Practical guide:Glucagon-like peptide-1 and dual glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus

Practical guide:Glucagon-like peptide-1 and dual glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus common second-line choice after metformin for treating T2DM.Various considerations can make selecting and switching between different GLP-1 RAs challenging.Our study aims to provide a comprehensive guide for the usage of GLP-1 RAs and dual GIP and GLP-1 RAs for the management of T2DM.

Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease(MAFLD)is a hepatic manifestation of the metabolic syndrome.It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries.MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma.Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis.The mechanisms involved in maintaining gut-liver axis homeostasis are complex.One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gutliver axis functionality.An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis.Moreover,alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are a class of drugs developed for the treatment of type 2 diabetes mellitus.They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis.The mechanisms reported to be involved in this effect include an improved regulation of glycemia,reduced lipid synthesis,β-oxidation of free fatty acids,and induction of autophagy in hepatic cells.Recently,multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment.A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD.This review presents the current understanding of the role of the gutliver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.

Glucagon-like peptide-1 receptor agonists as a possible intervention to delay the onset of type 1 diabetes:A new horizon

Type 1 diabetes(T1D)is a chronic autoimmune condition that destroys insulinproducing beta cells in the pancreas,leading to insulin deficiency and hyperglycemia.The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels.However,this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells.Recent research has explored the potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)as a novel intervention to modify the disease course and delay the onset of T1D.GLP-1RAs are medications initially developed for treating type 2 diabetes.They exert their effects by enhancing glucose-dependent insulin secretion,suppressing glucagon secretion,and slowing gastric emptying.Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D.This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D,possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells.This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification,which should open new avenues for preventing and treating T1D,improving the quality of life and long-term outcomes for individuals at risk of T1D.

Cardioprotective effects of glucagon-like peptide 1 receptor agonists in heart failure: Myth or truth?

Therapy with glucagon-like peptide 1(GLP1)receptor agonists has raised great interest for its beneficial cardiovascular effects in preventing atherosclerosis and heart failure-related outcomes.However,while evidence about atherosclerosis consistently suggests a cardioprotective potential with class effect,controversies remain on its impact on heart failure.GLP1 receptor agonists appear to prevent hospitalization for new-onset heart failure and reduce symptoms in heart failure with preserved ejection fraction(as demonstrated by the recent STEP-HFpEF Trial).Still,GLP1 agonism has resulted in neutral or even harmful effects in patients with established heart failure with reduced ejection fraction(the LIVE trial).GLP1 receptor agonists benefit the cardiovascular system indirectly through their marked metabolic effects(improved weight management,glycemic control,blood pressure,systemic and tissue inflammation),while direct effects on the heart have been questioned.Nonetheless,weight loss alone achieved through GLP1 receptor agonists has failed in improving left ventricular functions.Tirzepatide is a dual agonist of GLP1 and glucose-dependent insulinotropic polypeptide,representing an innovative treatment option in diabetes with a major impact on weight loss and promising cardiovascular benefits.Whether this class of therapies is going to change the history of heart failure is an ongoing debate.

Fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonists as a promising strategy for treating diabetes

The maintenance of appropriate glycemic control is important for the prevention of diabetic complications in people with type 2 diabetes(T2D). Numerous oral antidiabetic drugs are now clinically available, but in particular, the introduction of injection regimens using insulin and/or glucagon-like peptide-1 receptor agonist(GLP-1RA)s represents promising step-up options for oral antidiabetic drug treatment. The recently licensed fixed-ratio combination(FRC) products,which comprise basal insulin and a GLP-1RA, have potent anti-hyperglycemic effects and reduce the undesirable side-effects of each component, such as body weight gain, hypoglycemia, and gastrointestinal symptoms. Two FRCs-insulin degludec/Liraglutide and insulin glargine/Lixisenatide-are now clinically available and, to date, several phase Ⅱ/Ⅲ trials have been conducted in particular groups of subjects with T2D. However, their utility in real-world clinical settings is of interest for most clinicians. Recently reported real-world clinical trials of these two FRCs in various situations have demonstrated their efficacy regarding glycemic control and the quality of life of people with T2D. Their long-term safety and efficacy require confirmation, but a treatment strategy that includes an FRC may be compatible with the concept of “well-balanced” therapy in certain groups of patients with T2D who have inadequate glycemic control.

