ABSTRACT
Objective To investigate the effect of glucagon-like peptide 1(GLP-1)receptor agonists exendin-4 on the secretion of cyclophilin A(CyPA)to inhibit atherosclerosis(AS)and vascular calcification in mice role of the process.Methods Twenty ApoE-/-mice were randomly divided into model group and exendin-4 group,10 mice in each group,and were fed with high-fat diet to establish AS model,another 10 wild-type C57BL/6J mice were taken as the control group,and the exendin-4 group was intraperitoneally injected with the GLP-1R agonist exendin-4,1/d,for 8 weeks.After 8 weeks,the ELISA method was used to determine the level of triglyceride(TG),total cholesterol(TC),high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C)and CyPA,serum calcium level was detected by methylthymol blue colorimetric method,oil red O staining to detect the development of atherosclerotic plaques in the aorta,HE staining was used to observe the pathological changes of the aorta,Von Kossa staining was used to observe the calcium deposition in the aorta,immunohistochemical staining,Real-time PCR and Western blotting were used to detect the expression levels of aortic RUNX2 and bone morphogenetic protein 2(BMP-2),immunofluorescent staining was used to detect the positive expression of CyPA in aortic tissue.Results Compared with the control group,the serum levels of TG,TC,LDL-C,Ca and CyPA in the model group increased(P<0.05),the atherosclerotic plaque areas of the aorta increased(P<0.05),the aortic wall was thickened significantly and a large number of inflammatory cells were infiltrated,a large amount of calcium deposits were deposited in the aortic parietal membrane,the positive expression area ratio of RUNX2 and BMP-2,the relative mRNA expression of RUNX2 and BMP-2,the relative protein expression of RUNX2 and BMP-2 in aortic tissue all increased(P<0.05),and the red fluorescence of CyPA expression in aortic tissue was enhanced significantly.Compared with the model group,the serum levels of TG,TC,LDL-C,Ca and CyPA in the exendin-4 group decreased(P<0.05),the atherosclerotic plaque areas of the aorta decreased(P<0.05),the thickening of the aortic wall and the infiltration of inflammatory cells were alleviated significantly,the calcium deposition in the aortic wall was reduced,the positive expression area ratio of RUNX2 and BMP-2,the relative mRNA expression of RUNX2 and BMP-2,the relative protein expression of RUNX2 and BMP-2 in aortic tissue all decreased(P<0.05),and at the same time,the red fluorescence of CyPA expression in aortic tissue was weakened significantly.Conclusion GLP-1 receptor agonists exendin-4 can inhibit atherosclerosis and vascular calcification in mice,and the mechanism may be related to the reduction of CyPA secretion.
ABSTRACT
BACKGROUND:In the process of exploring the mechanism of Alzheimer's disease,the important role of bioinformatics for common target screening has been revealed,enabling the use of its screening results as a basis for exploring the therapeutic effects of drugs on the disease. OBJECTIVE:To predict the targets of liraglutide,a glucagon-like peptide-1 receptor agonist,in the treatment of Alzheimer's disease by bioinformatics and molecular biology. METHODS:DisGeNET database and SEA database were used to obtain the common genes of Alzheimer's disease and liraglutide.GO/KEGG enrichment analysis of common targets was conducted using DAVID online database.Protein-protein interaction networks were constructed using STRING database.The optimal dosage of liraglutide was determined using cell counting kit-8 assay.Expression of key proteins was analyzed using immunofluorescence and immunoblotting techniques.The mouse hippocampal neuron HT22 cell line was used for ex vivo experiments,and the cells were randomly divided into three groups:HT22 group,HT22+Aβ group,and HT22+Aβ+Lir group.No special treatment was done in the HT22 group,while Aβ1-42 was used to intervene in the HT22 cell line for 24 hours to construct an Aβ injury cell model in the HT22+Aβ group.In additional to modeling,liraglutide was added to the HT22+Aβ+Lir group for 12 hours. RESULTS AND CONCLUSION:A total of 3 333 genes associated with Alzheimer's disease were screened from DisGeNET database.Then 147 potential targets of liraglutide were obtained from SEA database.Finally,64 common targets of Alzheimer's disease and Liraglutide were determined using R packets.GO/KEGG analysis of common targets using DAVID online database suggested that common targets were mainly enriched in the following biological processes:neuroactive ligand-receptor interaction,renin-angiotensin system,bladder cancer,endopeptidase activity,peptide receptor activity,G protein-coupled peptide receptor activity,and transport vesicles.The obtained 64 common target proteins were imported into SRTING online database for protein-protein interaction network construction,and the top three genes,matrix metalloproteinases 2,9 and interleukin 1β,were obtained.The activity of cultured cells was detected by the cell counting kit-8 kit.Liraglutide at 100 nmol/L was the optimal concentration for antagonizing Aβ1-42.In the western blot and immunofluorescence assays,the expression of matrix metalloproteinases 2,9 and interleukin 1β was significantly increased in the HT22+Aβ group compared with the HT22 group(P＜0.05)but significantly decreased in the HT22+Aβ+Lir group compared with the HT22+Aβ group(P＜0.05).To conclude,the above bioinformatics data and secondary validation of differential genes in the GEO database suggest that both matrix metalloproteinases 2,9 and interleukin 1β could be potential targets of liraglutide in the treatment of Alzheimer's disease.
