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.

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.

Modulating effects of RAMPs on signaling profiles of the glucagon receptor family

Receptor activity-modulating proteins(RAMPs)are accessory molecules that form complexes with specific G protein-coupled receptors(GPCRs)and modulate their functions.It is established that RAMP interacts with the glucagon receptor family of GPCRs but the underlying mechanism is poorly understood.In this study,we used a bioluminescence resonance energy transfer(BRET)approach to comprehensively investigate such interactions.In conjunction with c AMP accumulation,Gaqactivation andβ-arrestin1/2 recruitment assays,we not only verified the GPCR-RAMP pairs previously reported,but also identified new patterns of GPCR-RAMP interaction.While RAMP1 was able to modify the three signaling events elicited by both glucagon receptor(GCGR)and glucagon-like peptide-1 receptor(GLP-1 R),and RAMP2 mainly affectedβ-arrestin1/2 recruitment by GCGR,GLP-1 R and glucagon-like peptide-2 receptor,RAMP3 showed a widespread negative impact on all the family members except for growth hormone-releasing hormone receptor covering the three pathways.Our results suggest that RAMP modulates both G protein dependent and independent signal transduction among the glucagon receptor family members in a receptor-specific manner.Mapping such interactions provides new insights into the role of RAMP in ligand recognition and receptor activation.

Crystal structure of full-length human glucagon receptor reveals novel receptor activation mechanisms

Subject Code:C05With the support by the National Natural Science Foundation of China,a team of scientists let by Profs.Wu Beili(吴蓓丽),Wang Mingwei and Jiang Hualiang from Shanghai Institute of Materia Medica,Chinese Academy of Sciences has determined the high-resolution atomic structure of a full-length class B

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.

Effects of glucagon-like peptide-1 receptor agonists on renal function

Glucagon-like peptide-1(GLP-1)receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus.A number of case reports show an association of GLP-1receptor agonists,mainly exenatide,with the development of acute kidney injury.The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function,their use in subjects with chronic renal failure and their possible association with acute kidney injury.Based on the current evidence,exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease.Liraglutide is not eliminated by renal or hepatic mechanisms,but it should be used with caution since there are only limited data in patients with renal or hepatic impairment.There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering effect.Additionally,there is evidence that GLP-1 receptor agonists influence water and electrolyte balance.These effects may represent new ways to improve or even prevent diabetic nephropathy.

Glucagon-like peptide-1 receptor agonists favorably address all components of metabolic syndrome

Cardiovascular death is the leading cause of mortality for patients with type 2 diabetes mellitus. The etiologyof cardiovascular disease in diabetes may be divided into hyperglycemia per se and factors operating through components of metabolic syndrome(Met S). Hyperglycemia causes direct injury to vascular endothelium and possibly on cardiac myocytes. Met S is a cluster of risk factors like obesity, hyperglycemia, hypertension and dyslipidemia. The incidence of this syndrome is rising globally. Glucagon-like peptide-1 receptor agonists(GLP-1RA) are a group of drugs, which address all components of this syndrome favorably. Experimental evidence suggests that they have favorable actions on myocardium as well. Several compounds belonging to GLP-1RA class are in market now and a large number awaiting their entry. Although, originally this class of drugs emerged as a treatment for type 2 diabetes mellitus, more recent data generated revealed beneficial effects on multiple metabolic parameters. We have studied literature published between 2000 and 2016 to look into effects of GLP-1RA on components of Met S. Results from recently concluded clinical trials suggest that some of the molecules in this class may have favorable effects on cardiovascular outcome.

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.

Development of therapeutic options on type 2 diabetes in years:Glucagon-like peptide-1 receptor agonist’s role intreatment; from the past to future

Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia.Type 2 diabetes (T2DM) accounting for 90% of cases globally.The worldwide prevalence of DM is rising dramatically over the last decades,from 30 million cases in 1985 to 382 million cases in 2013.It’s estimated that 451 million people had diabetes in 2017.As the pathophysiology was understood over the years,treatment options for diabetes increased.Incretin-based therapy is one of them.Glucagon-like peptide-1 receptor agonist (GLP-1 RA) not only significantly lower glucose level with minimal risk of hypoglycemia but also,they have an important advantage in themanagement of cardiovascular risk and obesity.Thus,we will review here GLP-1 RAsrole in the treatment of diabetes.

Glucagon peptide-like 1 receptor (GLP-1R) expression per se: a new insight into neurodegenerative disease?

Glucagon peptide-like 1（GLP-1）and GLP-1 receptor（GLP-1R）：GLP-1 is an incretin hormone secreted from gut L cells.GLP-1 exerts its action through binding to its specific receptor,GLP-1R,which is a member of the G protein-coupled receptor superfamily.GLP-1R is reportedly expressed in various organs,such as the liver,kidney,and peripheral tissues.

