Effects of stimulating single acupoint and combination acupoints on diabetic gastroparesis: A randomised controlled trial study.

Background and aim: The most effective among the acupoints remains to be determined for treating diabetic gastroparesis (DGP). This study aimed to compare single and combination acupoints for their effectiveness in DGP. Experimental procedure: A prospective, patient-assessor-blinded randomised controlled trial was designed to compare the efficacy of 8-week acupuncture at a single acupoint (Zhongwan, CV-12), combination acupoints (Zhongwan, CV-12 and Zusanli, ST-36), and a sham-acupoint, in 99 adults with DGP. The primary clinical outcome was measured using the Gastroparesis Cardinal Symptom Index (GCSI), while barium meal examination, fasting plasma glucose, the 2-h plasma glucose, short-form health survey (SF-36), and GCSI subscales were performed for evaluating secondary clinical outcomes. These results were analysed by two factorial analysis of variance (ANOVA) test, Chi-Square, Fisher Exact, Kruskal-Wallis tests and Tukey's Honest Significant Difference (HSD) test. Results: After randomization, 97 patients completed the study. GCSI scores of all groups decreased during both post-treatment and the follow-up period, they were statistically significant compared to the baseline period (p < 0.01), but there was no significant difference among the groups (p > 0.05) during the post-treatment period. GCSI scores improved more in the combination acupoints group than in the single acupoint group which was better than the sham group after treatment. During the follow-up period, the same trend was observed. Conclusions: Among patients with DGP, the combination acupoints were more beneficial compared with single and sham acupoints. Trial registration number: NCT02452489.

Dopamine Receptors and TAAR1 Functional Interaction Patterns in the Duodenum Are Impaired in Gastrointestinal Disorders.

Currently, there is a growing amount of evidence for the involvement of dopamine receptors and the functionally related trace amine-associated receptor, TAAR1, in upper intestinal function. In the present study, we analyzed their expression in the duodenum using publicly accessible transcriptomic data. We revealed the expression of DRD1, DRD2, DRD4, DRD5, and TAAR1 genes in different available datasets. The results of the gene ontology (GO) enrichment analysis for DRD2 and especially TAAR1 co-expressed genes were consistent with the previously described localization of D2 and TAAR1 in enteric neurons and secretory cells, respectively. Considering that co-expressed genes are more likely to be involved in the same biological processes, we analyzed genes that are co-expressed with TAAR1, DRD2, DRD4, and DRD5 genes in healthy mucosa and duodenal samples from patients with functional dyspepsia (FD) or diabetes-associated gastrointestinal symptoms. Both pathological conditions showed a deregulation of co-expression patterns, with a high discrepancy between DRDs and TAAR1 co-expressed gene sets in normal tissues and patients' samples and a loss of these genes' functional similarity. Meanwhile, we discovered specific changes in co-expression patterns that may suggest the involvement of TAAR1 and D5 receptors in pathologic or compensatory processes in FD or diabetes accordingly. Despite our findings suggesting the possible role of TAAR1 and dopamine receptors in functional diseases of the upper intestine, underlying mechanisms need experimental exploration and validation.

Low-intensity pulsed ultrasound combined with ST36 modulate gastric smooth muscle contractile marker expression via RhoA/Rock and MALAT1/miR-449a/DLL1 signaling in diabetic rats.

BACKGROUND: Low-intensity pulsed ultrasound (LIPUS) combined with acupoint can promote gastric motility of diabetic rats. The switch of gastric smooth muscle cell (GSMCs) phenotype was related to the diabetes-induced gastric dysfunction, but the mechanism is not clearly elucidated. This study was aimed at exploring the underlying mechanism of LIPUS stimulation application in diabetic gastroparesis rats. METHODS: In this study, Sprague-Dawley male rats were divided into three groups: control group (CON), diabetic gastroparesis group (DGP), and LIPUS-treated group (LIPUS). LIPUS irradiation was performed bilaterally at ST36 for 20 min per day for 4 weeks. The gastric emptying rate was measured by ultrasound examination. Contraction ability of GSMCs was assessed by muscle strip experiment. The expression of related proteins or mRNAs including α-SMA, SM22α, MHC, RhoA, Rock2, p-MYPT1, MYPT1, p-MLC, MLC, MALAT1, miR-449a, and DLL1 was detected by different methods such as western blotting, RT-qPCR, immunohistochemistry, and immunofluorescence staining, as appropriate. KEY RESULTS: (a) LIPUS stimulation at ST36 could improve the gastric motility dysfunction of diabetic rats. (b) LIPUS increased RhoA, Rock2, p-MYPT1, and p-MLC expression level. (c) MALAT1 and DLL1 contents were decreased, but the level of miR-449a was increased in the LIPUS group. CONCLUSIONS & INFERENCES: LIPUS may affect the contractile marker expression of gastric smooth muscle through the RhoA/Rock and MALAT1/miR-449a/DLL1 pathway to ameliorate DGP.