ABSTRACT
Diabetic retinopathy (DR) is one of the most frequent complications of diabetes (T2DM), which is the main eye disease causing blindness in adults in recent years. At present, glucagon-like peptide-1 receptor agonists (GLP-1RA) have become the main drugs used in the treatment of diabetes due to its superior hypoglycemic, lipid-lowering, hypertensive and cardiovascular effects. A large number of studies have shown that GLP-1RA drugs can protect retinal microvascular and optic nerves in the treatment of diabetes through various ways, but some studies have found that GLP-1RA drugs represented by semaglutide may lead to the progress of DR. Therefore, GLP-1RA should be used cautiously for patients who with severe non-proliferative DR or proliferative DR. Regardless of whether T2DM patients are complicated with DR, the fundus retinal condition should be monitored regularly after the use of GLP-1RA drugs, and timely countermeasures should be taken when DR occurs and develops. The benefits of GLP-1RA used by diabetes patients are obvious to all, and scientific and rational drug use can prevent the occurrence and progress of DR, which can better benefit DR Patients.
ABSTRACT
【Objective】 To investigate the association between genetic variations in the glucagon-like peptide-1 receptor (GLP-1R) gene and BP responses to sodium and potassium intake. 【Methods】 A total of 514 subjects from 124 families were recruited in Meixian County, Shaanxi Province, in 2004, resulting in the establishment of a "salt-sensitive hypertension study cohort" . The subjects followed a dietary regimen which involved a normal diet for 3 days, a low-salt diet for 7 days, a high-salt diet for 7 days, and a high-salt potassium-supplemented diet for 7 days. BP measurement was conducted at different intervention periods, and peripheral blood samples were collected. Additionally, eight single nucleotide polymorphisms (SNPs) of the GLP-1R gene were genotyped using the MassARRAY detection platform. 【Results】 The GLP-1R gene SNP rs9462472 exhibited a significant association with systolic BP, diastolic BP, and mean arterial pressure response to high-salt intervention. Similarly, SNP rs2268637 showed a significant association with systolic BP response to high-salt intervention. Furthermore, SNP rs2268637 was significantly associated with systolic BP and mean arterial pressure responses to high-salt plus potassium supplementation intervention. 【Conclusion】 Our findings indicate a significant association of genetic variations in the GLP-1R gene with BP responses to sodium and potassium intake. This suggests that the GLP-1R gene plays a role in the regulation of BP salt sensitivity and potassium sensitivity.
ABSTRACT
Glucagon-like peptide-1 receptor agonists （GLP-1RAs） have been widely used in diabetes and obese people in recent years， and they have also caused a series of adverse reactions， the most important of which is digestive system-related adverse reactions. The adverse reactions of the digestive system associated with GLP-1RAs involve the gastrointestinal， pancreatic， and biliary tracts； among them， nausea， vomiting， constipation， and diarrhea are the most common adverse reactions， which are the main reasons for drug withdrawal. The incidence of pancreatic and biliary system diseases is low， but there is no research evidence to exclude their association with GLP-1RAs. Tirzepatide appears on the market relatively late， and its safety still lacks sufficient real-world data. Medical staff should adopt active dietary guidance strategies for patients and strengthen medication education to help patients actively prevent and scientifically respond to adverse reactions in the digestive system.