A Retrospective Analysis of Glucagon-Like Peptide 1 Receptor Agonists in Treating Type 2 Diabetes Mellitus Complicated by Nonalcoholic Fatty Liver Disease

Background: The objective of this study was to compare and analyze the variations in clinical indices before and after treatment of type 2 mellitus (T2DM) combined with nonalcoholic fatty liver disease (NAFLD) that were treated with glucagon-like peptide 1 receptor agonists (GLP-1RAs). Methods: The electronic medical record system was utilized to search for a total of 16 patients with type 2 diabetes complicated by NAFLD who were hospitalized at the First Affiliated Hospital of Yangtze University from October 2022 to April 2023 and treated with GLP-1RA for the first time. The clinical indices were compared before and after 12 weeks of treatment with GLP-1RA. Results: The liver-spleen CT ratio (L/S), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) in all patients treated with GLP-1RA after 12 weeks were significantly different (P 0.05). The patients were categorized into two groups based on the types of GLP-1RAs. The changes in L/S, TC, TG, and LDL-C in the long-acting group after treatment were statistically significant (P Conclusions: GLP-1RAs can improve liver function, regulate lipid metabolism, and reduce the severity of fatty liver in patients with T2DM complicated by NAFLD, which demonstrates the importance of clinical applications.

Effects of glucagon-like peptide-1 receptor agonists on glucose excursion and inflammation in overweight or obese type 2 diabetic patients

BACKGROUND Currently,the lack of comparative studies between weekly and daily formulations of glucagon-like peptide-1 receptor agonists(GLP-1RAs)for glucose excursion is worth investigation.AIM To investigate the effects of weekly and daily formulations of GLP-1RA on glucose excursion and inflammation in overweight and obese patients with type 2 diabetes.METHODS Seventy patients with type 2 diabetes mellitus who were treated at our hospital between January 2019 and January 2022 were enrolled in this retrospective analysis.All patients were treated with metformin.We evaluated changes in blood glucose levels and a series of important indicators in patients before and after treatment with either a weekly or daily preparation of GLP-1RA(group A;n=33 and group B;n=37).RESULTS The degree of decrease in the levels of fasting blood glucose,mean blood glucose,mean amplitude of glycemic excursions,total cholesterol,triglycerides,tumor necrosis factor-α,interleukin-6,and high-sensitivity C-reactive protein after treatment in group A was higher than that in group B(P<0.05),whereas the 2-h postprandial blood glucose levels decreased more so in group B than in group A(P<0.001).However,there were no statistically significant differences in the levels of glycated hemoglobin,standard deviation of blood glucose,coefficient of variation,absolute mean of daily differences,percentage of time with 3.9 mmol/L<glucose<10 mmol/L,and high-and low-density lipoproteins between the two groups(P>0.05).The incidence of adverse reactions was significantly lower in group A than in group B(P<0.05).CONCLUSION The effect of the weekly preparation of GLP-1RA in controlling blood glucose levels in the patients,suppressing inflammation,and reducing adverse reactions was significantly higher than that of the daily preparations,which is worthy of clinical promotion.

Type-2 Diabetes Mellitus and Glucagon-Like Peptide-1 Receptor toward Predicting Possible Association