Analysis of gastric electrical rhythm in patients with type 2 diabetes mellitus.

AIM: To analysis the change of electrogastrogram (EGG) in patients with type 2 diabetes mellitus (T2DM), and evaluate the prevalence of abnormal gastric electrical rhythm (AGER) and its relative influencing factors. METHODS: A total of 65 patients with T2DM hospitalized at the Second Affiliated Hospital of Soochow University from Dec. 2020 to Dec. 2021 were included in the cross-sectional study. General information, clinical data, and medical history data of all study subjects, including name, gender, body mass index (BMI), duration of diabetes, anti-diabetic therapies, high blood pressure (HBP) history, smoking history, and medication history, were completely collected. The results of laboratory tests, including biochemical parameters, glycosylated hemoglobin (HbA1c), fasting C-peptide, 2 h postprandial C-peptide, 24 h urine total protein (24 hUTP), urine microalbumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were recorded. EGG, Gastroparesis Cardinal Symptom Index (GCSI), gastric emptying ultrasound, fundus examination, carotid artery ultrasonography, cardiac autonomic function test, heart rate variability (HRV) were all examined and recorded as well. According to the results of EGG, the subjects were divided into normal gastric electrical rhythm (NGER) group and abnormal gastric electrical rhythm (AGER) group. RESULTS: (1) Fasting blood glucose (FBG), HbA1c, the presence of diabetic peripheral neuropathy (DPN) and diabetic cardiac autonomic neuropathy (DCAN) were significantly higher in the AGER group (p < 0.05). Low frequency (LF) and high frequency (HF), the indicators of HRV, were significantly lower in the AGER group (p < 0.05). In addition, the prevalence of feeling excessively full after meals, loss of appetite, and stomach or belly visibly larger after meals of gastrointestinal symptoms of gastroparesis were significantly higher in the AGER group (p < 0.05). Multiple logistic regression analysis showed that FBG and the prevalence of DCAN were the independent risk factors. CONCLUSION: AGER was associated with high FBG and the presence of DCAN. EGG examination is recommended for patients with gastrointestinal symptoms and clues of DCAN.

Pathogenesis and management of diabetic gastroparesis: An updated clinically oriented review.

BACKGROUND AND AIMS: Diabetic gastroparesis (DGp) is a common and preventable complication of uncontrolled diabetes mellitus (D.M.) and significantly affects the Quality of Life of patients. Diagnosis and management present as a clinical challenge due to the disease's complexity and limited effective therapeutic options. This review aims to comprehensively outline the pathogenesis, diagnosis, and management of diabetic gastroparesis, evaluating evolving approaches to guide clinicians and provide future recommendations. METHODS: A literature review was conducted on scholarly databases of PubMed, Google Scholar, Scopus and Web of Science encompassing published articles, gray literature and relevant clinical guidelines. Data were synthesized and analyzed to provide a comprehensive overview of diabetic gastroparesis, focusing on pathogenesis, diagnosis, and management. RESULTS: The review intricately explores the pathogenesis contributing to diabetic gastroparesis, emphasizing autonomic neuropathy, oxidative stress, inflammation, hormonal dysregulation, microbiota alterations, and gastrointestinal neuropathy. Primary management strategies are underscored, including lifestyle modifications, symptom relief, and glycemic control. The discussion encompasses pharmacological and surgical options, highlighting the importance of a multidisciplinary approach involving various healthcare professionals for comprehensive patient care. CONCLUSION: This review offers a thorough understanding of pathogenesis, diagnosis, and management of diabetic gastroparesis, underlining evolving approaches for clinicians. A multidisciplinary approach is crucial to address both the physical and mental health aspects of diabetes and its complications.

Involvement of oxidative stress-AMPK-Cx43-NLRP3 pathway in extracellular matrix remodeling of gastric smooth muscle cells in rats with diabetic gastroparesis.

