Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon- like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They f...Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon- like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They function to stimulate insulin secretion while suppressing glucagon secretion. GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus (T2DM), and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases. As we know, along with change in lifestyles, the prevalence of non-alcoholic fatty liver disease (NAFLD) in China is rising more than that of viral hepatitis and alcoholic fatty liver disease, and NAFLD has become the most common chronic liver disease in recent years. Recent studies further suggest that GLP-1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels, cutting down the fat content to promote fat redistribution, directly decreasing fatty degeneration of the liver, reducing the degree of liver fibrosis and improving inflammation. This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.展开更多
Background Although the insulinotropic role of glucagon-like peptide-1 （GLP-1） in type 2 diabetes mellitus has been substantiated, its role in cardioprotection remains largely unknown. This study aimed to determine ...Background Although the insulinotropic role of glucagon-like peptide-1 （GLP-1） in type 2 diabetes mellitus has been substantiated, its role in cardioprotection remains largely unknown. This study aimed to determine the effects of GLP-1 on injury of rats cardiac myocytes induced by hypoxia-reoxygenation （H/R） and the possible mechanisms. Methods The cultured neonatal rats cardiac myocytes were randomly divided into seven groups： the normal control group, the H/R group, the GLP-1＋H/R group, the GLP-1＋H/R＋UO126 （the p42/44 mitogen-activated protein kinase （MAPK） inhibitor） group, the GLP-1＋H/R＋LY294002 （phosphatidylinositol 3-kinase （PI3K） inhibitor） group, the H/R＋UO126 group, and the H/R＋LY294002 group. The lactate dehydrogenase （LDH） activity, apoptosis rate of cardiac myocytes, and caspase-3 activity were detected after the injury of H/R. Results Compared with the normal control group, the activity of LDH, cardiac myocyte apoptosis rate, and caspase-3 activity all increased significantly in the H/R group （P 〈0.01）. Compared with the H/R group, these three indices all decreased in the H/R＋GLP-1 group （P 〈0.01）. However, the changes of LDH activity, apoptosis rate, and caspase-3 activity were inhibited by LY294002 and UO126 respectively. Conclusions GLP-1 can directly act on cardiac myocytes and protect them from H/R injury mainly by inhibiting their apoptosis. Its mechanism may be through the PI3K-Akt pathway and the MAPK signaling pathway.展开更多
AIM:To evaluate the effects of ginger on gastric motility and emptying,abdominal symptoms,and hormones that influence motility in dyspepsia.METHODS:Eleven patients with functional dyspepsia were studied twice in a ran...AIM:To evaluate the effects of ginger on gastric motility and emptying,abdominal symptoms,and hormones that influence motility in dyspepsia.METHODS:Eleven patients with functional dyspepsia were studied twice in a randomized double-blind manner.After an 8-h fast,the patients ingested three capsules that contained ginger(total 1.2 g) or placebo,followed after 1 h by 500 mL low-nutrient soup.Antral area,fundus area and diameter,and the frequency of antral contractions were measured using ultrasound at frequent intervals,and the gastric half-emptying time was calculated from the change in antral area.Gastrointestinal sensations and appetite were scored using visual analog questionnaires,and blood was taken for measurement of plasma glucagon-like peptide-1(GLP-1),motilin and ghrelin concentrations,at intervals throughout the study.RESULTS:Gastric emptying was more rapid after ginger than placebo [median(range) half-emptying time 12.3(8.5-17.0) min after ginger,16.1(8.3-22.6) min after placebo,P ≤ 0.05].There was a trend for more antral contractions(P = 0.06),but fundus dimensions and gastrointestinal symptoms did not differ,nor did serum concentrations of GLP-1,motilin and ghrelin.CONCLUSION:Ginger stimulated gastric emptying and antral contractions in patients with functional dyspepsia,but had no impact on gastrointestinal symptoms or gut peptides.展开更多
Type 2 diabetes (T2D) is a disorder characterized by chronic inflated blood glucose levels (hyperglycemia), at first due to insulin resistance and unregulated insulin secretion but with tendency towards global spreadi...Type 2 diabetes (T2D) is a disorder characterized by chronic inflated blood glucose levels (hyperglycemia), at first due to insulin resistance and unregulated insulin secretion but with tendency towards global spreading. The gut microbiota is recognized to have an influence on T2D, although surveys have not formed a clear overview to date. Because of the interactions between gut microbiota and host homeostasis, intestinal bacteria are believed to play a large role in various diseases, including metabolic syndrome, obesity and associated disease. In this review, we highlight the animal and human studies which have elucidated the roles of metformin,α-glucosidase inhibitors, glucagon-like peptide-1 agonists, peroxisome proliferator-activated receptors γ agonists, inhibitors of dipeptidyl peptidase-4, sodium/glucose cotransporter inhibitors, and other less studied medications on gut microbiota. This review is dedicated to one of the most widespread diseases, T2D, and the currently used antidiabetic drugs and most promising new findings. In general, the gut microbiota has been shown to have an influence on host metabolism, food consumption, satiety, glucose homoeostasis, and weight gain. Altered intestinal microbiota composition has been noticed in cardiovascular diseases, colon cancer, rheumatoid arthritis, T2D, and obesity. Therefore, the main effect of antidiabetic drugs is on the microbiome composition, basically increasing the short-chain fatty acids-producing bacteria, responsible for losing weight and suppressing inflammation.展开更多
Glucagon-like peptide-1(GLP-1)receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus.A number of c...Glucagon-like peptide-1(GLP-1)receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus.A number of case reports show an association of GLP-1receptor agonists,mainly exenatide,with the development of acute kidney injury.The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function,their use in subjects with chronic renal failure and their possible association with acute kidney injury.Based on the current evidence,exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease.Liraglutide is not eliminated by renal or hepatic mechanisms,but it should be used with caution since there are only limited data in patients with renal or hepatic impairment.There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering effect.Additionally,there is evidence that GLP-1 receptor agonists influence water and electrolyte balance.These effects may represent new ways to improve or even prevent diabetic nephropathy.展开更多