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。

司美格鲁肽对2型糖尿病合并超重及肥胖患者的胰腺和肝脏脂肪含量以及胰岛β细胞功能的影响

目的探讨司美格鲁肽对2型糖尿病(T2DM)合并超重及肥胖患者的血糖控制、胰腺和肝脏脂肪含量以及胰岛β细胞功能的影响。方法采用单中心、前瞻性、临床病例对照试验的方法,选取2021年10月至2022年10月在金华市中心医院诊断为T2DM合并超重(BMI 25~<28 kg/m2)及肥胖(BMI≥28 kg/m2)的86例患者为研究对象,均接受稳定剂量的二甲双胍单药或联合口服用药至少3个月,糖化血红蛋白(HbA1C)为6.5%~8.0%。采用随机数字表法将患者分为对照组和观察组,各43例。对照组继续原方案口服降糖,观察组在原方案的基础上联合司美格鲁肽(起始剂量0.25 mg,4周后增加至0.5 mg并稳定,1次/周,皮下注射)。两组均干预24周。比较两组患者血糖(FPG、餐后2 h血糖和HbA1C)、血脂(TC、TG、LDL-C、HDL-C)、BMI、腰围、胰岛细胞功能[空腹胰岛素(FINS)、胰岛β细胞功能指数(HOMA-β)和胰岛素抵抗指数(HOMA-IR)]。通过非对称回波的最小二乘估算法迭代水脂分离序列测量胰头、胰体和胰尾的胰腺脂肪分数(PFF),计算平均PFF并进行组间比较;测量肝脏右上、右下和左叶的肝脏脂肪分数(HFF),计算平均HFF并进行组间比较。结果对照组39例和观察组40例随访至研究结束。治疗后观察组患者FPG、餐后2 h血糖、HbA1C、BMI、FINS、HOMA-IR、平均PFF和平均HFF均低于对照组,而HOMA-β高于对照组,差异均有统计学意义(均P<0.01)。结论司美格鲁肽应用方便,对T2DM合并超重及肥胖患者能够在常规降糖药的基础上进一步改善胰岛素和胰岛β细胞功能,降低血糖水平、胰腺和肝脏脂肪含量,同时可产生额外的减重获益。

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。

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。

胰高血糖素样肽-1类似物研发进展

目的总结胰高血糖素样肽-1(GLP-1)类似物的研发进展。方法检索PubMed和Web of Science数据库自建库起至2024年2月20日的GLP-1类似物相关文献,从研发概况、单分子多靶点GLP-1受体激动剂(GLP-1RA)、除治疗糖尿病外的其他适应证及其药物研发新趋势方面,总结GLP-1类似物的研发进展。结果与结论GLP-1类似物的研发经历了从短效到长效,从注射剂到口服剂,并扩展到多靶点治疗的过程。目前,多靶点GLP-1RA包括GLP-1R/葡萄糖依赖性促胰岛素释放多肽受体、GLP-1R/胰高血糖素受体(GCGR)、GLP-1R/GLP-2R、GLP-1R/胰淀素3受体(AMY3R)、GLP-1R/成纤维细胞生长因子21受体(FGF-21R)等双靶点激动剂,以及GLPR/GLP-1R/GCGR、GLP-1R/GCGR/FGF-21R等三靶点激动剂。GLP-1类似物展现了在2型糖尿病、超重、肥胖症、心血管疾病、多囊卵巢综合征、非酒精性脂肪性肝炎、慢性肾脏病等疾病治疗的巨大潜力,疗效优于单靶点的双靶点和三靶点GLP-1RA是近年来研发的重点。GLP-1类似物的重组腺相关病毒载体基因治疗为研发新趋势,其现阶段存在的安全性、依从性等问题和可供参考的解决方法也一并被提出。

干预代谢危险因素对脑血管病影响的研究进展

代谢危险因素是脑血管病的重要影响因素。随着代谢性脑血管病概念的提出,如何通过干预代谢危险因素改善此类患者的预后是未来重要的研究方向。代谢危险因素可相互影响并协同作用,降压、调脂、控制血糖等对传统代谢危险因素的干预可有效降低脑血管病的发病率和复发率;抗炎、补充维生素、调节肠道菌群等对残余代谢危险因素的干预同样是影响脑血管病发病及预后的重要措施。新型代谢药物“一专多能”的特点为代谢性脑血管病的治疗和管理提供了新的思路。本综述总结干预代谢危险因素对脑血管病影响的循证医学证据,旨在为代谢性脑血管病的管理提供更多理论支持。

胰高血糖素样肽2受体基因对肝癌的预后及免疫浸润的影响

目的通过生物信息学方法研究胰高血糖素样肽2受体(glucagon like peptide 2 receptor,GLP2R)在肝癌(Hepatocellular carcinoma,HCC)组织与正常肝脏组织中的差异表达,探寻其在肝癌预后和免疫细胞浸润的作用。方法使用TIMER 2.0数据库探寻GLP2R在各种肿瘤组织及其对应正常组织中的表达差异性;下载TCGA数据库的肝细胞肝癌数据集,使用R软件探究GLP2R在肝癌组织与正常组织中的表达差异性,绘制Kaplan-Meier生存曲线分析GLP2R表达水平与HCC预后的关系;使用R软件对肝癌数据集分析得到差异基因;使用STRING和Cytoscape构建GLP2R与差异基因互作网络,获取关键基因;对GLP2R与关键基因做单因素与多因素Cox回归分析;对GLP2R与关键基因行GO分析富集通路;使用TIMER2.0数据库,探究GLP2R与TIMER、CIBERSORT中免疫细胞浸润的相关性,利用CIBERSORT进一步分析肝癌中浸润免疫细胞的差异性。结果与正常组织相比,肝癌组织GLP2R的mRNA表达水平下调;低表达GLP2R的肝癌患者预后较好,GLP2R可作为肝癌患者不良预后的独立预测因子;GO富集分析显示GLP2R相关基因主要富集在细胞对胰高血糖素刺激的反应等生物过程中;肝癌组织中GLP2R的表达与CD8^(+)T细胞的免疫浸润水平呈负相关。结论GLP2R在肝癌组织中低表达,低表达的GLP2R与肝癌患者较好预后相关,并且影响HCC免疫浸润水平。GLP2R基因可作为HCC潜在的免疫治疗靶点。

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。