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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.
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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.
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【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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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In recent years, with the continuous development of glucagon-like peptide-1 receptor agonists(GLP-1RA), its role in the management of blood glucose in hospitalized patients has been explored. GLP-1RA can not only control blood glucose in non-critically ill hospitalized patients, but also inhibit appetite, delay gastric emptying, protect nerves, anti-inflammation, reduce systolic blood pressure and blood lipids. At the same time, many studies have found that it can also improve cardiovascular and renal outcomes and reduce the risk of hospitalization complications. Therefore, this paper analyzes the role of GLP-1RA in glycemic management by reviewing domestic and international studies, consensus and guidelines related to inpatient blood glucose management, and helps to better manage blood glucose of patients in non-critical care setting.
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@#Parkinson's disease(PD)is the second common neurodegenerative disease that mostly occurs in middle-aged and elderly people. Currently,Levodopa is the main first-line treatment drug,but the long-term efficacy of patients is not good,and even side effects such as“on-off”phenomenon and orthostatic hypotension occur. Glucagon-like peptide-1receptor agonists(GLP-1RA)and analogues are endogenous peptide hormones that can be released into the blood and enter the central nervous system to exert neuroprotection by crossing the blood-brain barrier. Numerous studies have shown that GLP-1RA can improve movement disorders and restore dopaminergic neuron activity in PD. However,the mechanism of GLP-1RA is not yet fully clear. This paper summarized the mechanism of GLP-1RA and its analogues in improving PD movement disorders and restoring dopaminergic neuron activity,and reviewed the aspects of reducing neuroinflammation,inhibiting oxidative stress,inhibiting apoptosis,regulating mitochondrial morphology,increasing neuronal protrusions,enhancing autophagy,and regulating intestinal flora homeostasis,so as to provide new ideas for research of the mechanisms of PD and development of GLP-1RA-related new drugs.
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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.
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Male diabetic individuals present a marked impairment in fertility; however, knowledge regarding the pathogenic mechanisms and therapeutic strategies is unsatisfactory. The new hypoglycemic drug dapagliflozin has shown certain benefits, such as decreasing the risk of cardiovascular and renal events in patients with diabetes. Even so, until now, the effects and underlying mechanisms of dapagliflozin on diabetic male infertility have awaited clarification. Here, we found that dapagliflozin lowered blood glucose levels, alleviated seminiferous tubule destruction, and increased sperm concentrations and motility in leptin receptor-deficient diabetic db/db mice. Moreover, the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin (9-39) had no effect on glucose levels but reversed the protective effects of dapagliflozin on testicular structure and sperm quality in db/db mice. We also found that dapagliflozin inhibited the testicular apoptotic process by upregulating the expression of the antiapoptotic protein B-cell lymphoma 2 (BCL2) and X-linked inhibitor of apoptosis protein (XIAP) and inhibiting oxidative stress by enhancing the antioxidant status, including total antioxidant capacity, total superoxide dismutase (SOD) activity, and glutathione peroxidase (GPx) activity, as well as decreasing the level of 4-hydroxynonenal (4-HNE). Exendin (9-39) administration partially reversed these effects. Furthermore, dapagliflozin upregulated the glucagon-like peptide-1 (GLP-1) level in plasma and GLP-1R expression by promoting AKT8 virus oncogene cellular homolog (Akt) phosphorylation in testicular tissue. Exendin (9-39) partially inhibited Akt phosphorylation. These results suggest that dapagliflozin protects against diabetes-induced spermatogenic dysfunction via activation of the GLP-1R/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results indicate the potential effects of dapagliflozin against diabetes-induced spermatogenic dysfunction.