Aim: This study aimed to investigate the effect of non-synonymous SNPs (nsSNPs) of the Glucagon-like peptide-1 Receptor (GLP-1R) gene in protein function and structure using different computational software. Introduction: The GLP1R gene provides the necessary instruction for the synthesis of the insulin hormones which is needed for glucose catabolism. Polymorphisms in this gene are associated with diabetes. The protein is an important drug target for the treatment of type-2 diabetes and stroke. Material and Methods: Different nsSNPs and protein-related sequences were obtained from NCBI and ExPASY database. Gene associations and interactions were predicted using GeneMANIA software. Deleterious and damaging effects of nsSNPs were analyzed using SIFT, Provean, and Polyphen-2. The association of the nsSNPs with the disease was predicted using SNPs & GO software. Protein stability was investigated using I-Mutant and MUpro software. The structural and functional impact of point mutations was predicted using Project Hope software. Project Hope analyzes the mutations according to their size, charge, hydrophobicity, and conservancy. Results: The GLP1R gene was found to have an association with 20 other different genes. Among the most important ones is the GCG (glucagon) gene which is also a trans membrane protein. Overall 7229 variants were seen, and the missense variants or nsSNPs (146) were selected for further analysis. The total number of nsSNPs obtained in this study was 146. After being subjected to SIFT software (27 Deleterious and 119 Tolerated) were predicted. Analysis with Provean showed that (20 deleterious and 7 neutral). Analysis using Polyphen-2 revealed 17 probably damaging, 2 possibly damaging and 1 benign nsSNPs. Using two additional software SNPs & GO and PHD-SNPs showed that 14 and 17 nsSNPs had a disease effect, respectively. Project Hope software predicts the effect of the 14 nsSNPs on the protein function due to differences in charge, size, hydrophobicity, and conservancy between the wild and mutant types. Conclusion: In this study, the 14 nsSNPs which were highly affected the protein function. This protein is providing the necessary instruction for the synthesis of the insulin hormones which is needed for glucose catabolism. Polymorphisms in this gene are associated with diabetes and also affect the treatment of diabetic patients due to the fact that the protein acts as an important drug target.

GLP-1受体激动剂对心血管作用的研究进展

胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)由肠道内分泌细胞产生。GLP-1受体激动剂(GLP-1 receptor agonists,GLP-1RAs)促进葡萄糖相关的胰岛素分泌和抑制胰高血糖素分泌。GLP-1RAs还能抑制胃排空、食物摄入和限制体质量增加。在过去的十年中,GLP-1RAs对心血管系统影响的研究已经取得重大进展。口服小分子GLP-1RAs具有潜在优势,可以提高该类药物的应用。该文综述了GLP-1RAs在心血管疾病治疗中的多种作用,为GLP-1RAs的心血管获益提供新见解。

达格列净联合胰高血糖素样肽-1受体激动剂对2型糖尿病的疗效研究

目的探讨达格列净联合胰高血糖素样肽-1受体激动剂(GLP-1 RAs)对2型糖尿病患者血液流变学及胰岛素抵抗的影响。方法将2020年11月—2022年10月泉州市中医院收治的102例2型糖尿病患者随机分为2组,每组51例。对照组给予达格列净治疗,研究组采用达格列净联合GLP-1 RAs(利拉鲁肽)的治疗方案。比较2组临床疗效、血糖指标[空腹血糖(FBG)、餐后2 h血糖(2 hPG)、糖化血红蛋白(HbA1c)]、空腹胰岛素(FINS)及胰岛素抵抗[胰岛素抵抗指数(HOMA-IR)、胰岛素分泌指数(HOMA-β)]、血脂指标[总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)]、血液流变学指标[红细胞聚集指数(EAI)、红细胞压积(HCT)、红细胞变形指数(EDI)、血浆黏度(PV)]和不良反应。结果研究组总有效率为94.12%,高于对照组的80.39%,差异有统计学意义(P<0.05)。研究组和对照组治疗后FBG、2 hPG、HbAlc、BMI均低于治疗前,且研究组治疗后FBG、2 hPG、HbAlc水平低于对照组,差异有统计学意义(P<0.05)。治疗后,研究组FINS、HOMA-β水平高于对照组,HOMA-IR水平低于对照组,差异有统计学意义(P<0.05)。研究组和对照组治疗后HDL-C均高于治疗前,TC、TG、LDL-C水平均低于治疗前;研究组治疗后HDL-C水平高于对照组,TC、TG、LDL-C水平低于对照组,差异均有统计学意义(P<0.05)。治疗后,研究组和对照组EAI、HCT、EDI、PV水平均低于治疗前,且研究组EAI、HCT、EDI、PV水平低于对照组,差异均有统计学意义(P<0.05)。研究组不良反应总发生率为11.76%,与对照组的9.80%比较,差异无统计学意义(P>0.05)。结论达格列净联合GLP-1 RAs(利拉鲁肽)治疗2型糖尿病的疗效确切,可有效调节患者血糖及血脂水平,缓解胰岛素抵抗,改善血液流变学指标。