This study aimed to investigate the changes in oxidative stress, adenosine monophosphate-activated protein kinase (AMPK), connexin43 (Cx43), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression, and extracellular matrix (ECM) in the gastric smooth muscle tissues of rats with diabetic gastroparesis (DGP) and high glucose-cultured gastric smooth muscle cells, determine the existence of oxidative stress-AMPK-Cx43-NLRP3 pathway under high glucose condition, and the involvement of this pathway in ECM remodeling in DGP rats. The results showed that with increasing duration of diabetes, oxidation stress levels gradually increased, the AMPK activity decreased first and then increased, NLRP3, CX43 expression, and membrane/cytoplasm ratio of Cx43 expression were increased in the gastric smooth muscle tissues of diabetic rats. Changes in ECM of gastric smooth muscle cells were observed in DGP rats. The DGP group showed higher collagen type I content, increased expression of Caspase-1, transforming growth factor-beta 3 (TGF-ß3), and matrix metalloproteinase-2 (MMP-2), decreased tissue inhibitor of metalloproteinase-1 (TIMP-1) expression, and higher interleukin-1 beta content when compared with the control group. For gastric smooth muscle cells cultured under higher glucose, the MMP-2 and TGF-ß3 expression was decreased, TGF-ß1 and TIMP-1 expression was increased, the interleukin-1 beta content was decreased in cells after inhibition of NLRP3 expression; the NLRP3 and Caspase-1 expression was decreased, and adenosine triphosphate content was lower after inhibition of Cx43; the expression of NLRP3, Caspase-1, P2X7, and the membrane/cytoplasm ratio of CX43 expression was decreased in cells after inhibition of AMPK and oxidative stress, the phospho-AMPK expression was also decreased after suppressing oxidative stress. Our findings suggest that high glucose induced the activation of the AMPK-Cx43-NLRP3 pathway through oxidative stress, and this pathway was involved in the ECM remodeling of gastric smooth muscles in DGP rats by regulating the biological functions of TGF-ß3, TGF-ß1, MMP-2, and TIMP-1.

Factors Associated With Delayed Gastric Emptying in Symptomatic Diabetic and Non-diabetic Patients: A Retrospective Observational Study.

Background Gastroparesis, characterized by delayed gastric emptying without mechanical obstruction, is a significant complication, especially in diabetic individuals. It manifests through symptoms such as abdominal bloating, feelings of fullness, and pain. This study investigates the prevalence of gastroparesis among non-diabetic and diabetic patients, exploring associations with demographic data, hemoglobin A1C (HbA1C) levels, and symptoms. Methodology This retrospective, observational, cohort study included patients with gastroparesis symptoms who underwent a nuclear gastric emptying study from January 2021 to April 2023. The study analyzed demographic data, symptoms, and HbA1c levels to identify correlations with delayed gastric emptying. Results Of 157 patients, 34.4% exhibited delayed gastric emptying. Diabetic patients comprised 29.3% of the sample, with a notable disease duration of over 10 years in 77.3% of cases. Symptoms such as nausea, vomiting, epigastric pain, and early satiety were prevalent, with significant associations between delayed emptying and female gender, higher HbA1c, and vomiting. Conclusions Delayed gastric emptying is significantly associated with female gender, elevated HbA1c levels, and when vomiting is the presenting symptom. Highlighting the importance of awareness among healthcare providers and the community, the findings encourage collaborative efforts for further gastroparesis research to better understand the predictive factors and mechanisms.

Diabetic gastroparesis: a disease for which long-term therapeutic benefits are difficult to obtain.

The pathophysiology of diabetic gastroparesis (DGP), a common complication in diabetic patients, is not fully known. Its development has been linked to several causes, including hyperglycaemia, vagal nerve dysfunction, aberrant Cajal's interstitial cell network (ICC), lack of nerve nitric oxide synthase (nNOS) expression in the intermuscular plexus, and hormonal alterations in the gastrointestinal tract. Glucose management, diet control, gastric stimulants, anti-emetic medications, Helicobacter pylori eradication, stomach electrical stimulation, and surgery are the main current treatments. These methods, however, could have unfavourable consequences. By examining recent studies and literature reviews, we outline the state of the study on diabetic gastroparesis in this paper.

Efficacy of Pistacia lentiscus Plant (Rumi Mastagi) in Comparison to Levosulpiride in Patients with Diabetic Gastroparesis: A Double-Blind Non-Inferior Randomised Control Trial Study.

