Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease:Opportunities and challenges

Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide,paralleling the rising pandemic of obesity and type 2 diabetes.Due to the growing global health burden and com-plex pathogenesis of MASLD,a multifaceted and innovative therapeutic approach is needed.Incretin receptor agonists,which were initially developed for diabetes management,have emerged as promising candidates for MASLD treatment.This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists:glucagon-like peptide-1 receptor agonists,glucose-dependent insulinotropic polypeptide receptor agonists,and glucagon receptor agonists.Incretins and glucagon directly or indirectly impact various organs,including the liver,brain,pancreas,gastro-intestinal tract,and adipose tissue.Thus,these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis.Importantly,this study provides a summary of clinical trials analyzing the effect-iveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function,hepatic steatosis,and intrahepatic inflammation.There are emerging challenges associated with the use of these medications in the real world,particularly adverse events,drug-drug interactions,and barriers to access,which are discussed in detail.Additionally,this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.

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.

Vascular endothelial growth factor B improves impaired glucose tolerance through insulin-mediated inhibition of glucagon secretion

BACKGROUND Impaired glucose tolerance(IGT)is a homeostatic state between euglycemia and hyperglycemia and is considered an early high-risk state of diabetes.When IGT occurs,insulin sensitivity decreases,causing a reduction in insulin secretion and an increase in glucagon secretion.Recently,vascular endothelial growth factor B(VEGFB)has been demonstrated to play a positive role in improving glucose metabolism and insulin sensitivity.Therefore,we constructed a mouse model of IGT through high-fat diet feeding and speculated that VEGFB can regulate hyperglycemia in IGT by influencing insulin-mediated glucagon secretion,thus contributing to the prevention and cure of prediabetes.AIM To explore the potential molecular mechanism and regulatory effects of VEGFB on insulin-mediated glucagon in mice with IGT.METHODS We conducted in vivo experiments through systematic VEGFB knockout and pancreatic-specific VEGFB overexpression.Insulin and glucagon secretions were detected via enzyme-linked immunosorbent assay,and the protein expression of phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)was determined using western blot.Further,mRNA expression of forkhead box protein O1,phosphoenolpyruvate carboxykinase,and glucose-6 phosphatase was detected via quantitative polymerase chain reaction,and the correlation between the expression of proteins was analyzed via bioinformatics.RESULTS In mice with IGT and VEGFB knockout,glucagon secretion increased,and the protein expression of PI3K/AKT decreased dramatically.Further,in mice with VEGFB overexpression,glucagon levels declined,with the activation of the PI3K/AKT signaling pathway.CONCLUSION VEGFB/vascular endothelial growth factor receptor 1 can promote insulin-mediated glucagon secretion by activating the PI3K/AKT signaling pathway to regulate glucose metabolism disorders in mice with IGT.

三焦针法对原发性失眠大鼠Glu、GABA表达平衡的影响

目的:观察三焦针法对原发性失眠大鼠下丘脑组织谷氨酸(glutamic acid,Glu)、γ-氨基丁酸能神经元(gamma-aminobutyric acid,GABA)表达的影响,探讨三焦针法治疗PI的作用机制。方法:SD雄性大鼠随机分为空白组、模型组、地西泮组和三焦组,每组6只。除正常组外,其余各组采用“PCPA腹腔注射方式”建立PI大鼠模型。地西泮组予地西泮灌胃(0.9 mg/kg),三焦组针刺膻中、中脘、气海、血海(双侧)及足三里(双侧),诸穴行捻转补法30 s,1次/d,均治疗14 d。观察大鼠一般状态;测定大鼠体质量;Elisa法检测下丘脑组织Glu、GABA表达。结果:与空白组相比,PI模型大鼠一般状态较差,体质量显著降低(P<0.01),下丘脑组织中Glu表达水平显著升高(P<0.01)、GABA表达水平显著降低(P<0.01)。与模型组比较,地西泮组、三焦组大鼠体质量显著升高(P<0.01,P<0.05),下丘脑组织中Glu表达水平显著降低(P<0.01)、GABA表达水平显著升高(P<0.01),地西泮组与三焦组比较无统计学意义(P>0.05)。结论:三焦针法可改善PI大鼠失眠症状,这可能与调节下丘脑组织中Glu、GABA表达水平有关。

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.

