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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.
Subject(s)
Mice , Animals , Male , Proto-Oncogene Proteins c-akt/metabolism , Antioxidants , Phosphatidylinositol 3-Kinases/metabolism , Semen/metabolism , Diabetes MellitusABSTRACT
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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@#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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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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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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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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The incidence rate of nonalcoholic fatty liver disease (NAFLD) continues to rise around the world, and due to its complex pathogenesis, there is still a lack of effective treatment drugs. If NAFLD is not treated in time, it may increase the risk of related metabolic diseases such as diabetes and hyperlipidemia and even lead to liver fibrosis and liver cirrhosis. Glucagon-like peptide-1 is a hormone secreted by L-shaped cells of the small intestine and can regulate glucose-dependent stimulation of insulin secretion, reduce gastric emptying, and inhibit food intake. This article reviews the effect of glucagon-like peptide-1 receptor agonist in the treatment of NAFLD and related mechanism.
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Our previous studies have shown that puerarin, an active component of the traditional Chinese medicine-Pueraria Lobata, can improve glycometabolism in high-fat diet (HFD) mice with diabetes by activating the glucagon-like peptide-1 receptor (GLP-1R) pathway. This study intends to further evaluate the effect of puerarin on depressive symptoms in HFD mice. Long-term HFD induces type 2 diabetes and depressive-like symptoms in mice. Animal welfare and experimental procedures follow the regulations of the Animal Ethics Committee of the Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Traditional Chinese Medicine (approval No. AEWC-025). The experiment was divided into: control group, model group, model/puerarin (150 mg·kg-1·day-1) group, and model/fluoxetine (15 mg·kg-1·day-1) group. The oral glucose tolerance test (OGTT) and behavioral experimental analysis were performed after 6 weeks of continuous administration. Afterwards, enzyme-linked immunosorbent assay (ELISA) was used to detect interleukin-1β (IL-1β), interleukin-6 (IL-6), 5-hydroxytryptamine (5-HT), and corticosterone (CORT) in serum of mice for each group. Western blot assays were used to detect the level of activation and expression of proteins related to neuroplasticity and depressive disorder in the hippocampus. Moreover, HT-22 cell line was used to investigate the protective effect of puerarin on cell morphology and survival. The results show that puerarin can effectively maintain the survival of HT22 in an environment with high glucose and corticosterone. Meantime, the glycemic regulation of diabetic mice was improved after treatment of puerarin, the depressive symptoms were alleviated, the 5-HT increased, and the corticosterone, IL-1β, and IL-6 decreased in the serum. The up-regulation of related proteins in GLP-1R/Wnt/mTOR (mammalian target of rapamycin) signaling in hippocampus suggests that its effect on ameliorating depression in diabetic mice may be related to the activation of GLP-1R/Wnt/mTOR signaling pathway. This study shows that puerarin can significantly ameliorate the depressive symptoms of HFD induced diabetic mice which might be achieved through activating the GLP-1R/Wnt/mTOR signaling pathway and improving hippocampal neuroplasticity.
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Nonalcoholic fatty liver disease (NAFLD) is the manifestation of metabolic syndrome in the liver and is closely associated with glucose and lipid metabolism disorders, and they interact as both cause and effect of each other, with insulin resistance as the common pathogenesis. About three quarters of patients with obesity and type 2 diabetes mellitus have NAFLD, and current guidelines recommend reducing metabolic risk factors and treating metabolic syndrome as the primary treatment goals for patients with NAFLD. Although there are no approved drugs for the treatment of NASH at present, the hypoglycemic drugs on the market can bring varying degrees of benefits to NAFLD patients while lowering blood glucose. This article reviews the prospects of three types of hypoglycemic drugs on the market (thiazolidinediones, GLP-1 receptor agonists, and SGLT-2 inhibitors) in the treatment of NAFLD.
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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.
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ABSTRACT Sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) were initially approved to improve glycemic control in the treatment of type 2 diabetes. Clinical trials have also demonstrated beneficial effects with regards to cardiovascular and renal parameters. Beyond improving glycemic control, these therapies promote weight loss and lower blood pressure when used individually, and in an additive manner when used together. Accordingly, taking advantage of complementary mechanisms of action with the combined use of these two classes of agents to further improve cardiorenal outcomes is conceptually appealing, but has yet to be explored in detail in clinical trials. In this review, we discuss proposed mechanisms for renal protection, clinical benefits, and adverse events associated with the individual and combined use of SGLT2 inhibitors and GLP-1RA. The management of type 2 diabetes has significantly changed over the last few years, moving away from solely glycemic control towards the concurrent management of associated comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors and GLP-1RA in patients with type 2 diabetes.