Introduction: Gastrointestinal neuropathies are frequently found in diabetic patients. The pathogenesis of diabetic gastroparesis (DG) is multifactorial. The usual treatment for DG includes dietary modifications, prokinetic and antiemetic agents. There is increasing demand for more effective medicines to treat DG. The current study was conducted on the Pistacia lentiscus stem extract to add to the armamentarium of DG treatment and to find the efficacy of P. lentiscus plant extract (mastic gum) in comparison to levosulpiride in DG for improvement in gastroparesis symptoms and gastric emptying scintigraphy (GES) in a single centric double-blind non-inferiority randomised control trial. Methods: Thirty-eight individuals were recruited and equally randomised into two study groups based on Gastroparesis Cardinal Symptom Index (GCSI) score and TC99 Radionuclide GES, mastic gum group and levosulpiride group. Both pre and post-intervention (8 weeks) GCSI scores were calculated, GES was performed to quantify the improvement in gastric emptying. Power analysis was performed using G*POWER software version 3.1.9.7 and data analysis using SPSS 23.0, variables measured in mean ± standard deviation (SD). Various statistical tests were used such as independent t-test, Chi-square test or Fisher's exact test, Wilcox Mann-Whitney test, analysis of variance (ANOVA) test, and posthoc pairwise tests. Results: The mastic gum is found effective in the improvement of 4 h gastric emptying percentage from the mean (SD) 76.60 (± 9.96) to mean (SD) 97.20 (2.17)% (P < 0.001). Mastic gum has the property of HbA1c reduction, which is more significant than that of levosulpiride (P = 0.044). Mastic gum also had significant Low density lipoprotein (LDL) (mg/dL) levels reduction, (P < 0.001), compared to levosupiride. An absolute increase was observed in haemoglobin (HB) level in mastic gum at a 2-month mean (SD) of 1.03 (0.77) (g/dL) (P-value <0.001). Conclusions: To our knowledge, this is the first study to compare the effect of levosulpiride with mastic gum concerning improvement in diabetic gastroparesis (DG) using GES. In the study, mastic gum was found to have great properties to improve DG with many important pleiotropic effects.

A. officinarum Hance - P. cablin (Blanco) Benth drug pair improves oxidative stress, intracellular Ca2+ concentrations and apoptosis by inhibiting the AGE/RAGE axis to ameliorate diabetic gastroparesis: In vitro and in vivo studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Alpinia officinarum Hance is a perennial natural medicine herbivorous plant, has been used in the management of treat stomach pain and diabetes, it is abundantly cultivated in Qiongzhong, Baisha and other places. P. cablin (Blanco) Benth, one of the most important traditional Chinese plants, which plays functions in antioxidant and gastrointestinal regulation, has been extensively planted in Hainan, Guangdong and other regions. AIM OF THE STUDY: In this study, we investigated the role and underlying molecular mechanism of AP on diabetic gastroparesis (DGP) in vitro and in vivo. MATERIALS AND METHODS: In this study, using ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS) to identify active compounds in A. officinarum Hance-P. cablin (Blanco) Benth drug pair (AP). Molecular docking were utilized to explore the potential mechanism of AP treatment of DGP. In in vitro assays, gastric smooth muscle cells (GSMCs) were treated with 35 mM glucose to promote apoptosis and construct the DGP model, which was treated with different concentrations of AP. Furthermore, transfection technology was used to overexpress RAGE in GSMCs and elucidate the underlying mechanisms of alleviation of DGP by AP. RESULTS: Using UPLC-MS/MS analysis, nine components of AP were identified. We found that AP effectively blocked the increase in apoptosis, oxidative stress, and intracellular Ca2+ concentrations. For in vivo experiments, mice were fed with a high-fat irregular diet to construct DGP model, and AP was co-administered via oral gavage daily to prevent the development of DGP. Compared with DGP mice, AP significantly decreased fasting blood glucose levels and increased gastric emptying levels. Consistent with in vitro experiments, AP also considerably decreased the increase in oxidative stress in DGP mice. Mechanistically, AP alleviates apoptosis and DGP by decreasing oxidative stress and intracellular Ca2+ concentrations via the inhibition of the AGE/RAGE axis. CONCLUSIONS: Collectively, this study has established that AP can improve DGP, and the mechanism may be related to the inhibition the AGE/RAGE axis to mitigate apoptosis and DGP. To summarize, this study provides a novel supplementary strategy for DGP treatment.

Alpinia officinarum Hance extract ameliorates diabetic gastroparesis by regulating SCF/c-kit signaling pathway and rebalancing gut microbiota.

Diabetic gastroparesis (DGP) is a common complication of type 2 diabetes mellitus (T2DM). Alpinia officinarum Hance (AOH) is one of the most commonly used both as a food and folk medicines, which is rich in diarylheptanoids and flavonoids. The gastroprotection and hypoglycemic effect make AOH has great potential in developing of anti-DGP complementary medicine. However, the molecular mechanisms of AOH that act against DGP are yet to be elucidated. In this study, we evaluated the therapeutic effects, the potential molecular mechanism, and the changes of gut microbiota of AOH in DGP. The 5 components of the AOH were analyzed, and the potential signaling pathway of AOH improving DGP was predicted by molecular docking. Subsequently, DGP rat model was constructed using high-fat-irregular-diet, AOH intervention significantly reduced blood glucose levels, increased gastrointestinal propulsion rate, and improved gastric histological morphology in DGP rats. Meanwhile, AOH has been shown to regulate the SCF/c-kit signaling pathway and rebalance the gut microbiota, which may be closely related to its role in improving DGP. Taken together, AOH may play a protective role on DGP through multiple mechanisms, which might pave the road for development and utilization of AOH.