Glucagon-like peptide-1(GLP-1)-based therapies have demonstrated efficacy and safety in treating type 2 diabetes, which shares a similar pathophysiological mechanism with non-alcoholic fatty liver disease(NAFLD). Rece...Glucagon-like peptide-1(GLP-1)-based therapies have demonstrated efficacy and safety in treating type 2 diabetes, which shares a similar pathophysiological mechanism with non-alcoholic fatty liver disease(NAFLD). Recent studies showed that glucose-induced GLP-1 secretion was decreased in patients with NAFLD and that the level of dipeptidyl peptidase-4, which inactivates intact GLP-1, was upregulated. Moreover, the expression of the GLP-1 receptor was downregulated in livers from patients with NAFLD, indicating an association of defective GLP-1 signalling with NAFLD. Notably, GLP-1-based therapies are reported to be effective in improving hepatic endpoints in patients with NAFLD, such as reducing hepatic fat content, hepatic steatosis and plasma transaminase levels, and preventing fibrosis. GLP-1-based therapies are beneficial for body weight control and glycaemic normalisation, which are important for the management of NAFLD. Moreover, clinical and preclinical studies showed that GLP-1-based agents might directly exert their actions on the liver through activation of functional GLP-1 receptors in hepatocytes.The possible mechanisms involve regulating gene expression that is associated with insulin resistance and lipid metabolism, and suppressing oxidative stress in the liver cells, thus preventing the development and progression of NAFLD. Based on these promising data, large-scale randomised controlled trials are warranted to assess the efficacy and safety of GLP-1-based therapies in treating NAFLD.展开更多
Liver cirrhosis and diabetes mellitus(DM)are both common conditions with significant socioeconomic burden and impact on morbidity and mortality.A bidirectional relationship exists between DM and liver cirrhosis regard...Liver cirrhosis and diabetes mellitus(DM)are both common conditions with significant socioeconomic burden and impact on morbidity and mortality.A bidirectional relationship exists between DM and liver cirrhosis regarding both etiology and disease-related complications.Type 2 DM(T2DM)is a wellrecognized risk factor for chronic liver disease and vice-versa,DM may develop as a complication of cirrhosis,irrespective of its etiology.Liver transplantation(LT)represents an important treatment option for patients with end-stage liver disease due to non-alcoholic fatty liver disease(NAFLD),which represents a hepatic manifestation of metabolic syndrome and a common complication of T2DM.The metabolic risk factors including immunosuppressive drugs,can contribute to persistent or de novo development of DM and NAFLD after LT.T2DM,obesity,cardiovascular morbidities and renal impairment,frequently associated with metabolic syndrome and NAFLD,may have negative impact on short and long-term outcomes following LT.The treatment of DM in the context of chronic liver disease and post-transplant is challenging,but new emerging therapies such as glucagon-like peptide-1 receptor agonists(GLP-1RAs)and sodium–glucose cotransporter 2 inhibitors(SGLT2i)targeting multiple mechanisms in the shared pathophysiology of disorders such as oxidative stress and chronic inflammation are a promising tool in future patient management.展开更多
Objective:To investigate the protective effect of glucagon-like peptid-1(GLP-l) against cardiac microvascular endothelial cell(GTFCs) injured by high glucose.Methods:CMECs were isolated and cultured.Superoxide assay k...Objective:To investigate the protective effect of glucagon-like peptid-1(GLP-l) against cardiac microvascular endothelial cell(GTFCs) injured by high glucose.Methods:CMECs were isolated and cultured.Superoxide assay kit and dihydroethidine(DHE) staining were used to assess oxidative stress.TENEL staining and caspase 3 expression were used to assess the apoptosis of CMECs.H89 was used to inhibit eAMP/PKA pathway:fasudil was used to inhibit Rho/ROCK pathway.The protein expressions of Rho.ROCK uere examined by Western blol analysis.lesults:High glucose increased the production of ROS.the activity of NADPH.the apoptosis rate and the expression level of Rho/ROCK in CMECs.while GLP- 1 decreased high glucose-induced ROS production.the NADPH activity and the apoptosis rate and the expression level of Rho/ROCK in CMECs,the difference were statistically significant(P<0.05).Conclusions:GLP-1 could protect the cardiac microvessels against oxidative stress and apoptosis.The protective effects of GLP-1 are dependent on downstream inhibition of Rho through a cAMP/PKA-dependent manner,resulting in a subsequent decrease in the expression of NADPH oxidase.展开更多
Non-alcoholic fatty liver disease(NAFLD) is increasingly recognized as a significant liver disease,and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis(N...Non-alcoholic fatty liver disease(NAFLD) is increasingly recognized as a significant liver disease,and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis(NASH) to fibrosis,subsequent cirrhosis,end-stage liver failure,and liver cancer with a potential need for liver transplantation.NAFLD and NASH are closely related to obesity,metabolic syndrome,and type 2 diabetes(T2 D).The role of gut hormones,especially glucagon-like peptide 1(GLP-1),is important in NAFLD.Bariatric surgery has the potential for inducing great weight loss and may improve the symptoms of metabolic syndrome and T2 D.Recent data demonstrated significant effects of bariatric surgery on GLP-1 and other gut hormones and important lipid metabolic and inflammatory abnormalities in the pathophysiology of NAFLD.Therefore,bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients.In the present review,we describe NAFLD and NASH pathophysiology and the primary effects of bariatric surgery on metabolic pathways.We performed a systematic review of the beneficial and harmful effects and focused on changes in liver disease severity in NAFLD and NASH patients.The specific focus was liver histopathology as assessed by the invasive liver biopsy.Additionally,we reviewed several non-invasive methods used for the assessment of liver disease severity following bariatric surgery.展开更多
Background： As a organic acid, benzoic acid has become one of the most important alternatives for antibiotics,and its beneficial effect on performance in animals has been proven for a decade. However, knowledge of th...Background： As a organic acid, benzoic acid has become one of the most important alternatives for antibiotics,and its beneficial effect on performance in animals has been proven for a decade. However, knowledge of the effects of benzoic acid on jejunal digestive physiology, especially the antioxidant capacity and mucosal glucagon-like peptide2（GLP-2） concentrations is lacking.Methods： A total of 20 barrows [Duroc ×（Yorkshire × Landrace）] with an average body weight（BW） of 18.75 ± 0.2 kg were used in a 14-d trial to determine the potential mechanisms of benzoic acid supplementation on the performance,nutrient digestibility and jejunal digestive physiology in young pigs. All pigs were randomly allotted to 1 of 2 diets supplemented with 0 or 5000 mg/kg benzoic acid.Results： Relative to the control, benzoic acid supplementation increased the average daily feed intake（ADFI）, and average daily gain（ADG） in young pigs（P 〈 0.05）, improved the apparent total tract digestibility of dry matter（DM）,crude protein（CP）, ether extract（EE）, gross energy（GE） and crude ash（P 〈 0.05）, and enhanced the activities of trypsin,lipase and amylase in the jejunum（P 〈 0.05）. Similarly, relative to the control, supplementing benzoic acid in the diet resulted in a trend to reduce the p H values of the digesta（P = 0.06）, decreased crypt depth and increased the villus height to crypt depth ratio（P 〈 0.05） in the jejunum of pigs. Finally, benzoic acid supplementation increased the mR NA expression and concentration of glucagon-like peptide 2 and the activities of glutathione peroxidase and superoxide dismutase in the jejunal mucosa of young pigs（P 〈 0.05）.Conclusions： In conclusion, supplementation with 5000 mg/kg benzoic acid improved the performance of young pigs through promoting nutrient digestion, improving jejunal antioxidant capacity, and maintaining the jejunal morphology in young pigs.展开更多