ABSTRACT
Tirzepatide,a new glucagon-like peptide-1/glucose dependent insulin stimulating polypeptide(GLP-1/GIP)double receptor agonist,has been clinically shown to have a strong hypoglycemic effect and a very significant effect on reducing body mass.It can improve insulin sensitivity,and has superior cardiovascular protection and the effect of improving nonalcoholic fatty liver disease/nonalcoholic steatohepatitis(NAFLD/NASH),with few side effects and good compliance.As a dual gut hor-mone agonist,tirzepatide shows strong potential to improve metabolic levels.This article reviews the mechanism of action and clini-cal studies of the GLP-1/GIP dual receptor agonist tirzepatide.
ABSTRACT
Glucagon-like peptide 1 receptor agonists(GLP-1 RAs)can improve the adverse outcomes of diabetes mellitus.It can affect the occurrence and development of thyroid C cell tumors by stimulating the abnormal proliferation of thyroid C cells and release of calcitonin in rodents.This article reviews the research progress of GLP-1 RAs and thyroid tumors.
ABSTRACT
OBJECTIVE To assess the long-term cost-effectiveness of five glucagon-like peptide-1 receptor agonists （GLP- 1RAs） in the treatment of poorly controlled type 2 diabetes mellitus （T2DM） treated with metformin. METHODS Baseline data from patients in previously published meta-analysis and included randomized controlled trials （RCTs） were extracted to predict survival， long-term efficacy， and costs for each group using the United Kingdom prospective diabetes study outcome model 2.1. The cost-effectiveness of 5 GLP-1RAs （liraglutide， lixisenatide， exenatide， dulaglutide， and semaglutide） was analyzed by cost- utility analysis. Sensitivity analysis and scenario analysis were also performed to verify the uncertainty of basic analysis results. RESULTS A total of 21 RCTs with 6 796 patients were included. Survival analysis curves showed the superiority of semaglutide in reducing the risk of death from cardiovascular disease and dulaglutide in reducing the risk of all-cause mortality over other GLP- 1RAs. The cost-utility analysis showed that the five drugs were economically superior to inferior in the order of lixisenatide， semaglutide， exenatide， dulaglutide， and liraglutide； one-way and probabilistic sensitivity analyses indicated that the results were robust. The scenario analysis results indicated that the price of semaglutide should decrease by at least 54.64% to 369.21 yuan， which is cost-effectiveness compared to lixisenatide. CONCLUSIONS For T2DM patients in China with poor glycemic control after treatment with metformin， lixisenatide and semaglutide may be considered as the preferred regimen.
ABSTRACT
OBJECTIVE To assess the long-term cost-effectiveness of five glucagon-like peptide-1 receptor agonists （GLP- 1RAs） in the treatment of poorly controlled type 2 diabetes mellitus （T2DM） treated with metformin. METHODS Baseline data from patients in previously published meta-analysis and included randomized controlled trials （RCTs） were extracted to predict survival， long-term efficacy， and costs for each group using the United Kingdom prospective diabetes study outcome model 2.1. The cost-effectiveness of 5 GLP-1RAs （liraglutide， lixisenatide， exenatide， dulaglutide， and semaglutide） was analyzed by cost- utility analysis. Sensitivity analysis and scenario analysis were also performed to verify the uncertainty of basic analysis results. RESULTS A total of 21 RCTs with 6 796 patients were included. Survival analysis curves showed the superiority of semaglutide in reducing the risk of death from cardiovascular disease and dulaglutide in reducing the risk of all-cause mortality over other GLP- 1RAs. The cost-utility analysis showed that the five drugs were economically superior to inferior in the order of lixisenatide， semaglutide， exenatide， dulaglutide， and liraglutide； one-way and probabilistic sensitivity analyses indicated that the results were robust. The scenario analysis results indicated that the price of semaglutide should decrease by at least 54.64% to 369.21 yuan， which is cost-effectiveness compared to lixisenatide. CONCLUSIONS For T2DM patients in China with poor glycemic control after treatment with metformin， lixisenatide and semaglutide may be considered as the preferred regimen.