Clinical Observation on Navel Application of Jianpi Hewei Adhesive Plaster Combined with Oral Use of Modified Sini Hewei Anshen Decoction for the Treatment of Diabetic Gastroparesis Accompanied by Anxiety in Type 2 Diabetes / 广州中医药大学学报

Objective To evaluate the clinical efficacy of navel application of Jianpi Hewei Adhesive Plaster combined with oral use of modified Sini Hewei Anshen Decoction in treating diabetic gastroparesis(DGP)accompanied by anxiety of liver-stomach disharmony type in type 2 diabetes patients.Methods One hundred patients with DGP accompanied by anxiety of liver-stomach disharmony type were randomly divided into a treatment group and a control group,with 50 patients in each group.The control group was given oral use of Mosapride Citrate Tablets orally,and the treatment group was given navel application of Jianpi Hewei Adhesive Plaster combined with oral use of modified Sini Hewei Anshen Decoction.The course of treatment for the two groups covered 4 weeks.The two groups were observed in the changes of the traditional Chinese medicine(TCM)syndrome scores,Gastroparesis Cardinal Symptom Index(GCSI)scores,Hamilton Anxiety Scale(HAMA)scores,gastric emptying time,and levels of fasting blood glucose(FBG),2-hour postprandial blood glucose(2hPG),glycated hemoglobin(HbA1c),plasma motilin(MOT),gastrin(GAS),and serum tumor necrosis factor alpha(TNF-α)and interleukin 6(IL-6)before and after the treatment.After treatment,the clinical efficacy and safety of the two groups were evaluated.Results(1)During the trial,4 patients in the treatment group and 3 patients in the control group fell off,and eventually a total of 93 patients were included for the efficacy statistics,including 46 patients in the treatment group and 47 patients in the control group.(2)After 4 weeks of treatment,the total effective rate of the treatment group was 95.65%(44/46)and that of the control group was 76.60%(36/47).The intergroup comparison(tested by chi-square test)showed that the therapeutic effect of the treatment group was significantly superior to that of the control group(P＜0.01).(3)After treatment,the TCM syndrome scores(including epigastric and abdominal congestion,depression or irritability,and poor appetite)and GCSI scores in the two groups were decreased compared with those before treatment(P＜0.05)and the gastric emptying time was shortened compared with that before treatment(P＜0.05),and the effect of the treatment group on decreasing TCM syndrome scores and GCSI scores and on shortening the gastric emptying time were significantly superior to that of the control group(P＜0.01).(4)After treatment,the plasma MOT and GAS levels of the two groups were increased compared with those before treatment(P＜0.05),and the increase in the treatment group was significantly superior to that in the control group(P＜0.01).(5)After treatment,the levels of glucose metabolism indicators of FBG,2hPG,and HbA1c in the two groups were decreased compared with those before treatment(P＜0.05),but the differences of all glucose metabolism indicators between the two groups after treatment were not statistically significant(P＞0.05).(6)After treatment,the serum TNF-α and IL-6 levels in the two groups were decreased compared with those before treatment(P＜0.05),and the decrease in the treatment group was significantly superior to that in the control group(P＜0.05).(7)After treatment,the total HAMA scores and the scores of mental anxiety factor and somatic anxiety factor of HAMA in the two groups were decreased compared with those before treatment(P＜0.05),and the effect on lowering the scores in the treatment group was significantly superior to that in the control group(P＜0.05).(8)During the treatment period,no significant adverse reactions occurred in the two groups of patients,which has high safety.Conclusion Navel application of Jianpi Hewei Adhesive Plaster combined with oral use of modified Sini Hewei Anshen Decoction exerts certain efficacy in treating DGP accompanied by anxiety of liver-stomach disharmony type.The therapy is effective on relieving clinical symptoms,enhancing gastric motility,inhibiting inflammatory response,and improving anxiety emotion and the quality of life of the patients.