Background Bariatric surgery offers successful resolution of type 2 diabetes mellitus （T2DM）. However, recurrence of T2DM has been observed in a number of patients with initial resolution after bariatric surgery. Th...Background Bariatric surgery offers successful resolution of type 2 diabetes mellitus （T2DM）. However, recurrence of T2DM has been observed in a number of patients with initial resolution after bariatric surgery. This study aimed to induce reversal of the improvement of diabetes in T2DM rats after duodenal-jejunal bypass （DJB）, and identify the effects of weight changes and gut hormones that might be involved.展开更多
Parkinson's disease(PD) is the second most common neurodegenerative disease and is typically associated with progressive motor and non-motor dysfunctions.Currently, dopamine replacement therapy is mainly used to r...Parkinson's disease(PD) is the second most common neurodegenerative disease and is typically associated with progressive motor and non-motor dysfunctions.Currently, dopamine replacement therapy is mainly used to relieve the motor symptoms, while its long-term application can lead to various complications and does not cure the disease. Numerous studies have demonstrated that many brain-gut peptides have neuroprotective effects in vivo and in vitro, and may be a promising treatment for PD. In recent years, some progress has been made in studies on the neuroprotective effects of some newly-discovered braingut peptides, such as glucagon-like peptide 1, pituitary adenylate cyclase activating polypeptide, nesfatin-1, and ghrelin. However, there is still no systematic review on the neuroprotective effects common to these peptides. Thus,here we review the neuroprotective effects and the associated mechanisms of these four peptides, as well as other brain-gut peptides related to PD, in the hope of providing new ideas for the treatment of PD and related clinical research.展开更多
Non-alcoholic fatty liver disease is considered a hepatic manifestation of metabolic syndrome(MS).The current treatment of non-alcoholic fatty liver disease(NAFLD)principally includes amelioration of MS components by ...Non-alcoholic fatty liver disease is considered a hepatic manifestation of metabolic syndrome(MS).The current treatment of non-alcoholic fatty liver disease(NAFLD)principally includes amelioration of MS components by lifestyle modifications but the lack of success in their implementation and sustainment arises the need for effective pharmacological agent in fatty liver treatment.Incretins are gut derived hormones secreted into the circulation in response to nutrient ingestion that enhances glucose-stimulated insulin secretion.Glucagon-like peptide-1(GLP-1)is the most important incretin.Its receptor agonist and inhibitors of dipeptidyl peptidase-4(DPP-4)are used in treatment of type2 diabetes mellitus.DPP-4 serum activity and hepatic expression are shown to be elevated in several hepatic diseases.There are several experimental and clinical trials exploring the efficacy of incretin based therapies in NAFLD treatment.They suggest that GLP-1 analogues might have beneficial effect on hepatic steatosis acting as insulin sensitizers and directly by stimulating GLP-1 receptors expressed on hepatocytes.The use of DPP-4 inhibitors also results in hepatic fat reduction but the mechanism of action remains unclear.There is growing evidence that incretin based therapies have beneficial effects on hepatocytes,however further study analysis are needed to assess the long term effect of incretin based therapies on NAFLD.展开更多
Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatme...Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatments may help treat Parkinson's disease.To further investigate the mechanisms of action of these two compounds,we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin.We found that both exendin-4 and linagliptin reversed motor dysfunction,glial activation,and dopaminergic neuronal death in this model.In addition,both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion.Moreover,in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain-and leucine-rich-repeat-and pyrin-domaincontaining 3/caspase-1/interleukin-1βpathway and subsequent pyroptosis by decreasing the production of reactive oxygen species.These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotidebinding oligomerization domain-and leucine-rich-repeat-and pyrin-domain-containing 3/caspase-1/interleukin-1βpathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Therefore,these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.展开更多
Long-acting glucagon-like peptide-1(GLP-1) analogues marketed for type 2 diabetes(T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain....Long-acting glucagon-like peptide-1(GLP-1) analogues marketed for type 2 diabetes(T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2 D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors(GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions(e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2 D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation(thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2 D, stroke and Alzheimer disease(AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biom展开更多
AIM:To evaluate the efficacy and safety of the addition of vildagliptin to low-dose metformin and compare it to an uptitration of metformin in type 2 diabetes mellitus(T2DM) patients who have inadequate control with m...AIM:To evaluate the efficacy and safety of the addition of vildagliptin to low-dose metformin and compare it to an uptitration of metformin in type 2 diabetes mellitus(T2DM) patients who have inadequate control with metformin monotherapy.METHODS:Eligible patients were randomized to receive vildagliptin 100 mg qd or metformin(500 mg qd for 2 wk and then 500 mg bid) added to open label me tformin 500 mg bid for the 24 wk.The primary endpoi nt was baseline to endpoint hemoglobin A1c(HbA1c) change.RESULTS:The adjusted mean change from baseline in HbA1c at the 24th wk was-0.51% in the vildagliptin/metformin group(mean baseline HbA1c:7.4%) and-0.37% in the metformin monothera py group(mean baseline HbA1c:7.3%).The mean diffe rence was-0.14% with 95% Confidence Interval(-0.24%,-0.05%).As non-inf e riority(margin of 0.4%) was achieved,a test for superiority was performed.This test showed statistically significant superiority of the combination over monotherapy group(P = 0.002).Gastrointestinal(GI) adverse events were signif icantly more frequent in the metformin group than the combin ation group(21.0% vs 15.4%,P = 0.032).CONCLUSION:In patients with T2DM inadequately controlled with metformin up to 1000 mg daily,the addition of vildagliptin 100 mg daily achieved larger HbA1c reduction with fewer GI events than with increa sing the metformin dose.展开更多