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Mice , Animals , Male , Proto-Oncogene Proteins c-akt/metabolism , Antioxidants , Phosphatidylinositol 3-Kinases/metabolism , Semen/metabolism , Diabetes MellitusABSTRACT
Objective:To evaluate the role of glucagon-like peptide-1 receptor (GLP-1R) signaling pathway in sevoflurane postconditioning-induced attenuation of myocardial ischemia-reperfusion (I/R) injury in rats.Methods:Eighty SPF healthy adult male Sprague-Dawley rats, aged 8-10 weeks, weighing 300-340 g, were divided into 4 groups ( n=20 each) by a random number table method: sham operation group (group S), myocardial I/R group (group I/R), myocardial I/R plus sevoflurane postconditioning group (group ISP), and myocardial I/R plus sevoflurane postconditioning plus GLP-1R antagonist group (group ISPE). The myocardial I/R injury model was developed by ligating the left anterior descending branch of the coronary artery for 40 min followed by 2-h reperfusion in anesthetized rats.In group ISP, the rats inhaled 2.4% sevoflurane for 15 min starting from the beginning of reperfusion.In group ISPE, GLP-1R antagonist Exendin9-39 50 μg/kg (in 1 ml 0.9% normal saline) was intraperitoneally injected once a day from 28 days before development of the model, the last intraperitoneal injection was completed at 40 min before inhalation of sevoflurane, and the other treatments were the same as those previously described in group ISP.Blood samples from the abdominal aorta were collected immediately after reperfusion to determine the serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH). Then the rats were sacrificed, and the hearts were obtained for microscopic examination of the histopathological changes of myocardial tissues (by HE staining) and the ultrastructure of cardiomyocytes (with a transmission electron microscope) for determination of the myocardial infarct size (TTC staining), expression of GLP-1R in myocardium (by immunohistochemical staining), expression of GLP-1R, cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response element-binding protein (CREB), phospho-CREB (p-CREB), B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated x protein (Bax) in myocardium (by Western blot). The ratios of p-CREB/CREB and Bcl-2/Bax were calculated. Results:Compared with group S, the serum levels of CK-MB and LDH and percentage of myocardial infarct size were significantly increased, the expression of GLP-1R was up-regulated, the expression of cAMP and PKA was down-regulated, and the p-CREB/CREB ratio and Bcl-2/Bax ratio were decreased in group I/R ( P<0.05). Compared with group I/R, the serum levels of CK-MB and LDH and percentage of myocardial infarct size were significantly decreased, the expression of GLP-1R, cAMP and PKA was up-regulated, and p-CREB/CREB ratio and Bcl-2/Bax ratio were increased in group ISP ( P<0.05). Compared with group ISP, the serum levels of CK-MB and LDH and percentage of myocardial infarct size were significantly increased, the expression of GLP-1R, cAMP and PKA was down-regulated, and the p-CREB/CREB ratio and Bcl-2/Bax ratio were decreased in group ISPE ( P<0.05). Conclusions:Sevoflurane postconditioning can attenuate myocardial I/R injury by activation of GLP-1R signal pathway and inhibition of cardiomyocyte apoptosis in rats.
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OBJECTIVE To mine and analyze the risk signal of glucagon- like peptide -1 receptor agonists （GLP-1RA）related adverse drug reaction （ADR）. METHODS ADR data related to GLP- 1RA from April 1，2005 to October 16，2021 in the openFDA database were collected ，and the Bayesian confidence propagation neoral network （BCPNN）method was used for data mining. ADR were classified and described by using systematic organ classification （SOC）of drug ADR terminology set in 24.0 edition of MedDRA. RESULTS & CONCLUSIONS A total of 175 719 ADR reports related to GLP- 1RA were retrieved ，with 140 ADR positive signals ，involving five drugs such as exenatide （77 027 cases of ADR and 31 ADR positive signals ），dulaglutide （45 329 cases of ADR and 26 ADR positive signals ），liraglutide （42 748 cases of ADR and 32 ADR positive signals ）， semaglutide（8 844 cases of ADR and 27 ADR positive signals ）and lixisenatide （1 771 cases of ADR and 24 ADR positive signals）. According to SOC classification ，GLP-1RA-induced ADR involved gastrointestinal system ，hepatobiliary system ，nervous system，urinary and renal system ，endocrine system ，immune system and administration site. In the gastrointestinal system ，the risk of （acute）pancreatitis was higher ，and the order of risk was liraglutide ＞exenatide＞semaglutide＞dulaglutide＞lixisenatide； ADR signal of hepatobiliary system was stronger for cholelithiasis ，and the order of risk was liraglutide ＞semaglutide＞exenatide＞ lixisenatide＞dulaglutide. In the nervous system ，the risk of taste disorder was higher ；compared with dulaglutide and lixisenatide ， liraglutide，exenatide and semaglutide were more likely to cause headache and dizziness. In urinary and renal system ， compared with exena tide，dulaglutide and lixisenatide ，liraglutide and semaglutide were more likely to cause acute renal injury. In the endocrine system ，the risk of hypoglycemia was higher ，and the order of risk was exenatide ＞liraglutide＞lixisenatide＞ semaglutide＞dulaglutide. In the immune system ，lixisenatide was more likely to develop urticaria than other drugs ，dulaglutide and liraglutide did not caused ADR signal. Among the administration sites ，the risk of ADR caused by exenatide and dulaglutide was higher，while the risk of related ADR caused by semaglutide was lower. When using GLP- 1RA clinically ，we should closely monitor the renal function and blood glucose of patients ，and pay attention to patients with sudden upper abdominal pain ；in case of relevant ADR ，timely intervention measures should be taken to ensure the safety and effectiveness of medication.
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Osteoporosis is one of the common complications of type 2 diabetes mellitus (T2DM). Recent studies have shown that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can promote bone formation and inhibit bone resorption, suggesting that this hypoglycemic drugs may benefit T2DM patients with osteoporosis and high fracture risk, but its underlying mechanism is not fully understood, and different GLP-1RAs exhibit different skeletal effects and molecular mechanisms. In this paper, the effects of several GLP-1RAs on bone metabolism are reviewed.