ABSTRACT
Glucagon-like peptide-1 ( GLP-1 ) is secreted by gut enteroendocrine cells. GLP-1 receptor agonists ( GLP-1 RAs) control glucose-related augmentation of insulin and suppress glu-cagon secretion. GLP-lRAs also inhibit gastric emptying, food intake and limit weight gain. In the past decade, significant progresses have been made in the investigation on the effects of GLP-1 RAs on cardiovascular system. The potential advantages of oral small-molecule GLP-1 RAs could improve the application of this class of drugs. This review highlights the multiple cardiovascular profiles of GLP-1 RAs in the treatment of cardiovascular diseases to provide new insights into cardiovascular benefits of GLP-1 RAs.
ABSTRACT
OBJECTIVE To comprehensively evaluate four weekly preparations of glucagon-like peptide-1 receptor agonist （GLP-1RA） marketed in China，and to provide evidence for hospitals to optimize drug catalogs and clinical rational drug use. METHODS Mini health technology assessment method was used to establish detailed evaluation rules according to A Quick Guideline for Drug Evaluation and Selection in Chinese Medical Institutions， and conduct comprehensive evaluation of four GLP- 1RA weekly preparations from aspects of pharmaceutical characteristics， effectiveness， safety， economy and other attributes. RESULTS Mini health technology assessment scores of the four GLP-1RA weekly preparations from high to low were dulaglutide 78.60 points， semaglutide 77.35 points，polyethylene glycol loxenatide 67.40 points， and exenatide microspheres 65.50 points， respectively. Dulaglutide had advantages in reducing blood sugar， arteriosclerotic cardiovascular disease， kidney benefits， and cost- effectiveness. Semaglutide had advantages in reducing blood sugar and weight loss， but its cost-effectiveness was lower than that of dulaglutide. Exenatide microspheres had advantages in the use of children， but its daily average treatment cost is the highest. Polyethylene glycol loxenatide needed further clinical evidence. CONCLUSIONS Four GLP-1RA weekly preparations all have high pharmaceutical comprehensive scores. Dulaglutide and semaglutide may have more comprehensive pharmaceutical value among them， while the use of exenatide microspheres for children is unique.
ABSTRACT
A new study in Cell from Ivan de Araujo and colleagues reported that intestinal GLP-1 acts on an inter-organ sympathetic neural circuit that induces appetite suppression. This study revealed that GLP-1， secreted by ileal L cells， sensing by intestinal myenteric layer intestinofugal neurons activated a sympatho-gastro-spinal-reticular-hypothalamic pathway involved in appetite suppression， linking stomach distention to craniofacial programs for food rejection. These molecularly indentified， delimited enteric circuits may be targeted to ameliorate the abdominal bloating and loss of appetite typical of gastric motility disorders.
ABSTRACT
ObjectiveTo discuss the effect of modified Gegen Qinliantang （MGQT） on blood glucose and lipids and Takeda G protein-coupled receptor 5 （TGR5）-related pathways in pancreatic tissue of obese type 2 diabetes mellitus （T2DM） mice. MethodA total of 10 male specific pathogen free （SPF） m/m mice （7 weeks old） and 50 male SPF （7 weeks old） were adaptively fed for one week in SPF laboratory. The m/m mice were included in the blank group. T2DM was induce d in the 50 db/db mice. The model mice were randomized into the model group， metformin group （0.2 g·kg-1）， high-dose， medium-dose， and low-dose （31.9， 19.1， 6.4 g·kg-1） MGQT groups， with 10 in each group， and the drug dose was10 mL·kg-1. The model group and the blank group received distilled water of the same volume. The administration lasted 12 weeks （once/day）. Fasting blood glucose （FBG） was detected regularly. After 12 weeks of administration， serum levels of glycated serum protein （GSP）， serum glucose （GLU）， total cholesterol （TC）， triglycerides （TG）， high-density lipoprotein cholesterol （HDL-C）， and low-density lipoprotein cholesterol （LDL-C） were detected. Pathological changes in the pancreatic tissue were based on hematoxylin-eosin （HE） staining. Western blot was used to