Objective To evaluate the effects of incretin-based therapies on body weight as the primary outcome,as well as on body mass index(BMI)and waist circumference(WC)as secondary outcomes.Methods Databases including Medlin...Objective To evaluate the effects of incretin-based therapies on body weight as the primary outcome,as well as on body mass index(BMI)and waist circumference(WC)as secondary outcomes.Methods Databases including Medline,Embase,the Cochrane Library,and clinicaltrials.gov(www.clinicaltrials.gov)were searched for randomized controlled trials(RCTs).Standard pairwise meta-analysis and network meta-analysis(NMA)were both carried out.The risk of bias(ROB)tool recommended by the Cochrane handbook was used to assess the quality of studies.Subgroup analysis,sensitivity analysis,meta-regression,and quality evaluation based on the Grading of Recommendations Assessment,Development,and Evaluation(GRADE)were also performed.Results A total of 292 trials were included in this study.Compared with placebo,dipeptidyl-peptidase IV inhibitors(DPP-4 Is)increased weight slightly by 0.31 kg[95%confidence interval(CI):0.05,0.58]and had negligible effects on BMI and WC.Compared with placebo,glucagon-like peptide-1 receptor agonists(GLP-1 RAs)lowered weight,BMI,and WC by-1.34 kg(95%CI:-1.60,-1.09),-1.10 kg/m2(95%CI:-1.42,-0.78),and-1.28 cm(95%CI:-1.69,-0.86),respectively.Conclusion GLP-1 RAs were more effective than DPP-4 Is in lowering the three indicators.Overall,the effects of GLP-1 RAs on weight,BMI,and WC were favorable.展开更多
Objective： To observe the clinical efficacy of electroacupuncture for functional dyspepsia（FD）, and explore the corresponding mechanism.Methods： Sixty-four FD patients were randomly divided into electroacupuncture...Objective： To observe the clinical efficacy of electroacupuncture for functional dyspepsia（FD）, and explore the corresponding mechanism.Methods： Sixty-four FD patients were randomly divided into electroacupuncture group and western medicine group, with 32 cases in each group. In electroacupuncture group, electroacupuncture at Zusanli（足三里ST 36）,Sanyinjiao（三阴交SP 6）,Gongsun（公孙SP 4） and Neiguan（内关PC 6） was performed for once a day, and the needles were retained for 30 min. In western medicine group, oral administration of mosapride citrate dispersible tablets in a dosage of 5 mg/time was carried out for 3 times a day. Treatment was conducted for 30 consecutive days in both groups. The scores of Leeds dyspepsia questionnaire（LDQ） and functional digestive disorder quality of life（FDDQL） of patients in both groups were recorded before and after treatment. Serum Ghrelin, CGRP and GLP-1 levels of patients were tested before and after treatment respectively, and the clinical efficacy of patients in both groups was evaluated after treatment.Results： In western medicine group, LDQ score after treatment was lower than that before treatment（P 0.05）, FDDQL score after treatment was higher than that before treatment, while the differences were not statistically significant（P0.05）. LDQ score in electroacupuncture group after treatment was lower than that before treatment（P0.05）, and also lower than that in western medicine group at the same time point（P 0.05）. FDDQL score in electroacupuncture group after treatment was higher than that before treatment（P0.05）, and also higher than that in western medicine group at the same time point（P0.05）. In western medicine group, Ghrelin level after treatment was higher than that before treatment（P 0.05）, CGRP level reduced, and the differences were not statistically significant（P 0.05）. GLP-1 level after treatment was also higher than that before treatment（P0.05）. In electroacupuncture group,Ghrelin le展开更多
Objective:To observe the effects of acupoint thread-embedding therapy on serum apelin and glucagon-like peptide-1(GLP-1)in type 2 diabetes mellitus patients with obesity due to dampness-heat encumbering spleen.Methods...Objective:To observe the effects of acupoint thread-embedding therapy on serum apelin and glucagon-like peptide-1(GLP-1)in type 2 diabetes mellitus patients with obesity due to dampness-heat encumbering spleen.Methods:Sixty-six patients were randomly divided into a control group and an observation group according to the random number table method,with 33 cases in each group.Patients in the control group were treated with exenatide and metformin,while patients in the observation group were treated with additional acupoint thread-embedding.After 12-week treatment,the obesity-related indicators,including body mass index(BMI),waist circumference and body fat rate,the glycometabolism indicators,including fasting blood glucose,2 h postprandial blood glucose and glycosylated hemoglobin,and the lipid metabolism indicators,including total cholesterol(TC),triglyceride(TG)and low-density lipoprotein cholesterol(LDL-C),as well as serum apelin and GLP-1 levels were observed in patients of the two groups.Results:After treatment,the BMI,waist circumference and body fat rate of patients in the two groups were all reduced(all P<0.05),and were lower in the observation group than in the control group(all P<0.05);the fasting blood glucose,2 h postprandial blood glucose and glycosylated hemoglobin levels of patients in both groups were all decreased(all P<0.05),and were significantly lower in the observation group than in the control group(all P<0.05);the TC level was decreased(P<0.05),while the TG and LDL-C levels did not change significantly in the control group(both P>0.05);the TC,TG and LDL-C levels were all significantly reduced in the observation group(all P<0.05),lower than those in the control group(all P<0.05);the serum apelin level was decreased(P<0.05)and the serum GLP-1 level was increased(P<0.05)in the observation group,statistically different from those in the control group(both P<0.05).Conclusion:Combined with the conventional medication,acupoint thread-embedding therapy can significantly improve the obesity-related in展开更多
AIM To investigate the role of glucagon-like peptide-1(GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS Chronic high-fat diet fed C57 BL/6 J mice, streptozotocintr...AIM To investigate the role of glucagon-like peptide-1(GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS Chronic high-fat diet fed C57 BL/6 J mice, streptozotocintreated high-fat diet fed C57 BL/6 J mice and diabeticC57 BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocintreated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment. RESULTS Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes(SREBP-1 C, FAS, and SCD-1) was decreased, and expression of genes involved in β-oxidation(CPT-1 and PPAR-α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-?. Coagonist treatment reduced expression of inflammatory(TNF-α, MCP-1, and MMP-9) and pro-fibrotic(TGF-β, COL1 A1, and α-SMA) genes and also improved histological derangement in renal tissue.CONCLUSION Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.展开更多
文摘Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon- like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They function to stimulate insulin secretion while suppressing glucagon secretion. GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus (T2DM), and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases. As we know, along with change in lifestyles, the prevalence of non-alcoholic fatty liver disease (NAFLD) in China is rising more than that of viral hepatitis and alcoholic fatty liver disease, and NAFLD has become the most common chronic liver disease in recent years. Recent studies further suggest that GLP-1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels, cutting down the fat content to promote fat redistribution, directly decreasing fatty degeneration of the liver, reducing the degree of liver fibrosis and improving inflammation. This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.