GLP-1RAs在治疗非典型抗精神病药相关代谢紊乱中的研究进展

接受非典型抗精神病药物(Atypical antipsychotics, AAPs)治疗的精神障碍患者发生代谢紊乱的风险明显升高。然而,针对AAPs相关代谢紊乱的干预措施有限。近年来,胰高血糖素样肽-1受体激动剂(GLP-1RAs)的减重作用已在非糖尿病患者中得到认可,且此类药物用于治疗AAPs导致的代谢紊乱的研究也愈加广泛,这可能具有显著临床意义。本文主要对GLP-1RAs治疗AAPs相关代谢紊乱的研究进展进行综述。

胰高血糖素样肽1受体激动剂治疗阿尔茨海默病的潜在靶点预测及验证

背景:阿尔茨海默病的机制探究过程中揭示了生物信息学对共同靶点筛选的重要作用,能够利用其筛选结果为基础,探究药物对该疾病的治疗效果。目的:采用生物信息学与分子生物学等方法预测胰高血糖素样肽1受体激动剂利拉鲁肽治疗阿尔茨海默病的作用靶点。方法:利用DisGeNET数据库及SEA数据库获取阿尔茨海默病和利拉鲁肽作用的共同基因;利用DAVID在线数据库对共同靶点进行GO/KEGG富集分析;使用STRING数据库构建蛋白互作网络;使用CCK-8判断利拉鲁肽的最佳使用剂量;使用免疫荧光和免疫印迹技术对关键蛋白的表达情况进行分析。采用小鼠海马神经元HT22细胞系进行体外实验,细胞被随机分为3组:HT22组、HT22+Aβ组和HT22+Aβ+Lir组。HT22组不做特殊处理,HT22+Aβ组使用Aβ1-42干预HT22细胞系24 h构建Aβ损伤细胞模型,HT22+Aβ+Lir组在HT22+Aβ组的基础上添加利拉鲁肽12 h。结果与结论:①从DisGeNET数据库筛选出阿尔茨海默病相关联的基因,共得到3333个关联基因。再从SEA数据库中,得到利拉鲁肽的潜在作用靶点147个。最后使用R包筛选出阿尔茨海默病与利拉鲁肽共同靶点64个。②用DAVID数据库进行共同靶点的GO/KEGG分析,结果提示共同靶点主要富集在:神经活性配体-受体相互作用、肾素-血管紧张素系统、膀胱癌、内肽酶活性、肽受体活性、G蛋白偶联肽受体活性和转运囊泡等生物进程。③将已经得到的64个共同靶点蛋白导入至SRTING在线数据库进行蛋白互作网络构建,得到排名前3位的基因为基质金属蛋白酶2,9和白细胞介素1β。④采用CCK-8试剂盒检测了培养细胞的活性,确定利拉鲁肽拮抗Aβ1-42的最佳浓度为100 nmol/L。⑤在免疫印迹实验与免疫荧光实验中,较HT22组相比,在HT22+Aβ组内基质金属蛋白酶2,9和白细胞介素1β表达量明显上升(P<0.05);HT22+Aβ+Lir组较HT22+Aβ组相比基质金属蛋白酶2,9和白细胞介素1β的表达量显著下降(P<0.05)。⑥结合上述生物信息学数据及在GEO数据库的差异基因二次验证结果提示,基质金属蛋白酶2,9和白细胞介素1β均可作为利拉鲁肽治疗阿尔茨海默病的潜在作用靶点。

胰高血糖素样肽-1受体激动剂在儿童患者中的临床应用进展

胰高血糖素样肽-1受体激动剂(GLP-1RA)在成人2型糖尿病的治疗中已有广泛应用,近年来的研究结果表明,GLP-1RA也可用于儿童肥胖和短肠综合征的治疗。本篇综述主要关注GLP-1RA在儿童患者中的临床应用进展。GLP-1RA通过改善胰岛素敏感性、减轻体重、降低血压和降低代谢综合征发生风险来改善儿童肥胖患者的代谢异常和心血管疾病风险。在短肠综合征中,GLP-1RA可增加肠道对养分的吸收,刺激胰岛素分泌,促进葡萄糖的利用和减少外源性葡萄糖的使用,增加脂肪的利用。GLP-1RA虽在临床应用中具有良好的安全性和耐受性,但也存在低血糖、恶心和呕吐、胰腺炎和甲状腺癌等风险,故需要密切监测患者的不良反应,进一步开展更加系统和深入的研究。