RESUMO Inibidores do cotransporter-2 de glicose sódica (SGLT2) e agonistas do receptor peptídeo-1 do tipo glucagon (GLP-1RA) foram inicialmente aprovados para melhorar o controle glicêmico no tratamento da diabetes tipo 2. Os ensaios clínicos também demonstraram efeitos benéficos em relação aos parâmetros cardiovasculares e renais. Além de melhorar o controle glicêmico, essas terapias promovem perda de peso e redução da pressão arterial quando usadas individualmente, e de forma aditiva quando usadas em conjunto. Consequentemente, tirar proveito de mecanismos de ação complementares com o uso combinado dessas duas classes de agentes para melhorar ainda mais os resultados cardiorrenais é conceitualmente atraente, mas ainda precisa ser explorado em detalhes em ensaios clínicos. Nesta revisão, discutimos os mecanismos propostos para proteção renal, benefícios clínicos e eventos adversos associados ao uso individual e combinado de inibidores de SGLT2 e GLP-1RA. O tratamento do diabetes tipo 2 mudou significativamente nos últimos anos, passando do controle exclusivamente glicêmico para o tratamento simultâneo de comorbidades associadas em uma população de pacientes com risco significativo de doença cardiovascular e progressão da doença renal crônica. É nessa perspectiva que procuramos delinear a justificativa para o uso sequencial e/ou combinado de inibidores de SGLT2 e GLP-1RA em pacientes com diabetes tipo 2.
Subject(s)
Humans , Cardiovascular Diseases/prevention & control , Diabetes Mellitus, Type 2/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Glucagon-Like Peptide-1 Receptor , Hypoglycemic Agents/therapeutic useABSTRACT
OBJECTIVE：To reappraise systematic review/Meta-analysis （SRs/MAs）of the efficacy and safety of glucagon-like peptide 1（GLP-1）receptor agonist in the treatment of type 2 diabetes mellitus （T2DM），and to provide evidence-based reference for clinical use of these drugs in the treatment of T 2DM. METHODS ：Retireved from Cochrane library ，PubMed，Embase，CBM， Wanfang database and CNKI ，systematic review/Me ta-analysis about GLP- 1 receptor agonist in the treatment of T 2DM were collected during the inception to Dec. 2019. After data extraction of literatures met inclusion and exclusion criteria ，GRADE system was used to evaluate the quality of evidence included in the study ，and the evidence of efficacy and safety outcome indexes were summarized. RESULTS ：Finally 31 literatures were included ，involving 91 outcome indexes ，and GRADE evidence quality was medium，among which 4（4.4％）were very-low-quality ，33（36.3％）were low-quality ，45（49.5％）were medium-quality ，and 9 （9.9％）were high-quality outcome indicators. The results of evidence summary showed that GLP- 1 receptor agonists were better than or similar to placebo and other oral hypoglycemic drugs ， better than dipeptidyl peptidase 4 （DPP-4） inhibitors in . reducing the level of HbA 1c；better than or similar to placebo ， JDZX2015240） better than other oral hypoglycemic agents and DPP- 4 2276299207@qq.com inhibitors in reducing the level of fasting glucose ；similar to DDP-4 inhibitors，higher than or similar to placebo ，lower than other oral hypoglycemic dru gs in the incidence of hypoglycemia；higher than other oral hypoglycemic drugs ，placebo and DPP- 4 inhibitors in the incidence of diarrhea and nausea ； higher than other oral hypoglycemic drugs and placebo in the incidence of vomiting. CONCLUSIONS ：The evidence quality of systematic review/Meta-analysis about GLP- 1 receptor agonist in the treatment of T 2DM are moderate. These drugs have good clinical efficacy in the treatment of T 2DM，but their safety are not as good as placebo or other oral hypoglycemic drugs.