文摘Background Although the insulinotropic role of glucagon-like peptide-1 （GLP-1） in type 2 diabetes mellitus has been substantiated, its role in cardioprotection remains largely unknown. This study aimed to determine the effects of GLP-1 on injury of rats cardiac myocytes induced by hypoxia-reoxygenation （H/R） and the possible mechanisms. Methods The cultured neonatal rats cardiac myocytes were randomly divided into seven groups： the normal control group, the H/R group, the GLP-1＋H/R group, the GLP-1＋H/R＋UO126 （the p42/44 mitogen-activated protein kinase （MAPK） inhibitor） group, the GLP-1＋H/R＋LY294002 （phosphatidylinositol 3-kinase （PI3K） inhibitor） group, the H/R＋UO126 group, and the H/R＋LY294002 group. The lactate dehydrogenase （LDH） activity, apoptosis rate of cardiac myocytes, and caspase-3 activity were detected after the injury of H/R. Results Compared with the normal control group, the activity of LDH, cardiac myocyte apoptosis rate, and caspase-3 activity all increased significantly in the H/R group （P 〈0.01）. Compared with the H/R group, these three indices all decreased in the H/R＋GLP-1 group （P 〈0.01）. However, the changes of LDH activity, apoptosis rate, and caspase-3 activity were inhibited by LY294002 and UO126 respectively. Conclusions GLP-1 can directly act on cardiac myocytes and protect them from H/R injury mainly by inhibiting their apoptosis. Its mechanism may be through the PI3K-Akt pathway and the MAPK signaling pathway.
基金Supported by Grant from National Research Program from National Science Council (NMRP870071)
文摘AIM:To evaluate the effects of ginger on gastric motility and emptying,abdominal symptoms,and hormones that influence motility in dyspepsia.METHODS:Eleven patients with functional dyspepsia were studied twice in a randomized double-blind manner.After an 8-h fast,the patients ingested three capsules that contained ginger(total 1.2 g) or placebo,followed after 1 h by 500 mL low-nutrient soup.Antral area,fundus area and diameter,and the frequency of antral contractions were measured using ultrasound at frequent intervals,and the gastric half-emptying time was calculated from the change in antral area.Gastrointestinal sensations and appetite were scored using visual analog questionnaires,and blood was taken for measurement of plasma glucagon-like peptide-1(GLP-1),motilin and ghrelin concentrations,at intervals throughout the study.RESULTS:Gastric emptying was more rapid after ginger than placebo [median(range) half-emptying time 12.3(8.5-17.0) min after ginger,16.1(8.3-22.6) min after placebo,P ≤ 0.05].There was a trend for more antral contractions(P = 0.06),but fundus dimensions and gastrointestinal symptoms did not differ,nor did serum concentrations of GLP-1,motilin and ghrelin.CONCLUSION:Ginger stimulated gastric emptying and antral contractions in patients with functional dyspepsia,but had no impact on gastrointestinal symptoms or gut peptides.
文摘Type 2 diabetes (T2D) is a disorder characterized by chronic inflated blood glucose levels (hyperglycemia), at first due to insulin resistance and unregulated insulin secretion but with tendency towards global spreading. The gut microbiota is recognized to have an influence on T2D, although surveys have not formed a clear overview to date. Because of the interactions between gut microbiota and host homeostasis, intestinal bacteria are believed to play a large role in various diseases, including metabolic syndrome, obesity and associated disease. In this review, we highlight the animal and human studies which have elucidated the roles of metformin,α-glucosidase inhibitors, glucagon-like peptide-1 agonists, peroxisome proliferator-activated receptors γ agonists, inhibitors of dipeptidyl peptidase-4, sodium/glucose cotransporter inhibitors, and other less studied medications on gut microbiota. This review is dedicated to one of the most widespread diseases, T2D, and the currently used antidiabetic drugs and most promising new findings. In general, the gut microbiota has been shown to have an influence on host metabolism, food consumption, satiety, glucose homoeostasis, and weight gain. Altered intestinal microbiota composition has been noticed in cardiovascular diseases, colon cancer, rheumatoid arthritis, T2D, and obesity. Therefore, the main effect of antidiabetic drugs is on the microbiome composition, basically increasing the short-chain fatty acids-producing bacteria, responsible for losing weight and suppressing inflammation.
文摘Glucagon-like peptide-1(GLP-1)receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus.A number of case reports show an association of GLP-1receptor agonists,mainly exenatide,with the development of acute kidney injury.The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function,their use in subjects with chronic renal failure and their possible association with acute kidney injury.Based on the current evidence,exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease.Liraglutide is not eliminated by renal or hepatic mechanisms,but it should be used with caution since there are only limited data in patients with renal or hepatic impairment.There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering effect.Additionally,there is evidence that GLP-1 receptor agonists influence water and electrolyte balance.These effects may represent new ways to improve or even prevent diabetic nephropathy.