Mechanism of oxidative stress-AMPK-Cx43-NLRP3 pathway regulating extracellular matrix remodeling of rat gastric smooth muscle cells under high glucose condition / 中国病理生理杂志

AIM:To investigate the regulatory effect of oxidative stress-AMP-activated protein kinase(AMPK)-connexin 43(Cx43)-nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)pathway on extracellular matrix(ECM)remodeling of gastric smooth muscle cells under high glucose(HG)condition.METHODS:Primary rat smooth muscle cells cultured in vitro were divided into normal glucose group,HG group,HG+NLRP3 inhibitor MCC950(15 nmol/L)group,HG+Cx43 hemichannel blocker GAP19(100 μmol/L)group,HG+AMPK inhibitor Compound C(CC;10 μmol/L)group,and high glucose+antioxidant α-lipoic acid(α-LA;100 μmol/L)group,which were all cultured for 48 h for detection.The protein levels of caspase-1,matrix metalloproteinase-2(MMP-2),NLRP3,Cx43,transforming growth factor-β1(TGF-β1),TGF-β3,tissue inhibitor of metalloproteinase-1(TIMP-1),purinergic P2X7 receptor(P2X7R)and phosphorylated AMPK(p-AMPK)in the cells were detected by Western blot.The levels of adenosine tri-phosphate,interleukin-1β,collagen type Ⅰ(Col I)and collagen type Ⅲ(Col Ⅲ)in the cell culture medium were deter-mined by ELISA.RESULTS:Compared with HG group,the levels of MMP-2 and TGF-β3 in HG+MCC950 group were decreased(P<0.01),while the levels of TGF-β1 and TIMP-1 were increased(P<0.01).The levels of NLRP3 and cas-pase-1 in HG+GAP19 group were decreased(P<0.01),while the expression of P2X7R was not changed.The levels of NLRP3,caspase-1,P2X7R,total Cx43 and membrane Cx43,and the ratio of membrane Cx43 to cytoplasmic Cx43 were decreased in HG+CC group(P<0.01).The levels of p-AMPK,caspase-1,NLRP3,P2X7R,total Cx43 and membrane Cx43,and the ratio of membrane Cx43 to cytoplasmic Cx43 were decreased in HG+α-LA group(P<0.05).CONCLU-SION:High glucose regulates the content of Col I and Col Ⅲ through the oxidative stress-AMPK-Cx43-NLRP3 pathway,thereby participating in the extracellular matrix remodeling of gastric smooth muscle cells.

