| Part 1:Literature researchDiabetic gastroparesis (DGP) is one of the common gastrointestinal complications of diabetes mellitus. Studies have confirmed that DGP can affect the control of blood glucose and reduce the quality of life, meanwhile increasing the risk of cardiovascular and cerebrovascular complications related to diabetes. Therefore, the prevention of DGP is around the corner. However, as western medicine has limited efficacy in the treatment of DGP, more effective treatments need to be explored. DGP has been given the name as "Pi syndrome" in Traditional Chinese Medicine (TCM). Suppression of the liver and impotence of the spleen is the main pathogenesis, thus, Soothing the liver and strengthening the spleen is the solution which was proven to be efficient in clinic, however, not in evidence-based medicine. It is known that the interstitial cells of Cajal (ICC) which is induced by SCF/c-kit signal way plays an important role in the generation of gastrointestinal motility. Disfunction or decrease of local ICCs is associated with most of the gastrointestinal motility disorders that pushs the ICCs to the highlight. The herbal tablet Jiangtang Sanhuang Tablet (JST) was created by Professor Xiong Man-qi. JST was composed on the basis of Taohe Chengqi Decoction, and its curative effect for type 2 diabetes was also observed by many clinical and experimental researches. However, the application of JST in diabetic gastrointestinal diseases has not been explored so far. Part 2:Evidence-based researchObjectiveAbnormal gastrointestinal hormone is one of the important mechanisms for DGP. Many studies have found that the level of gastrointestinal hormones in patients with DGP was significantly different compared with healthy people. However, the correlation between gastrointestinal hormones and DGP remains unclear. Therefore, this study employed Meta-analysis to investigate the correlation between DGP and gastrointestinal hormones. Above the confirmed correlation, the method of systematic review was utilized to assess the intervention effect of Chinese herbal medicine that represents the principle of soothing the liver and strengthening the spleen for DGP from multi-perspectives such as gastrointestinal hormones, gastric emptying function, improvement of TCM syndromes and glucose metabolism.Methods1. Methods for the evidence-based research regarding the correlation between DGP and gastrointestinal hormones:according to the inclusion and exclusion criteria, literatures describing the correlation between gastrointestinal hormone and DGP were comprehensively searched. Papers that agreed the objective of this study were included. Basic information and gastrointestinal hormone indicators were extracted. Then Meta-analysis was conducted by statistical software RevMan 5.3. Final synthesized datas confirmed the correlation between DGP and gastrointestinal hormones.2. Methods for the systematic review regarding the effect assessment based on gastrointestinal hormones of Chinese herbal medicine that represents the principle of soothing the liver and strengthening the spleen for DGP:according to the inclusion criteria, clinical randomized controlled trials assessing the curative effect of Chinese herbal medicine that represents the principle of soothing the liver and strengthening the spleen by gastrointestinal hormones were comprehensively searched. Basic information and outcome indicators of included trials were extracted. Methodological quality of the trials were assessed in accordance with the Cochrane standard. Datas of outcome measures were analyzed by Meta-analysis. The heterogeneity of outcomes was also explored and disposed. To check the publication bias, we also performed funnel chart.Results1. Results for the evidence-based research regarding the correlation between DGP and gastrointestinal hormones:19 studies were enrolled with a recruiment of 1433 subjects. The level of gastrointestinal hormones was significantly different in DGP patients from healthy people. Compared to the healthy, the lever of plasmic MOT in DGP patients rises by 125.76 ng/L in average; the lever of plasmic GAS in DGP patients rises by 71.62 ng/L in average; however, the lever of plasmic SS in DGP patients decreases by 27.93 ng/L in average.2. Results for the systematic review regarding the effect assessment based on gastrointestinal hormones of Chinese herbal medicine that represents the principle of soothing the liver and strengthening the spleen for DGP:14 RCTs were enrolled with a total of 1023 subjects. The quality of included trials was generally poor. Chinese herbal medicine can remarkably lower plasmic MOT (P<0.01), improve gastric emptying rate (P <0.01), improve the total effective rate and the cure rate (P<0.01), lower FBG and PBG (P<0.01), with efficacy and safety superior to western medicine.ConclusionThe level of gastrointestinal hormones like MOT, GAS, SS was significantly different in DGP patients from healthy people. Based on gastrointestinal hormones represented by MOT, gastric emptying function and other indicators, this systematic review confirms the effectiveness and safety of Chinese herbal medicine representing the principle of soothing the liver and strengthening the spleen in the treatment of DGP. According to this research, it also proves that suppression of the liver and impotence of the spleen is the key pathogenesis for DGP. However, flaws such as low methodological quality and heterogeneity weakens the strength of the evidence provided by this study. Therefore, the effect of Chinese herbal medicine for DGP is yet to be verified by more clinical researches with larger sample, higher quality and multicenter. Part 3:Experimental researchObjectiveBased on the theory of "circular movement of yang qi", the underlying principle of JST within TCM in treating DGP was discussed. Based on the ICCs of stomach and SCF/c-kit signal pathway, we used modern biology technologies to explore the effect and relevant mechanisms of JST for DGP rats by animal experiment, cell ultrastructure and molecular biology, aiming at enlarging the application of JST and providing effective