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice

AIM: To investigate whether a glucagon-like peptide-1(GLP-1) analogue inhibits nonalcoholic steatohepatitis(NASH), which is being increasingly recognized in Asia, in non-obese mice. METHODS: A methionine-choline-deficient diet(MCD) along with exendin-4(20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice(non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride(TG) and free fatty acid(FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry.RESULTS: Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fattyacid transport protein 4(FATP4), a hepatic FFA influxrelated gene; macrophage recruitment; and the level of malondialdehyde(MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c(SREBP-1c) m RNA(lipogenesis-related gene) and acyl-coenzyme A oxidase 1(ACOX1) m RNA(β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein m RNA(a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 m RNA level. CONCLUSION: These results suggest that GLP-1 inhibits hepatic steatosis and inflammation through the inhibition of hepatic FFA influx and oxidative stress in a non-obese NASH model.

Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation

Glucagon-like peptide1(GLP-1)is secreted from Langerhans cells in response to oral nutrient intake.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are a new class of incretin-based anti-diabetic drugs.They function to stimulate insulin secretion while suppressing glucagon secretion.GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus(T2DM),and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases.As we know,along with change in lifestyles,the prevalence of non-alcoholic fatty liver disease(NAFLD)in China is rising more than that of viral hepatitis and alcoholic fatty liver disease,and NAFLD has become the most common chronic liver disease in recent years.Recent studies further suggest that GLP-1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels,cutting down the fatcontent to promote fat redistribution,directly decreasing fatty degeneration of the liver,reducing the degree of liver fibrosis and improving inflammation.This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials.

Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates kidney injury in murine models of obesity and diabetes mellitus

AIM To investigate the role of glucagon-like peptide-1(GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS Chronic high-fat diet fed C57 BL/6 J mice, streptozotocintreated high-fat diet fed C57 BL/6 J mice and diabeticC57 BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocintreated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment. RESULTS Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes(SREBP-1 C, FAS, and SCD-1) was decreased, and expression of genes involved in β-oxidation(CPT-1 and PPAR-α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-?. Coagonist treatment reduced expression of inflammatory(TNF-α, MCP-1, and MMP-9) and pro-fibrotic(TGF-β, COL1 A1, and α-SMA) genes and also improved histological derangement in renal tissue.CONCLUSION Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.

鹅去氧胆酸通过FXR调控高脂饮食诱导小鼠肠道GLP-1表达水平改善胰岛素抵抗的作用

目的 探究鹅去氧胆酸(chenodeoxycholic acid, CDCA)通过FXR对高脂饮食诱导小鼠肠道GLP-1表达水平的影响及相关机制。方法 C57BL/6小鼠40只分为对照组(Control组)、高脂饮食组(HFD组)、HFD+CDCA组、HFD+Z-Gug(FXR拮抗剂)组、HFD+CDCA+Z-Gug组,每组8只。干预8周,期间每周检测体质量及24 h摄食量。第8周进行口服葡萄糖耐量实验(OGTT)、腹腔葡萄糖耐量实验(IPGTT)。小鼠处死后,检测血清学指标GLu、TG、CHO、LDL-C、HDL-C;免疫荧光检测小鼠肠道组织GLP-1及FXR表达水平;RT-qPCR检测炎性因子TNF-α、IL-6、IL-1β、Gcg及FXR mRNA表达;ELISA试剂盒检测血清GLP-1含量;流式细胞术检测小肠IELs亚群比例及CD26/DPP4表达水平。结果 与Control组相比,HFD组小鼠体质量增加,血清糖脂代谢异常,口服糖耐量受损,胃肠激素分泌减弱(P<0.05);FXR mRNA及蛋白表达水平增加,Gcg mRNA表达及GLP-1分泌水平下降(P<0.05);肠道炎性因子TNF-α、IL-6、IL-1β mRNA表达水平升高(P<0.05);TCRαβ+IELs、TCRαβ+CD8αα+IELs与TCRαβ+CD8αβ+IELs细胞比例增加,TCRγδ+IELs比例下降,IELs总CD26/DPP4表达增加(P<0.05)。与HFD组相比,HFD+CDCA组小鼠体质量增加,口服糖耐量异常,胃肠激素分泌减弱(P<0.05);肠组织FXR mRNA及蛋白表达增加,Gcg mRNA表达及GLP-1分泌降低(P<0.05);肠道炎性因子表达降低,TCRαβ+IELs、TCRαβ+CD8αα+IELs与TCRαβ+CD8αβ+IELs细胞比例下降,TCRγδ+IELs占IELs比例升高,IELs总CD26/DPP4表达升高(P<0.05),以上作用在加入FXR拮抗剂Z-Gug后被明显抑制(P<0.05)。结论 CDCA可能通过激活FXR受体抑制肠道组织GLP-1表达,减少GLP-1分泌;同时可能抑制相关炎症因子表达调节IELs亚群比例,上调CD26/DPP4表达水平,促进GLP-1降解,加重胰岛素抵抗。