Hedysari Radix Polysaccharide Regulates Apoptosis of Smooth Muscle Cells in Gastric Antrum of Rat Model of Diabetic Gastroparesis via IGF-1/PI3K/Akt Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo observe the effects of Hedysari Radix polysaccharide on the apoptosis of gastric sinus smooth muscle cells and explore the underlying mechanism via the insulin-like growth factor-1 （IGF-1）/phosphatidylinositol 3-kinase （PI3K）/serine-threonine kinase （Akt） pathway in the rat model of diabetic gastroparesis （DGP）. MethodSixty-two Wistar male rats were randomized into a blank group （n=12） and a modelling group （n=50）. The rat model of DGP was established by small-dose multiple intraperitoneal injections of streptozotocin combined with an irregular high-fat and high-sugar diet for 4 weeks. The modeled rats were randomized into model group， mosapride citrate （1.35 mg·kg-1）， and high-， medium-， and low-dose （200， 100， and 50 mg·kg-1， respectively） Hedysari Radix polysaccharide groups. The rats were administrated with corresponding drugs by gavage， and those in the blank and model groups with equal volumes of pure water by gavage once a day for 8 consecutive weeks. The random blood glucose and body mass were measured every 2 weeks， and gastric emptying rate was calculated. Hematoxylin-eosin （HE） staining was used to observe the pathological changes of smooth muscle in gastric antrum， and terminal deoxynucleoitidyl transferase-mediated nick-end labeling （TUNEL） was employed to detect the apoptosis of smooth muscle cells in the gastric antrum. The expression of IGF-1， phosphorylated （p）-PI3K， and p-Akt in the smooth muscle of gastric sinus tissue was detected by immunohistochemistry. Western blot was employed to determine the protein levels of IGF-1， p-PI3K/PI3K， p-Akt/Akt， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax） in the smooth muscle of the gastric antrum. ResultCompared with the blank group， the model group showed elevated random blood glucose at all time points （P<0.01）， decreased body mass and gastric emptying rate （P<0.01）， increased apoptotic index of smooth muscle cells in the gastric antrum （P<0.01）， down-regulated protein levels of IGF-1， p-PI3K/PI3K， p-Akt/Akt， and Bcl-2， and up-regulated protein level of Bax （P<0.01）. Compared with the model group， the 8 weeks of drug administration lowered the random blood glucose， increased the body mass and gastric emptying rate （P<0.05， P<0.01）， decreased the apoptotic index of smooth muscle cells in the gastric antrum （P<0.05， P<0.01）， up-regulated the protein levels of IGF-1， p-PI3K/PI3K， p-Akt/Akt， and Bcl-2， and down-regulated the protein level of Bax （P<0.05， P<0.01）. Compared with the mosapride citrate group，the administration of low-dose Hedysari Radix polysaccharide for 6 and 8 weeks lowered the random blood glucose and decreased the body mass （P<0.05， P<0.01），low and medium-dose Hedysari Radix polysaccharide decreased the gastric emptying rate and the apoptotic index of smooth muscle cells in the astragaloside low-dose group decreased （P<0.05）. The protein levels of IGF-1，p-PI3K/PI3K，p-Akt/Akt and Bcl-2（low dose）were down-regulated and the protein level of Bax was up-regulated by low doses of Hedysari Radix polysaccharide （P<0.05， P<0.01）. Compared with high-dose Hedysari Radix polysaccharide， low-dose Hedysari Radix polysaccharide elevated random blood glucose and reduced body mass after 6 and 8 weeks of administration （P<0.05， P<0.01）， and the low and medium doses decreased the gastric emptying rate， increased the apoptotic index of smooth muscle cells in the gastric antrum （P<0.05， P<0.01）， down-regulated the protein levels of IGF-1， p-PI3K/PI3K， p-Akt/Akt， and Bcl-2， and up-regulated the protein level of Bax （P<0.05， P<0.01）. Compared with the medium-dose group，the low-dose group of Hedysari Radix polysaccharide had lower body mass，lower gastric emptying rate in rats，higher apoptotic index of smooth muscle cells in gastric sinus tissue after 6 and 8 weeks of administration （P<0.05， P<0.01）， and lower protein expression of IGF-1，p-PI3K/PI3K，p-Akt/Akt. ConclusionHedysari Radix polysaccharide protects the smooth muscle cells in gastric antrum against apoptotic injury and promotes gastric motility by activating the IGF-1/PI3K/Akt signaling pathway， as manifested by the up-regulated expression of IGF-1， p-PI3K， p-Akt， and Bcl-2 and down-regulated expression of Bax.

Effect of Faeces Bombycis Extract on Cajal Interstitial Cells in Diabetic Gastroparesis Rats Based on PI3K/Akt/mTOR Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo explore the therapeutic mechanism of Faeces Bombycis on diabetic gastroparesis （DGP） rats based on phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein （PI3K/Akt/mTOR） signaling pathway. MethodDGP rat model was prepared by random selection of 15 out of 105 rats as blank group. The rats successfully constructed were randomly divided into model group， high-，medium- and low- dose groups （3.2， 1.6， 0.8 g·kg-1） and moxapride group （1.5 mg·kg-1）， with 12 rats in each group， and were given gavage for 4 weeks. The gastric emptying rate and random blood glucose were measured. The morphological changes of gastric antrum were observed by hematoxylin-eosin （HE） staining， and the expression of the c-Kit gene was analyzed by immunohistochemistry. The apoptosis of Cajal interstitial cells was observed by in situ end labeling （TUNEL） staining， and the protein expressions of PI3K， phosphorylation（p）-PI3K， Akt， p-Akt， mTOR， and p-mTOR were detected by Western blot. ResultCompared with the blank group， the gastric emptying rate of the model group decreased significantly （P<0.01）， and the glandular structure of the gastric antrum was destroyed. The expression of c-Kit decreased （P<0.01）， and the apoptosis of Cajal interstitial cells （ICC） increased. Compared with the model group， the gastric emptying rate in the high， middle， and low-dose groups of Faeces Bombycis extract and mosapride group increased significantly （P<0.01）. The glandular structure of the gastric antrum became closer， and the apoptosis of ICC decreased. The expression of c-Kit in the high dose group of Faeces Bombycis extract increased significantly. After Western blot testing， compared with the blank group， the protein expression of p-Akt/Akt， p-PI3K/PI3K， and p-mTOR/mTOR in the model group increased. Compared with the model group， the protein expression of p-Akt/Akt in the high dose group of Faeces Bombycis extract decreased （P<0.01）， and the protein expression of p-PI3K/PI3K decreased in the middle and low dose groups of Faeces Bombycis extract and mosapride group decreased （P<0.05， P<0.01）. The protein expression of p-mTOR/mTOR decreased in the low dose group of Faeces Bombycis extract （P<0.05）. In terms of random blood glucose， compared with the blank group， the random blood glucose in the model group increased significantly （P<0.01）， and compared with the model group， the random blood glucose in the high and middle dose groups of Faeces Bombycis extract decreased significantly （P<0.05）. Compared with mosapride group， the protein expression of p-Akt/Akt decreased in the high dose group of Faeces Bombycis extract （P<0.05）， and the protein expression of p-PI3K/PI3K increased in the high， middle， and low dose groups of Faeces Bombycis extract （P<0.05， P<0.01）. ConclusionFaeces Bombycis extract can increase gastric emptying rate， reduce ICC apoptosis， and lower random blood glucose in DGP rats. The high dose group of Faeces Bombycis extract has a significant effect on inhibiting ICC apoptosis， and its mechanism may be related to the regulation of the PI3K/Akt/mTOR signaling pathway.