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ABSTRACT Background: Recently, studies had shown that incretin-based therapies could reduce the levels of pro-inflammatory markers. The data on the effects of incretin-based therapies on serum high-sensitivity C-reactive protein (hs-CRP) in type 2 diabetes (T2DM) were inconsistent. Objective: The objective of the study was to assess the effects of incretin-based therapies on hs-CRP in patients with T2DM by meta-analysis. Methods: We searched PubMed, EMBASE, the Cochrane Collaboration Library, and Web of Science to identify the eligible randomized clinical trials until August 2019. The pooled standard mean differences (SMD) were calculated by random-effects model using STATA 11.0. Results: Twenty-five studies with 28 randomized controlled trials were finally included into the meta-analysis. Meta-analysis revealed a significant reduction in hs-CRP following treatment with incretin-based regimens compared to controls (SMD = −0.452, p < 0.001). Subgroup analysis of different class of incretin-based drugs showed that therapy with both dipeptidyl peptidase 4 inhibitors (DPP-4Is, SMD = −0.338, p = 0.026) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs, SMD = −0.544, p = 0.003) caused significant reductions in hs-CRP. Besides, there was a significant reduction in hs-CRP with an intervention duration more than 24 weeks (SMD = −0.465, p = 0.001), while no significant difference with <24 weeks. Meta-regression analyses showed that better glycemic control and more body mass index (BMI) decline were associated with hs-CRP reduction after incretin-based therapies. Conclusions: This meta-analysis suggests that incretin-based therapies, both GLP-1 RAs and DPP-4Is, can cause a significant reduction in hs-CRP in patients with T2DM, which is related to long intervention duration, better glycemic control, and more BMI decline.
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OBJECTIVE：To ex plore the improvement effects of small-molecule glucagon-like peptide- 1 receptor（GLP-1R） agonists（6，7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline，DMB）on osteoporosis model mice. METHODS ：C57BL/ 6J mice were randomly divided into sham operation group ，model group ，positive control group （17β-estradiol，10 μg/kg）and DMB group （1 mg/kg），with 10 mice in each group. The sham operation group received bilateral laparotomy without ovariectomy ， and the other groups received bilateral ovariectomy to reproduce the osteoporosis model. At 4th week after operation ，sham operation group and model group were given constant volume of florence oil intragastrically ；administration groups were given relevant medicine intragastrically ，once a day ，for consecutive 8 weeks. After last medication ，Micro-CT was used to detect the femur microstructure ，bone mineral density （BMD），bone mineral content （BMC）and bone morphometric parameters [bone tissue volume fraction （BV/TV），trabecular thickness （Tb.Th），trabecular number （TB.N）and trabecular spacing （Tb.Sp）]. ELISA assay was used to detect the expression of bone formation indexes [bone specific alkaline phosphatase （BALP），osteoprotegerin（OPG）] and bone resorption indexes [tartrate resistant acid phosphatase （TRAP）and C-terminal cross-linked peptide of type Ⅰ collagen （CTX-Ⅰ）]. Three-point bending test was used to detect biomechanical parameters （maximum load ，stiffness，stress and Young ’s modulus）of femur of mice in each group. RESULTS ：In sham operation group ，trabeculae were numerous ，thick，complete in morphological structure ，well-organized and reticular ；bone Δ 基金项目：国家自然科学基金资助项目（No.81402931）；陕西省 重点研发计划项目（No.2017SF-261）；西安医学院 2016年博士科研启 microstructure and bone mass were normal. Compared with 动基金项目（No.2016DOC27） sham operation group ， the number of trabecular bone ＊讲师，博士。研究方向 ：分子药理学 。E-mail：zhouying209@ decreased，the thickness became thinner ，twisted or broken ， 163.com and the trabecular space increased ；the bone microstructure ·284· China Pharmacy 2021Vol. 32 No. 3 中国药房 2021年第32卷第3期 deteriorated and the bone m ass decreased ；BMD，BMC，BV/TV，Tb.Th，Tb.N and biomechanical parameters of femur were decreased significantly ，while Tb.Sp and serum levels of BLAP ，OPG，TRAP and CTX- Ⅰ were increased significantly （P＜0.05 or P＜0.01）. Compared with model group ，the bone mass of positive control group and DMB group were increased ，while the number，thickness and shape of trabecular bone partially recovered ；BMD，BMC，BV/TV，Tb.Th，Tb.N and biomechanical parameters of femur were increased significantly （P＜0.05 or P＜0.01）；Tb.Sp，serum levels of BLAP and OPG were increased significantly （P＜0.01）， while the levels of TRAP and CTX- Ⅰ were decreased significantly （P＜0.05 or P＜0.01）. CONCLUSIONS：DMB can improve osteoporosis by increasing bone mass ，improving bone microstructure ，increasing the expression of bone formation related indexes and biomechanical parameters and decreasing bone resorption related indexes.