determine the protein expression of TGR5， protein kinase A （PKA）， phosphorylated （p）-PKA， cyclic-AMP response element binding protein （CREB）， p-CREB， proprotein convertase 1/3 （PC1/3）， and glucagon-like peptide-1 （GLP-1） in pancreatic tissues. The level of cyclic adenosine monophosphate （cAMP） in pancreatic tissue was determined by enzyme-linked immunosorbent assay （ELISA）. ResultCompared with the blank group， the model group had pathological changes in pancreatic tissue， high levels of FBG， GSP， GLU， TC， TG， and LDL-C （P<0.01）， low level of HDL-C （P<0.05）， low protein expression of TGR5， p-PKA （Thr197）/PKA， p-CREB （Ser133）/CREB， PC1/3， and GLP-1 in pancreatic tissue （P<0.01）， and low content of cAMP in the pancreas （P<0.01）. Pancreatic tissue lesion in the treatment groups were milder than that in the model group. Both the high-dose MGQT and metformin can reduce the levels of FBG， GSP， GLU， TC， TG， and LDL-C in db/db mice （P<0.05， P<0.01） and increase the level of HDL-C （P<0.01）. Except the GLP-1 protein in the medium-dose MGQT group， the protein expression of TGR5， p-PKA （Thr197）/PKA， p-CREB （Ser133）/CREB， PC1/3， and GLP-1 in the high-dose and medium-dose MGQT groups and the metformin group increased compared with that in the model group （P<0.05， P<0.01）. The content of cAMP in the pancreatic tissue of the high-dose and medium-dose MGQT groups and the metformin group was raised compared with that in model group （P<0.05， P<0.01）. ConclusionMGQT can improve the glucose homeostasis in db/db mice with T2DM by regulating TGR5/cAMP/GLP-1 signaling pathway-related protein expression.
ABSTRACT
ObjectiveTo observe the pharmacodynamic effects of Cinnamomi Cortex on the incretin effect in the rat model of diabetes mellites （DM） induced by streptozotocin （STZ） and explore the underlying mechanism from glucagon-like peptide-1 （GLP-1） and dipeptidyl peptidase-4 （DPP-4）. MethodForty SD rats were randomly assigned into blank， model， sitagliptin （0.1 g·kg-1）， and low- and high-dose Cinnamomi Cortex （0.45 and 0.9 g·kg-1， respectively） groups. The DM rat model was established by a high-fat diet combined with intraperitoneal injection of 40 mg·kg-1 STZ in other groups except the blank group. The intervention lasted for 8 weeks. The status， body weight， water intake， food intake， and fasting blood glucose （FBG） of the rats were observed and determined. Hematoxylin-eosin staining was employed to reveal the pathological changes of the pancreas， and immunohistochemistry to detect the expression of glucagon in the pancreas. Biochemical assay was employed to measure the serum levels of lipid metabolism indexes such as total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein （LDL）， and high-density lipoprotein （HDL）. Enzyme-linked immunosorbent assay was employed to determine the levels of glycosylated hemoglobin， insulin， glucagon， GLP-1， and glucose-dependent insulinotropic polypeptide （GIP） in rat serum， and Western blot to determine the protein levels of GLP-1 and DPP-4 in the pancreas. ResultAfter 8 weeks of intervention， the model group showed higher body weight， FBG， TC， TG， LDL， glycosylated hemoglobin， glucagon， insulin， and insulin resistance index and lower HDL， GLP-1， and GIP than the blank group （P<0.05， P<0.01）. The Cinnamomi Cortex groups showed lower body weight， FBG， TC， TG， LDL， glycosylated hemoglobin， glucagon， insulin， and insulin resistance index and higher HDL， GLP-1， and GIP than the model group （P<0.05， P<0.01）. The Cinnamomi Cortex groups showed recovered morphology of islet cells and no nucleus aggregation. Compared with the model group， the Cinnamomi Cortex groups showed declined levels of glucagon in the center of islet cells. Compared with the blank group， the model group showed up-regulated protein level of DPP-4 and down-regulated protein level of GLP-1 （P<0.01）. Compared with the model group， the high-dose Cinnamomi Cortex groups showed down-regulated protein level of DPP-4 and up-regulated protein level of GLP-1 （P<0.05）. ConclusionCinnamomi Cortex may reduce blood glucose and improve incretin effect to lower the blood glucose level by regulating DPP-4 and GLP-1 in DM rats.