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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-4Is) increased weight slightly by 0.31 kg [95% confidence interval ( ): 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% : -1.60, -1.09), -1.10 kg/m (95% : -1.42, -0.78), and -1.28 cm (95% : -1.69, -0.86), respectively.@*Conclusion@#GLP-1 RAs were more effective than DPP-4Is in lowering the three indicators. Overall, the effects of GLP-1 RAs on weight, BMI, and WC were favorable.
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Glucagon-like peptide-1 (GLP-1) is an incretin which plays a role in regulating glucose hornêbstasis and appetite, involved in the occurrence and development of type 2 diabetes and obesity. GLP-1 plays the role through regulating insulin secretion and activating the GLP-1 receptor (GLP-1R). Recent studies have found the association between GLP-1 and addictive behaviors caused by cocaine, nicotine, alcohol and amphetamine. This article reviews the role and mechanism of GLP-1 in drug addiction.
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Objective • To investigate the role and mechanism of glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide in dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD). Methods • The drinking water with DSS concentration of 3% was prepared by using DSS and sterile water, and the mice were free to drink for 7 days, to construct IBD model. The experimental mice were randomly divided into four groups with five mice in each group: the control group [drinking sterile water, intraperitoneal injection of phosphate buffered saline (PBS)], the liraglutide group (drinking sterile water, intraperitoneal injection of 0.6 mg/kg liraglutide), the model group (drinking DSS water solution, intraperitoneal injection of PBS) and the treatment group (drinking DSS water solution, intraperitoneal injection of 0.6 mg/kg liraglutide). During the experiment, the fecal morphology, body weight, and colon length were observed. And hematoxylin-eosin (H-E) staining was used to observe the degree of colitis in mice. Flow cytometry was used to detect the proportion of neutrophils and eosinophils, as well as the changes of the innate lymphoid cell (ILC) subsets and function in the colon. Results • Compared with the model group, the symptoms of loose stool and bloody stool were improved, and the shortened colon length was also improved (P=0.007) in the treatment group. H-E staining showed that the infiltration of inflammatory cells in the colon of the treatment group was significantly reduced. Flow cytometry analysis of the colonic lamina propria showed that the proportion of neutrophils in the colon of the treatment group was significantly reduced (P=0.004), and the proportion of eosinophils was also reduced (P=0.002); the proportion of ILC (ILC2) in group 2 decreased (P=0.032), but the proportion of ILC (ILC3) in group 3 increased (P=0.008); the cytokine interleukin-22 secreted by ILC3 was increased (P=0.008). Conclusion • Liraglutide may delay the development of IBD by affecting the proportion of ILC subsets and secretion function.
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Objective@#To investigate the distribution of polymorphisms of glucagon-like peptide-1 receptor gene (GLP-1R) rs10305420 and rs3765467 in Chinese Han type 2 diabetic patients, and the effects on body weight, blood glucose and serum lipid levels.@*Methods@#Two SNPs of GLP-1R rs3765467 and rs10305420 were genotyped by Sanger dideoxy termination sequencing method. The racial difference and the association between the gene polymorphisms and the metabolic markers including BMI, serum lipids and blood glucose were analyzed.@*Results@#The distribution of gene polymorphisms was consistent with the Hardy-Weinberg equilibrium. High-density lipoprotein (HDL-C) levels were significantly lower in the rs10305420 T allele carriers than in the CC genotype (1.00±0.18 vs 1.09±0.22, P=0.02). The triglyceride (TG) level of the rs3765467 A allele carrier was higher than that of the GG type (2.75±2.19 vs 2.07±1.36, P=0.03). The allele frequency of rs10305420 C/T was highly statistically significant compared with European population (P=0.000 3). The allele frequency of rs3765467 G/A was statistically different from that of European and African populations (P<0.01).@*Conclusions@#The two genetic polymorphisms were significantly associated with lipid levels in patients with type 2 diabetes, and there was a significant racial difference in the frequency distribution of the two variants.