基金Supported by Chinese National 973 Program No.2012CB517502the Research Fund for the Doctoral Program of Higher Education of China No.20120001120069
文摘Glucagon-like peptide-1(GLP-1)-based therapies have demonstrated efficacy and safety in treating type 2 diabetes, which shares a similar pathophysiological mechanism with non-alcoholic fatty liver disease(NAFLD). Recent studies showed that glucose-induced GLP-1 secretion was decreased in patients with NAFLD and that the level of dipeptidyl peptidase-4, which inactivates intact GLP-1, was upregulated. Moreover, the expression of the GLP-1 receptor was downregulated in livers from patients with NAFLD, indicating an association of defective GLP-1 signalling with NAFLD. Notably, GLP-1-based therapies are reported to be effective in improving hepatic endpoints in patients with NAFLD, such as reducing hepatic fat content, hepatic steatosis and plasma transaminase levels, and preventing fibrosis. GLP-1-based therapies are beneficial for body weight control and glycaemic normalisation, which are important for the management of NAFLD. Moreover, clinical and preclinical studies showed that GLP-1-based agents might directly exert their actions on the liver through activation of functional GLP-1 receptors in hepatocytes.The possible mechanisms involve regulating gene expression that is associated with insulin resistance and lipid metabolism, and suppressing oxidative stress in the liver cells, thus preventing the development and progression of NAFLD. Based on these promising data, large-scale randomised controlled trials are warranted to assess the efficacy and safety of GLP-1-based therapies in treating NAFLD.
文摘Liver cirrhosis and diabetes mellitus(DM)are both common conditions with significant socioeconomic burden and impact on morbidity and mortality.A bidirectional relationship exists between DM and liver cirrhosis regarding both etiology and disease-related complications.Type 2 DM(T2DM)is a wellrecognized risk factor for chronic liver disease and vice-versa,DM may develop as a complication of cirrhosis,irrespective of its etiology.Liver transplantation(LT)represents an important treatment option for patients with end-stage liver disease due to non-alcoholic fatty liver disease(NAFLD),which represents a hepatic manifestation of metabolic syndrome and a common complication of T2DM.The metabolic risk factors including immunosuppressive drugs,can contribute to persistent or de novo development of DM and NAFLD after LT.T2DM,obesity,cardiovascular morbidities and renal impairment,frequently associated with metabolic syndrome and NAFLD,may have negative impact on short and long-term outcomes following LT.The treatment of DM in the context of chronic liver disease and post-transplant is challenging,but new emerging therapies such as glucagon-like peptide-1 receptor agonists(GLP-1RAs)and sodium–glucose cotransporter 2 inhibitors(SGLT2i)targeting multiple mechanisms in the shared pathophysiology of disorders such as oxidative stress and chronic inflammation are a promising tool in future patient management.
基金supported by Shanghai Municipal Health Bureau Youth Subject(NO.20134y116)
文摘Objective:To investigate the protective effect of glucagon-like peptid-1(GLP-l) against cardiac microvascular endothelial cell(GTFCs) injured by high glucose.Methods:CMECs were isolated and cultured.Superoxide assay kit and dihydroethidine(DHE) staining were used to assess oxidative stress.TENEL staining and caspase 3 expression were used to assess the apoptosis of CMECs.H89 was used to inhibit eAMP/PKA pathway:fasudil was used to inhibit Rho/ROCK pathway.The protein expressions of Rho.ROCK uere examined by Western blol analysis.lesults:High glucose increased the production of ROS.the activity of NADPH.the apoptosis rate and the expression level of Rho/ROCK in CMECs.while GLP- 1 decreased high glucose-induced ROS production.the NADPH activity and the apoptosis rate and the expression level of Rho/ROCK in CMECs,the difference were statistically significant(P<0.05).Conclusions:GLP-1 could protect the cardiac microvessels against oxidative stress and apoptosis.The protective effects of GLP-1 are dependent on downstream inhibition of Rho through a cAMP/PKA-dependent manner,resulting in a subsequent decrease in the expression of NADPH oxidase.
文摘Non-alcoholic fatty liver disease(NAFLD) is increasingly recognized as a significant liver disease,and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis(NASH) to fibrosis,subsequent cirrhosis,end-stage liver failure,and liver cancer with a potential need for liver transplantation.NAFLD and NASH are closely related to obesity,metabolic syndrome,and type 2 diabetes(T2 D).The role of gut hormones,especially glucagon-like peptide 1(GLP-1),is important in NAFLD.Bariatric surgery has the potential for inducing great weight loss and may improve the symptoms of metabolic syndrome and T2 D.Recent data demonstrated significant effects of bariatric surgery on GLP-1 and other gut hormones and important lipid metabolic and inflammatory abnormalities in the pathophysiology of NAFLD.Therefore,bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients.In the present review,we describe NAFLD and NASH pathophysiology and the primary effects of bariatric surgery on metabolic pathways.We performed a systematic review of the beneficial and harmful effects and focused on changes in liver disease severity in NAFLD and NASH patients.The specific focus was liver histopathology as assessed by the invasive liver biopsy.Additionally,we reviewed several non-invasive methods used for the assessment of liver disease severity following bariatric surgery.
基金financially supported by a China Pig Modern Industrial Technology System Grant (CARS-36)
文摘Background： As a organic acid, benzoic acid has become one of the most important alternatives for antibiotics,and its beneficial effect on performance in animals has been proven for a decade. However, knowledge of the effects of benzoic acid on jejunal digestive physiology, especially the antioxidant capacity and mucosal glucagon-like peptide2（GLP-2） concentrations is lacking.Methods： A total of 20 barrows [Duroc ×（Yorkshire × Landrace）] with an average body weight（BW） of 18.75 ± 0.2 kg were used in a 14-d trial to determine the potential mechanisms of benzoic acid supplementation on the performance,nutrient digestibility and jejunal digestive physiology in young pigs. All pigs were randomly allotted to 1 of 2 diets supplemented with 0 or 5000 mg/kg benzoic acid.Results： Relative to the control, benzoic acid supplementation increased the average daily feed intake（ADFI）, and average daily gain（ADG） in young pigs（P 〈 0.05）, improved the apparent total tract digestibility of dry matter（DM）,crude protein（CP）, ether extract（EE）, gross energy（GE） and crude ash（P 〈 0.05）, and enhanced the activities of trypsin,lipase and amylase in the jejunum（P 〈 0.05）. Similarly, relative to the control, supplementing benzoic acid in the diet resulted in a trend to reduce the p H values of the digesta（P = 0.06）, decreased crypt depth and increased the villus height to crypt depth ratio（P 〈 0.05） in the jejunum of pigs. Finally, benzoic acid supplementation increased the mR NA expression and concentration of glucagon-like peptide 2 and the activities of glutathione peroxidase and superoxide dismutase in the jejunal mucosa of young pigs（P 〈 0.05）.Conclusions： In conclusion, supplementation with 5000 mg/kg benzoic acid improved the performance of young pigs through promoting nutrient digestion, improving jejunal antioxidant capacity, and maintaining the jejunal morphology in young pigs.