ABSTRACT
Inflammatory bowel disease(IBD)is a non-specific and easily recurrent chronic inflammatory disease of the intestine,mainly including ulcerative colitis(UC)and Crohn's disease(CD).Its etiology and pathogenesis have not been fully elucidated,but it is currently believed to be related to environmental,genetic,immune response abnormalities,and other factors.At present,IBD has become a disease of great concern worldwide.According to the epidemiological data and data of inflammatory bowel disease in China,the incidence rate of IBD is on the rise year by year in China,but so far,there has not been a drug that can completely cure the disease.Recently,glucagon-like peptide(GLP)and its degradation enzyme inhibitor dipeptidyl peptidase-4(DPP-4)inhibitors have attracted widespread research and attention in the treatment of IBD.This article reviewed the roles and mechanisms of GLP and DPP-4 inhibitors in the treatment of IBD diseases.
ABSTRACT
Objective:To observe the effects of glucagon-like peptide-1 receptor agonist(GLP-1RA) combined with metformin on glucolipid metabolism and reproductive function in overweight/obesity polycystic ovarian syndrome(PCOS) patients.Methods:Retrospectively analyzed changes in clinical parameters of body measurements, glucolipid metabolism, menstrual cycle, hormones, and polycystic ovary in 200 overweight/obese PCOS Patients who received 12 weeks of treatment(liraglutide+ metformin or exenatide+ metformin) in the Department of Endocrinology at the Second Affiliated Hospital of Army Medical University from July 2017 to July 2022.Results:In terms of metabolism improvement, body weight, body mass index, waist circumference, hip circumference, waist-hip ratio, glutamic-oxalacetic transaminase, γ-glutamyltransferase, glycosylated hemoglobin, fasting blood glucose, insulin(including fasting, 30, 60, 120, and 180 minutes), homeostasis model assessment for insulin resistance, area under curve-insulin, triglyceride, and total cholesterol were significantly decreased after treatment( P<0.05 or P<0.01 or P<0.001). In terms of reproductive function, testosterone, luteinizing hormone, follicle stimulating hormone/luteinizing hormone and free androgen index were decreased( P<0.001), while sex hormone-binding globulin was increased( P<0.01). There were no significant differences in progesterone, prolactin, follicle-stimulating hormone and dehydroepiandrosterone sulfate compared with before treatment( P>0.05). The proportion of subjects with regular menstrual cycle increased from 23.53% to 57.52%( P<0.05). The proportion of subjects with polycystic ovarian changes decreased from 65.30% to 50.32%, and the proportion with dominant follicles increased from zero to 18.30%( P<0.05 or P<0.01). Some patients(25.49%) experienced adverse reactions such as nausea, diarrhea, abdominal distension, and vomiting after medication. Conclusion:The combination of GLP-1RA and metformin effectively improves glucose lipid metabolism disorder and reproductive dysfunction in overweight/obese PCOS patients.
ABSTRACT
Diabetic retinopathy (DR) is one of the most serious complications of diabetes mellitus. Severe diabetic macular edema or proliferative retinopathy may lead to impaired vision or even blindness in diabetic patients. The glucagon-like peptide-1 receptor agonist (GLP-1RA) is now commonly used as novel glucose-lowering agents in the clinical management of type 2 diabetes, but the rapid glycaemic changes associated with the use of the GLP-1RA may aggravate the risk of an increase in the occurrence of short-term potential DR. Potential effects and mechanisms of DR include oxidative stress, vascular endothelial growth factor, inflammation, retinal neurodegeneration, and other cytokines.Whether GLP-1RA leads to the increased risk of DR remains controversial. More basic and clinical studies are needed with the aim of further clarifying the correlation between GLP-1RA and DR risk.