ABSTRACT
OBJECTIVE： To systematically evaluate therapeutic efficacy and safety of long-acting glucagon like peptide-1 （GLP-1） receptor agonist Semaglutide vs. placebo or other glucose-lowering drugs in the treatment of type 2 diabetes mellitus （T2DM）， and to provide evidence-based reference for T2DM in clinic. METHODS： Retrieved from PubMed， Embase， Medline， Cochrane library， randomized controlled trials （RCT） about Semaglutide （trial group） vs. placebo or other glucose-lowering drugs （control group） in the treatment of T2DM were selected during the establishment of database to Sept. 2018. After data extraction and quality evaluation with Cochrane system evaluator manual 5.1.0， Meta-analysis was performed for HbA1c level and compliance rate， fasting plasma glucose （FPG） level， systolic blood pressure （SBP）， diastolic blood pressure （DBP）， body mass index （BMI）， body weight pulse frequency level， the incidence of hypoglycemia and gastrointestinal reaction by using Rev Man 5.3 software. RESULTS： A total of 12 RCTs involving 9 966 patients were included. The results of Meta-analysis showed that compared with control group， trial group could effectively decrease the levels of HbA1c [MD＝－1.03， 95％CI（－1.22，－0.85）， P＜0.001] and FPG [MD＝－1.14， 95％CI（－1.53，－0.76）， P＜0.001]， increase compliance rate of HbA1c [RD＝0.40， 95％CI（0.31，0.49）， P＜0.001]， reduce SBP [MD＝－2.61， 95％CI （－3.23， －1.98）， P＜0.001] and DBP [MD＝－0.56， 95％CI （－0.96， －0.16）， P＝0.006]， decrease BMI [MD＝－1.25， 95％CI （－1.51， －0.99）， P＜0.001] and body weight [MD＝ －3.60， 95％CI（－4.24， －2.96）， P＜0.001]， increase pulse frequency [MD＝2.16， 95％CI （1.51， 2.81）， P＜0.001]. The major adverse drug reactions were gastrointestinal reaction； the incidence of gastrointestinal reaction was higher than control group [RD＝0.20， 95％CI（0.15，0.26）， P＜0.001]， but there was no statistical significance in the incidence of hypoglycemia events between 2 groups [RD＝0.00， 95％CI（－0.01，0.02）， P＝0.44]. CONCLUSIONS： Semaglutide can significantly decrease HbA1c， FPG， body weight， blood pressure and increase pulse frequency in T2DM patients， and increase the compliance rate of HbA1c. Although the incidence of gastrointestinal reaction is higher than control group， but the risk of hypoglycemia is not higher， indicating Semaglutide is well tolerated and safe.
ABSTRACT
Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer's disease (AD), and insulin-resistance is commonly seen in patients with Hhcy. Liraglutide (Lir), a glucagon-like peptide that increases the secretion and sensitivity of insulin, has a neurotrophic or neuroprotective effect. However, it is not known whether Lir ameliorates the AD-like pathology and memory deficit induced by Hhcy. By vena caudalis injection of homocysteine to produce the Hhcy model in rats, we found here that simultaneous administration of Lir for 2 weeks ameliorated the Hhcy-induced memory deficit, along with increased density of dendritic spines and up-regulation of synaptic proteins. Lir also attenuated the Hhcy-induced tau hyperphosphorylation and Aβ overproduction, and the molecular mechanisms involved the restoration of protein phosphatase-2A activity and inhibition of β- and γ-secretases. Phosphorylated insulin receptor substrate-1 also decreased after treatment with Lir. Our data reveal that Lir improves the Hhcy-induced AD-like spatial memory deficit and the mechanisms involve the modulation of insulin-resistance and the pathways generating abnormal tau and Aβ.
ABSTRACT
Weight loss is an important goal in the management of several chronic conditions, including type 2 diabetes mellitus, and pharmacological therapies that aid weight loss are appealing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel glucose-lowering therapies that have been shown to induce clinically significant reductions in body weight. However, this weight loss may not be attributed solely to fat mass (FM). Given the importance of skeletal muscle and lean body mass (LBM) on cardio-metabolic health and physical function, we reviewed the available literature reporting the effects of GLP-1RAs and SGLT2is on body composition. Results demonstrate that, in most circumstances, the weight loss associated with both therapies predominantly comprises a reduction in FM, although significant heterogeneity exists between studies. In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery. No clear differences existed between GLP-1RAs and SGLT2is. Consequently, the loss of LBM and skeletal muscle associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. Strategies to preserve skeletal muscle and improve physical function, for example through structured exercise, are of great importance.