treatment for DGP.Methods70 male SD rats were fed for 1 week to adapt to the experimental environment.10 rats were randomly assigned to normal group with normal food, and the rest 60 rats were high sugar and high fat feed. After 1 month, the 60 rats were injected intraperitoneally with STZ at a dose of 35 mg/kg, while rats in the normal group were injected with citric acid buffer at the same amount. After 72 h, those, with the lever of fasting blood glucose beyond 11.1 mmol/L and symptoms of diabetes, were identified as diabetes rats. After 2 weeks of observation, we removed the dead rats and rats with blood glucose recovery. Finally,49 rats were eligible for future experiment. Then we randomly assigned 13 rats to DGP group,12 to JST group of low dose, 12 to JST group of high dose,12 to Banxia Xiexin Decoction (BXD) group. Rats in the JST group of low dose were administrated with JST at a dose of 0.781 g/kg, while Rats in the JST group of high dose were administrated with JST at a dose of 1.563 g/kg. BXD group were administrated with BXD at a dose of 5.4 g/kg, and rats in the other groups were given distilled water. After intervention for eight weeks, two rats in each group were randomly selected to detect gastric emptying function. When retard of gastric emptying was confirmed, the DGP modle developed. During the experiment, we observed the general condition of rats, such as weight and diet. We detected FBG every 2 weeks. FINS was checked at the end of the experiment, which was used for calculating Homa-IR. Blood lipid measurements like TC, TG, HDL-C, LDL-C, were also included. Further more, we estimated the gastric residual rate using semisolid paste method to reflect gastric emptying function. Electron microscope was employed to observe the ultrastructure of ICCs and smooth muscle cells. Moreover, we applied immunohistochemical method to carry out quantitive analysis of ICCs, Western blotting method to detect protein expression of c-kit in gastric antrum. Finally, RTQ-PCR method was refered to detect mRNA expression of SCF, c-kit.Results1. For glucose metabolism, compared to model group, after 4 weeks, both JST groups and BXD group can significantly inhibit the rise of FBG (P< 0.01); after 8 weeks, JST groups still showed effect on the improvement of FBG, but BXD group did not. After 8 weeks, JST groups can reduce FINS and Homa IR (P< 0.01). BXD group can’t reduce FINS (P> 0.05), but can lower Homa-IR (P< 0.05). For the improvement in lipid metabolism, after 8 weeks, JST groups can decrease TC, TG, LDL-C (P< 0.01), but can’ t increase HDL-C (P> 0.05), while BXD group seemed useless to lipid indicators (P> 0.05). In terms of improvement in gastric emptying, both JST and BXD significantly and similarly reduced the gastric residual rate (P< 0.01). For all above aspects, we didn’t detect any significant difference between JST groups of low dose and high dose (P> 0.05).2. Ultrastructure of cells by electron microscope showed, compared to the normal group, the cellular structure and cell-cell junction of ICCs and smooth muscle cell in gastric antrum was impaired in DGP group. Both JST groups and BXD group showed similar recovery of ICCs and smooth muscle cell.3. Immunohistochemical staining of ICCs showed, compared to the normal group, the amount of ICCs obviously decreased with incontinuous or even absent distribution in DGP group. Accordingly, I0D value of c-kit protein in DGP group decreased significantly (P< 0.01); Both JST groups and BXD group can increase the amount of ICCs, and up-regulate IOD value (P< 0.01). Compared to DGP group, the expression of c-kit protein by Western blotting showed that both JST groups and BXD group can enhance the expression of c-kit protein (P< 0.01), and the effect was similar among the three groups (P>0.05).4. mRNA expression of SCF and c-kit detected by RTQ-PCR showed that the mRNA expression of SCF and c-kit in DGP group decreased significantly (P< 0.01) compared to normal group. Both JST groups and BXD group can enhance the expression of c-kit mRNA (P< 0.01) compared to DGP group, and insignificant difference among the three herbal intervention groups was found (P> 0.05). Although JST group of high dose showed up-regulation in the expression of SCF mRNA (P< 0.05), the up-regulation in JST group of low dose didn’t obtain statistical significance (P= 0.062). BXD group can obviously increase the expression of SCF mRNA (P< 0.01), that was even better than JST groups (P< 0.01). ConclusionBased on the theory of "circular movement of yang qi" and the conclusion drawn from the evidence-based research, we held that "disorder of qi activity" caused by suppression of the liver and impotence of the spleen is an essential pathogenesis in DGP. Regulating qi activity could be the principle underlying JST for DGP. According to this experimental study, JST could effectively restore the abnormal glucose metabolism by decreasing DGP rats’fasting plasma insulin, alleviating insulin resistance to reduce fasting blood glucose; also, JST could improve lipid metabolism. A promoting gastric motility effect of JST was found. In terms of recovering ICC impairment, JST could improve the generation and transmission of gastric slow wave to strengthen the pacemaker function in stomach, which was realized by increasing the expression of SCF and c-kit to recover the damaged SCF/c-kit signal pathway, meanwhile, increasing amount and repairing damaged ultrastructure of ICCs and smooth muscle cell, so as to promote the proliferation, differentiation and maintain the phenotype of ICCs. In addition, this study also observed that BXD could reduce insulin resistance and lower fasting blood glucose. However, its hypoglycemic effect was instable, and BXD had no obvious effect on lipid disorder. Besides, this study further confirmed that BXD has a role on improving motility of stomach by parallel ability in repairing ICCs that JST has. The results of this experiment could also support the phenomenon in TCM that treating one disorder using different methods explained by the theory of "circular movement of yang qi". |
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