ABSTRACT
Glucagon-like peptide 1 (GLP-1) is a kind of incretin produced in the intestinal with multiple pharmacological effects, which can stimulate insulin secretion effectively. Various GLP-1 analogues have been widely used in the treatment of type 2 diabetes mellitus. Alzheimer's disease (AD) is closely related to type 2 diabetes mellitus, with some common pathological features, such as insulin resistance, and epidemiological studies also showed that patients with type 2 diabetes mellitus have an increased risk of developing AD. GLP-1 analogues have shown beneficial effects in both preclinical animal research and clinical trials of AD. Therefore, the authors summarized the main characteristics of GLP-1 and AD, and analyzed the mechanisms of GLP-1 in preclinical AD studies of animal models. GLP-1 readily crosses the blood-brain barrier and exerts its neuroprotective effects by binding to and activating the widely distributed GLP-1 receptors (GLP-1Rs) in the brain, affecting multiple physiological and pathological processes including glucose metabolism, neuroinflammation, mitochondrial function, and cell proliferation. Insulin resistance and inflammation are key common pathways in AD and type 2 diabetes. GLP-1 may exert its neuroprotective effects by improving mitochondrial function and glycolysis, reducing oxidative stress levels, exerting anti-inflammatory and anti-apoptotic effects, inducing neurogenesis, and inhibiting glial cell proliferation. This paper maybe provide the reference for further study of GLP-1 analogues in AD, hoping to open new therapy venues for AD patients.
ABSTRACT
Stroke is a prevalent acute cerebrovascular disease associated with significant morbidity and mortality,which highly demand effective prevention and treatment strategies.Glucagon-like peptide-1 receptor agonists(GLP-1RA)is a novel type of antidiabetic drug that exerts hypoglycemic and weight loss effects on GLP-1 receptors.Additionally,GLP-1RA possess the potential to reduce infarction size and promote nerve recovery by inhibiting inflammation,oxidative stress,apoptosis,and improving blood-brain barrier permeability and other pathologies.This paper provides a comprehensive summary of the role of GLP-1 in stroke occurrence while also explores the underlying mechanisms by which GLP-1RA influences stroke pathogenesis.Furthermore,it briefly reviews the therapeutic efficacy of GLP-RA in managing stroke.
ABSTRACT
ObjectiveTo explore the potential mechanism of Zuogui Jiangtang Tongmai prescription （ZJT） in the treatment of diabetes mellitus complicated with cerebral infarction （DM-CI） in rats based on the short-chain fatty acids （SCFAs）/G protein-coupled receptor 43 （GPR43）/glucagon-like peptide-1 （GLP-1）/GLP-1 receptor （GLP-1R） signaling pathway. MethodSixty SD rats were randomly divided into sham operation group， model group， low- and high-dose ZJT groups （12， 24 g·kg-1）， western medicine group （140 mg·kg-1 pioglitazone metformin tablets + 27 mg·kg-1 enteric-coated aspirin tablets）. Except for the sham operation group， all other groups were fed a high-sugar high-fat diet for 4 weeks and then subjected to intraperitoneal injection of 1% streptozotocin at 35 mg·kg-1 combined with middle cerebral artery occlusion （MCAO） to establish a DM-CI rat model. The corresponding interventions were performed with distilled water， low-dose ZJT， high-dose ZJT， pioglitazone metformin tablets， and enteric-coated aspirin tablets. After surgery， National Institutes of Health Stroke Scale （NIHSS） scoring and triphenyltetrazolium chloride （TTC） staining to measure the rat's cerebral infarct volume were carried out. Random blood glucose levels were measured， and hematoxylin-eosin （HE） staining was used to observe histopathological changes in rat brain tissues. Gas chromatography was employed to detect the content of SCFAs in the cecum contents. Enzyme-linked immunosorbent assay （ELISA） was adopted to measure serum GLP-1 level. Western blot was used to detect the protein expression of GPR43 in rat ileal tissues and GLP-1R in the ischemic brain tissues. ResultCompared with the sham operation group， the model group showed significantly increased NIHSS scores， random blood glucose levels， and cerebral infarct volumes （P<0.01）， and significantly decreased SCFAs content， GLP-1 levels， and GPR43 and GLP-1R protein expression （P<0.01）. Compared with the model group， the high-dose ZJT group and the western medicine group exhibited significantly reduced NIHSS scores， random blood glucose levels， and cerebral infarct volumes （P<0.05， P<0.01）， and significantly increased SCFAs content， GLP-1 levels， and GPR43 and GLP-1R protein expression （P<0.01）. ConclusionZJT can improve glucose metabolism disorder and reduce neurological damage in DM-CI rats， and its mechanism may be related to the increase in SCFAs content and the upregulation of the GPR43/GLP-1/GLP-1R signaling pathway.