基金This work was supported by grants from the National Natural Science Foundation of China （No. 81070642/H0713）, the Specialized Research Fund for the Doctoral Program of Higher Education （No. 20100131110049） and the Graduate Independent Innovation Foundation of Shandong University （No. yzc09094, No. yzcl1068）.
文摘Background Bariatric surgery offers successful resolution of type 2 diabetes mellitus （T2DM）. However, recurrence of T2DM has been observed in a number of patients with initial resolution after bariatric surgery. This study aimed to induce reversal of the improvement of diabetes in T2DM rats after duodenal-jejunal bypass （DJB）, and identify the effects of weight changes and gut hormones that might be involved.
基金supported by grants from the National Natural Science Foundation of China (31571054 and 81430024)the Excellent Innovative Team of Shandong Province and Taishan Scholars Construction Project, China
文摘Parkinson's disease(PD) is the second most common neurodegenerative disease and is typically associated with progressive motor and non-motor dysfunctions.Currently, dopamine replacement therapy is mainly used to relieve the motor symptoms, while its long-term application can lead to various complications and does not cure the disease. Numerous studies have demonstrated that many brain-gut peptides have neuroprotective effects in vivo and in vitro, and may be a promising treatment for PD. In recent years, some progress has been made in studies on the neuroprotective effects of some newly-discovered braingut peptides, such as glucagon-like peptide 1, pituitary adenylate cyclase activating polypeptide, nesfatin-1, and ghrelin. However, there is still no systematic review on the neuroprotective effects common to these peptides. Thus,here we review the neuroprotective effects and the associated mechanisms of these four peptides, as well as other brain-gut peptides related to PD, in the hope of providing new ideas for the treatment of PD and related clinical research.
文摘Non-alcoholic fatty liver disease is considered a hepatic manifestation of metabolic syndrome(MS).The current treatment of non-alcoholic fatty liver disease(NAFLD)principally includes amelioration of MS components by lifestyle modifications but the lack of success in their implementation and sustainment arises the need for effective pharmacological agent in fatty liver treatment.Incretins are gut derived hormones secreted into the circulation in response to nutrient ingestion that enhances glucose-stimulated insulin secretion.Glucagon-like peptide-1(GLP-1)is the most important incretin.Its receptor agonist and inhibitors of dipeptidyl peptidase-4(DPP-4)are used in treatment of type2 diabetes mellitus.DPP-4 serum activity and hepatic expression are shown to be elevated in several hepatic diseases.There are several experimental and clinical trials exploring the efficacy of incretin based therapies in NAFLD treatment.They suggest that GLP-1 analogues might have beneficial effect on hepatic steatosis acting as insulin sensitizers and directly by stimulating GLP-1 receptors expressed on hepatocytes.The use of DPP-4 inhibitors also results in hepatic fat reduction but the mechanism of action remains unclear.There is growing evidence that incretin based therapies have beneficial effects on hepatocytes,however further study analysis are needed to assess the long term effect of incretin based therapies on NAFLD.
基金supported by the National Natural Science Foundation of China,Nos.81771271(to JF),31800898(to WL),81430025(to JYL),and U1801681(to JYL)Key Research and Development Program of Liaoning Province,No.2020JH2/10300047(to JF)+1 种基金the Key Field Research Development Program of Guangdong Province,No.2018B030337001(to JYL)the Outstanding Scientific Fund of Shengjing Hospital,No.M0475(to JF)。
文摘Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatments may help treat Parkinson's disease.To further investigate the mechanisms of action of these two compounds,we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin.We found that both exendin-4 and linagliptin reversed motor dysfunction,glial activation,and dopaminergic neuronal death in this model.In addition,both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion.Moreover,in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain-and leucine-rich-repeat-and pyrin-domaincontaining 3/caspase-1/interleukin-1βpathway and subsequent pyroptosis by decreasing the production of reactive oxygen species.These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotidebinding oligomerization domain-and leucine-rich-repeat-and pyrin-domain-containing 3/caspase-1/interleukin-1βpathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Therefore,these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.
基金Supported by FEDER(Programa Operacional Factores de Competitividade-COMPETE)Portuguese funds via Portuguese Science Foundation(FCT)(Projects:PTDC/SAUNMC/110990/2009,PTDC/SAU-TOX/117481/2010 and Pest/SAU/LA0001/2011fellowships:SFRH/BD/90036/2012,PTDC/SAU-TOX/117481/2010,SFRH/BPD/95770/2013,SFRH/BPD/84163/2012,QREN Do IT,"DIAMARKER PROJECT",n.o 13853,SFRH/BD/73388/2010,SFRH/BPD/84473/2012)
文摘Long-acting glucagon-like peptide-1(GLP-1) analogues marketed for type 2 diabetes(T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2 D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors(GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions(e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2 D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation(thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2 D, stroke and Alzheimer disease(AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biom
基金Supported by Novartis Pharmaceuticals Corporation, NC-T00396357
文摘AIM:To evaluate the efficacy and safety of the addition of vildagliptin to low-dose metformin and compare it to an uptitration of metformin in type 2 diabetes mellitus(T2DM) patients who have inadequate control with metformin monotherapy.METHODS:Eligible patients were randomized to receive vildagliptin 100 mg qd or metformin(500 mg qd for 2 wk and then 500 mg bid) added to open label me tformin 500 mg bid for the 24 wk.The primary endpoi nt was baseline to endpoint hemoglobin A1c(HbA1c) change.RESULTS:The adjusted mean change from baseline in HbA1c at the 24th wk was-0.51% in the vildagliptin/metformin group(mean baseline HbA1c:7.4%) and-0.37% in the metformin monothera py group(mean baseline HbA1c:7.3%).The mean diffe rence was-0.14% with 95% Confidence Interval(-0.24%,-0.05%).As non-inf e riority(margin of 0.4%) was achieved,a test for superiority was performed.This test showed statistically significant superiority of the combination over monotherapy group(P = 0.002).Gastrointestinal(GI) adverse events were signif icantly more frequent in the metformin group than the combin ation group(21.0% vs 15.4%,P = 0.032).CONCLUSION:In patients with T2DM inadequately controlled with metformin up to 1000 mg daily,the addition of vildagliptin 100 mg daily achieved larger HbA1c reduction with fewer GI events than with increa sing the metformin dose.
