanisms may be related to regulating fatty acid metabolism,bile acid metabolism,arachidonic acid metabolism,lipid metabolism,amino acid metabolism and retinol metabolism.The GPS has the most significant improvement effect on serum metabolite disorders,indicating that the synergistic effect of saponins and polysaccharides in anti-Qi-deficiency diabetes may be related to the regulation of serum metabolites and lipid metabolism disorders.4.Effects of different active ingredients of ginseng on gut microbiome and their metabolites in Qi-deficiency diabetic ratsThis chapter uses fecal non-targeted metabolomics based on UPLC-Q-TOF/MS,combined with UPLC-TQ/MS-based rat fecal bile acid-targeted metabolomics method,to study the changes of rat intestinal metabolites.Then,GC/MS was used to determine the content of short-chain fatty acids,and 16 S r RNA sequencing was used to study the changes in the gut microbiome of rats to explore the intervention effect of various ingredients of ginseng on the gut microbiome and metabolites of Qi-deficiency diabetic rats.The results showed that the active ingredients of ginseng had a significant regulatory effect on fecal metabolic disorders in qi-deficiency diabetic rats,mainly involving arachidonic acid metabolism pathway,unsaturated fatty acid biosynthesis pathway,bile acid biosynthesis pathway,linoleic acid and linolenic acid metabolism pathway and retinol metabolism.The quantitative results of bile acids showed that different active ingredients of ginseng could significantly improve bile acid disorder in Qi-deficiency diabetic rats.Compared with GS and GP,GPS showed a more significant effect on regulating bile acid disorders.The quantitative results of short-chain fatty acids showed that various ingredients of ginseng could adjust the content of various short-chain fatty acids,making it closer to the normal level.The regulating effect of fatty acid is more obvious.The results of intestinal flora analysis showed that the GPS improved the flora disturbance of Qi-deficiency diabetic rats to a certain extent,while total saponins had a weak regulatory effect on intestinal flora.Polysaccharide sites play a key role in the regulation of gut microbiota.The above results indicate that the mechanism of the active ingredients of ginseng in anti-Qi-deficiency diabetic rats may be related to the regulation of intestinal microbial structure and its metabolite disorders.The combined use of saponins and polysaccharides is more conducive to improving the metabolic disorders of bile acids and short-chain fatty acids,which may be the potential mechanism of the synergistic effect of the combined use of saponins and polysaccharides.5.Study on the material basis of ginsenoside and polysaccharide combined with anti-Qi-deficiency diabetic ratsThe active substances of ginsenosides in anti-Qi-deficiency diabetes were preliminarily clarified by analyzing the in vitro and in vivo substance groups of ginsenosides,and the effect of polysaccharides on the pharmacokinetic behavior of saponins in vivo was analyzed by means of pharmacokinetic analysis,and combined with PK-PD correlation analysis,the material basis and mechanism of action of saponins and polysaccharides in anti-Qi-deficiency diabetes were further elaborated.The results showed that nine PPD-type ginsenosides Rd,Rc,Rb1,Rb2,Rb3,F2,Rg3,Ra1,Ra2 and two PPT-type ginsenosides Rg1 and Re prototype components were found in Qi-deficiency diabetic rats.At the same time,the pharmacokinetic results showed that polysaccharides can affect the pharmacokinetic behavior of ginsenoside active components Re,Rb1,Rc,Rb2,Rb3 and Rd in Qi-deficiency diabetic rats,mainly by increasing the Cmax and AUC of saponins.value,while shortening Tmax and MRT.PKPD correlation analysis found that there was a complex relationship between pharmacodynamic substances and pharmacodynamic indicators and a delayed effect of pharmacodynamics.The pharmacodynamic components could improve metabolite disorder in rats.The above results show that 11 kinds of blood-introducing components may be the pharmacological substances of ginsenosides against qi deficiency type diabetes.Polysaccharides can play a synergistic effect with saponins by promoting the absorption of saponin active components in rats.Saponins and polysaccharides have multiple targets through multiple pathways by regulating the metabolism of bile acids,amino acids and unsaturated fatty acids to play an anti-Qi-deficiency diabetes role.In conclusion,it is more reliable to evaluate the efficacy of different components of ginseng based on the rat model of Qi-deficiency diabetes.Different ginseng components have different intervention effects on Qi-deficiency diabetic rats.Among them,total saponins play a major role in regulating serum metabolites and lipid disorders,and total polysaccharides play a key role in regulating intestinal flora and its metabolites.Structure and promotion of the absorption of saponin active substances enhance the regulating effect of saponins on endogenous substances.Combining advanced analytical techniques,this paper discusses the mechanism and material basis of ginseng in anti-Qi-deficiency diabetes,and provides a theoretical basis for elucidating the overall mechanism of action of ginsenosides and polysaccharides in anti-Qi-deficiency diabetes,and also provides a systematic study of the mechanism of action of traditional Chinese medicine.