GLP-1R基因多态性与血压钠钾反应性的相关性分析

目的 研究胰高血糖素样肽-1受体(GLP-1R)基因遗传变异与血压钠钾反应性的关系。方法 2004年在陕西眉县共招募了来自124个家系的514名受试者,并建立了“盐敏感性高血压研究队列”。对受试者进行了为期3 d的正常饮食、7 d的低盐饮食、7 d的高盐饮食和7 d的高盐补钾饮食干预,并测量不同干预期的血压,并采集外周血标本。此外,采用MassARRAY检测平台对GLP-1R基因的8个单核苷酸多态性(SNP)进行了分型检测。结果 GLP-1R基因SNP rs9462472与低盐期的收缩压、舒张压和平均动脉压反应呈显著相关性。而SNP rs2268637则与高盐期的收缩压反应呈显著相关性。此外,SNP rs2268637还与高盐补钾饮食期的收缩压和平均动脉压反应呈显著相关性。结论 GLP-1R基因的多态性与血压钠钾反应性密切相关,提示其参与调节血压盐敏感性及钾反应性的发生与发展。

Review on the Effect of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease（NAFLD） is a common liver disease and it represents the hepatic manifestation of metabolic syndrome, which includes type 2 diabetes mellitus（T2DM）, dyslipidemia, central obesity and hypertension. Glucagon-like peptide-1（GLP-1） analogues and dipeptidyl peptidase-4（DPP-4） inhibitors were widely used to treat T2 DM. These agents improve glycemic control, promote weight loss and improve lipid metabolism. Recent studies have demonstrated that the GLP-1 receptor（GLP-1R） is present and functional in human and rat hepatocytes. In this review, we present data from animal researches and human clinical studies that showed GLP-1 analogues and DPP-4 inhibitors can decrease hepatic triglyceride（TG） content and improve hepatic steatosis, although some effects could be a result of improvements in metabolic parameters. Multiple hepatocyte signal transduction pathways and m RNA from key enzymes in fatty acid metabolism appear to be activated by GLP-1 and its analogues. Thus, the data support the need for more rigorous prospective clinical trials to further investigate the potential of incretin therapies to treat patients with NAFLD.

Mutated recombinant human glucagon-like peptide-1 induces differentiation of PC12 cells

Glucagon-like peptide-1 （GLP-1） and its long-acting analogues have neuroprotective and neurotrophic properties and are emerging as potential treatments for neurodegenerative diseases. Its short half-life has limited the application of GLP-1 in the clinic. We generated a mutated form of human GLP-1 （mGLP-1） using site-directed mutagenesis and gene recombination techniques, and found that these modifications significantly prolonged the biological half-life of GLP-1 compared with native GLP-1 （nGLP-1）. This study investigated the role of mGLP-1 on inducing PC12 cell differentiation, mGLP-1 induced PC12 cell differentiation with neurite outgrowth and increased the expression of growth-associated protein-43 and neuronal class III I^-tubulin, and significantly increased cyclic adenosine monophosphate level. No significant difference was found between mGLP-1 and nGLP-I. The results indicate that mGLP-1 activates the GLP-1 receptor, induces PC12 cell differentiation, and has neurotrophic effects.