基金supported by the National Natural Science Foundation of China[No.81302508,71673003,81473067,and 91646107].
文摘Objective To evaluate the effects of incretin-based therapies on body weight as the primary outcome,as well as on body mass index(BMI)and waist circumference(WC)as secondary outcomes.Methods Databases including Medline,Embase,the Cochrane Library,and clinicaltrials.gov(www.clinicaltrials.gov)were searched for randomized controlled trials(RCTs).Standard pairwise meta-analysis and network meta-analysis(NMA)were both carried out.The risk of bias(ROB)tool recommended by the Cochrane handbook was used to assess the quality of studies.Subgroup analysis,sensitivity analysis,meta-regression,and quality evaluation based on the Grading of Recommendations Assessment,Development,and Evaluation(GRADE)were also performed.Results A total of 292 trials were included in this study.Compared with placebo,dipeptidyl-peptidase IV inhibitors(DPP-4 Is)increased weight slightly by 0.31 kg[95%confidence interval(CI):0.05,0.58]and had negligible effects on BMI and WC.Compared with placebo,glucagon-like peptide-1 receptor agonists(GLP-1 RAs)lowered weight,BMI,and WC by-1.34 kg(95%CI:-1.60,-1.09),-1.10 kg/m2(95%CI:-1.42,-0.78),and-1.28 cm(95%CI:-1.69,-0.86),respectively.Conclusion GLP-1 RAs were more effective than DPP-4 Is in lowering the three indicators.Overall,the effects of GLP-1 RAs on weight,BMI,and WC were favorable.
文摘Objective： To observe the clinical efficacy of electroacupuncture for functional dyspepsia（FD）, and explore the corresponding mechanism.Methods： Sixty-four FD patients were randomly divided into electroacupuncture group and western medicine group, with 32 cases in each group. In electroacupuncture group, electroacupuncture at Zusanli（足三里ST 36）,Sanyinjiao（三阴交SP 6）,Gongsun（公孙SP 4） and Neiguan（内关PC 6） was performed for once a day, and the needles were retained for 30 min. In western medicine group, oral administration of mosapride citrate dispersible tablets in a dosage of 5 mg/time was carried out for 3 times a day. Treatment was conducted for 30 consecutive days in both groups. The scores of Leeds dyspepsia questionnaire（LDQ） and functional digestive disorder quality of life（FDDQL） of patients in both groups were recorded before and after treatment. Serum Ghrelin, CGRP and GLP-1 levels of patients were tested before and after treatment respectively, and the clinical efficacy of patients in both groups was evaluated after treatment.Results： In western medicine group, LDQ score after treatment was lower than that before treatment（P 0.05）, FDDQL score after treatment was higher than that before treatment, while the differences were not statistically significant（P0.05）. LDQ score in electroacupuncture group after treatment was lower than that before treatment（P0.05）, and also lower than that in western medicine group at the same time point（P 0.05）. FDDQL score in electroacupuncture group after treatment was higher than that before treatment（P0.05）, and also higher than that in western medicine group at the same time point（P0.05）. In western medicine group, Ghrelin level after treatment was higher than that before treatment（P 0.05）, CGRP level reduced, and the differences were not statistically significant（P 0.05）. GLP-1 level after treatment was also higher than that before treatment（P0.05）. In electroacupuncture group,Ghrelin le
文摘Objective:To observe the effects of acupoint thread-embedding therapy on serum apelin and glucagon-like peptide-1(GLP-1)in type 2 diabetes mellitus patients with obesity due to dampness-heat encumbering spleen.Methods:Sixty-six patients were randomly divided into a control group and an observation group according to the random number table method,with 33 cases in each group.Patients in the control group were treated with exenatide and metformin,while patients in the observation group were treated with additional acupoint thread-embedding.After 12-week treatment,the obesity-related indicators,including body mass index(BMI),waist circumference and body fat rate,the glycometabolism indicators,including fasting blood glucose,2 h postprandial blood glucose and glycosylated hemoglobin,and the lipid metabolism indicators,including total cholesterol(TC),triglyceride(TG)and low-density lipoprotein cholesterol(LDL-C),as well as serum apelin and GLP-1 levels were observed in patients of the two groups.Results:After treatment,the BMI,waist circumference and body fat rate of patients in the two groups were all reduced(all P<0.05),and were lower in the observation group than in the control group(all P<0.05);the fasting blood glucose,2 h postprandial blood glucose and glycosylated hemoglobin levels of patients in both groups were all decreased(all P<0.05),and were significantly lower in the observation group than in the control group(all P<0.05);the TC level was decreased(P<0.05),while the TG and LDL-C levels did not change significantly in the control group(both P>0.05);the TC,TG and LDL-C levels were all significantly reduced in the observation group(all P<0.05),lower than those in the control group(all P<0.05);the serum apelin level was decreased(P<0.05)and the serum GLP-1 level was increased(P<0.05)in the observation group,statistically different from those in the control group(both P<0.05).Conclusion:Combined with the conventional medication,acupoint thread-embedding therapy can significantly improve the obesity-related in
文摘AIM To investigate the role of glucagon-like peptide-1(GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS Chronic high-fat diet fed C57 BL/6 J mice, streptozotocintreated high-fat diet fed C57 BL/6 J mice and diabeticC57 BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocintreated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment. RESULTS Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes(SREBP-1 C, FAS, and SCD-1) was decreased, and expression of genes involved in β-oxidation(CPT-1 and PPAR-α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-?. Coagonist treatment reduced expression of inflammatory(TNF-α, MCP-1, and MMP-9) and pro-fibrotic(TGF-β, COL1 A1, and α-SMA) genes and also improved histological derangement in renal tissue.CONCLUSION Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.