Mechanism of Chinese Medicine Against Diabetic Gastroparesis： A Review / 中国实验方剂学杂志

Diabetic gastroparesis （DGP） is a common diabetic neuropathy that affects the normal function of gastric motility and emptying. Clinically， it often manifests as abdominal distension， nausea and vomiting， early satiety， dyspepsia， etc. The pathogenesis of DGP is multifactorial， closely related to many factors， such as chronic hyperglycemia， neuropathy， autonomic nervous system disorders， inflammation， and oxidative stress. These factors can interact with each other， leading to delayed gastric emptying and the occurrence of related symptoms. Traditional Chinese medicine （TCM） has significant advantages in the prevention and treatment of DGP， including a long history， remarkable efficacy， individualized treatment， diverse therapeutic formulations， and improvement in the quality of life. Additionally， TCM is known for its low adverse reactions， good tolerance， and multi-targeted effects， making it an important approach in the management of DGP. Previous research has found that the main mechanisms of Chinese medicine in the prevention and treatment of DGP include the regulation of gastrointestinal hormones， inhibition of inflammatory responses， reduction of oxidative stress， enhancement of interstitial cells of Cajal activity， inhibition of pyroptosis， and modulation of related signaling pathways such as stem cell factor （SCF）/cellular growth factor receptor （c-Kit）， adenosine monophosphate-activated protein kinase （AMPK）， Ras homologous genome member A （RhoA）/Rho-associated coiled-coil forming kinase （ROCK）. This article primarily summarized the research progress on Chinese medicine in preventing and treating DGP through the inhibition of inflammatory responses， reduction of oxidative stress， enhancement of interstitial cells of Cajal activity， inhibition of pyroptosis， and regulation of related signaling pathways， aiming to provide a reference and basis for further research on the application value of Chinese medicine in the prevention and treatment of DGP.

Relamorelin in Gastroparesis and Diabetic Gastroparesis: A Meta-Analysis on Its Efficacy and Safety.

This meta-analysis aimed to evaluate the efficacy and safety of relamorelin, a synthetic ghrelin receptor agonist, for the treatment of gastroparesis and diabetic gastroparesis. A total of 1,033 participants from five randomized controlled trials were included. The primary outcome was the mean change in gastric emptying time from baseline. Relamorelin demonstrated a statistically significant improvement in gastric emptying time with a mean difference of -11.40 minutes compared to the placebo group. Furthermore, a significant improvement was observed specifically in diabetic gastroparesis patients, with a mean difference of -8.43 minutes. However, adverse effects, such as headaches, dizziness, and gastrointestinal symptoms, were more prevalent in the relamorelin group. Despite these adverse effects, the study concludes that relamorelin offers a promising avenue for gastroparesis treatment, especially given the limited existing therapeutic options. This comprehensive meta-analysis synthesizes existing evidence to inform clinical practice and guides future research in this domain.

A Type 2 Diabetes Mellitus Patient With Severe Diabetic Gastroparesis Successfully Treated With Intravenous Erythromycin.

Gastroparesis, characterized by a decrease in gastric emptying, can lead to worsened diabetes control and a reduced quality of life. The patient was a 32-year-old male with type 2 diabetes. He was initially admitted for control of diabetes, and two months later, he was readmitted due to nausea and vomiting. He showed resistance to various drugs, including antiemetics, and an upper gastrointestinal endoscopy revealed significant gastric residue, leading to a diagnosis of gastroparesis. We administered intravenous erythromycin. After three days of treatment, the vomiting resolved. Gastroparesis is challenging to manage, and there are limited effective treatment options. We experienced a case of diabetic gastroparesis with severe vomiting and loss of appetite that responded remarkably well to intravenous erythromycin treatment. Intravenous administration of erythromycin may be a potentially effective treatment for gastroparesis.