方氏头针结合子午流注纳子法对失眠患者血清GABA、Glu及睡眠质量的影响

目的:探索方氏头针结合子午流注纳子法治疗失眠症的疗效,并探讨其可能的机制。方法:选择60例失眠症患者随机分为观察组(30例)和对照组(30例,脱落1例)。对照组给予常规针刺,观察组给予方氏头针结合子午流注纳子法针刺治疗。两组患者1次/d,每周5次,连续2周。分别于治疗前后评定匹兹堡睡眠质量指数量表(PSQI)评分、血清γ-氨基丁酸(GABA)及谷氨酸(Glu)的变化情况。结果:治疗2周,两组患者PSQI均较治疗前下降,差异有统计学意义(P<0.05)。治疗后血清GABA水平较治疗前比较均有所上升,Glu水平较治疗前比较均有所下降。方氏头针联合子午流注纳子法组在血清GABA水平上与常规针刺组比较,差异具有统计学意义(P<0.05)。结论:方氏头针结合子午流注纳子法治疗失眠确有疗效,能够明显地改善患者的临床症状,其机制可能与调节血清GABA、Glu水平有关。

84例NIDDM辨证分型与IR Glucagon的关系

非胰岛素依赖型糖尿病（ＮＩＤＤＭ）的病因目前尚不十分清楚，近年的研究表明，胰岛素抵抗（Ｉｎｓｕｌｉｎｒｅｓｉｓｔａｎｃｅ，ＩＲ）、胰升糖素（Ｇｌｕｃａｇｏｎ）分泌异常与ＮＩＤＤＭ的发生、发展密切相关。笔者观察了８４例ＮＩＤＤＭ患者临床辨证分型的情况及其与胰岛素抵抗、胰升糖素分泌异常的关系，并与正常组作了对比。结果表明：①气阴两虚型是ＮＩＤＤＭ的常见证型。阴虚热盛型、气阴两虚型与阴阳两虚型均存在胰岛素抵抗和胰升糖素分泌异常，但各证型在程度上存在不同，提示各证型有着不同的病理生理特点。②对气阴两虚型的进一步观察证实，即使是同一证型，由于兼挟证的不同，其病理生理改变亦存在不同。气阴两虚兼燥热偏盛型其胰岛素抵抗、胰岛素分泌缺陷和胰升糖素分泌异常均较气阴两虚非燥热偏盛型更为明显。提示燥热偏盛与上述三者的改变有一定的联系。

玉米肽和有氧运动对肥胖大鼠血浆Glucagon、MCP-1、PP和PYY水平的影响

目的 通过观察玉米肽和有氧运动对肥胖大鼠血浆内胰高血糖素（Glucagon）、单核细胞趋化蛋白-1 （monocyte chemoattractant protein-1,MCP-1）、胰多肽（Pancreatic polypeptide,PP）和酪酪肽（Peptide YY,PYY）水平的影响,探讨其减控大鼠体质量的可能激素相关机制.方法 雄性SD大鼠150只,随机选取15只作为普通饲料组（C组）,给予普通饲料,其余135只给予高脂饲料以建肥胖模型.8周后将40只雄性肥胖大鼠随机分为肥胖对照组（OC组）、酪蛋白组（Cas组）、玉米肽组（CP组）、运动组（OE组）和玉米肽运动组（OEC组）,其中OE组和OEC组进行4周的有氧运动.使用ELISA方法检测血浆中Glucagon、MCP-1、PP和PYY水平.结果 建模成功后经过4周干预,OC组大鼠体质量显著高于C组,OE组和OEC组大鼠体质量与OC组相比显著降低.OC组大鼠血Glucagon水平与C组无显著差异,CP组大鼠血Glucagon水平与OC组相比显著降低.OC组大鼠血MCP-1水平显著高于C组,CP组、OE组和OEC组与OC组大鼠血MCP-1水平相比显著降低.OC组大鼠血PYY水平均显著低于C组,OEC组大鼠血PYY水平显著高于OC组和CP组;各组大鼠间血PP水平均无显著性差异.结论 单纯服用玉米肽可以降低肥胖大鼠血Glucagon和MCP-1水平.玉米肽结合有氧运动可降低肥胖大鼠体质量以及血液内的MCP-1水平,并提高肥胖大鼠血液内PYY水平.

Glu-D1d与Wx-B1b基因聚合在强筋小麦育种中的利用

Glu-D1d与Wx-B1b基因遗传效应是面包面条兼用型强筋小麦的主要遗传基础,二者聚合可实现蛋白质(面筋)质量和淀粉特性的同步改良,并拓宽和提升强筋小麦的加工用途和商品价值。本文总结了Glu-D1d与Wx-B1b基因及其聚合对强筋小麦品质的影响,并对两个基因聚合育种策略和注意事项进行探讨,以期为面包面条兼用型强筋小麦育种提供理论依据和实践经验。

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.

宁神安脏饮对失眠大鼠模型行为学和下丘脑GABA及GLU表达的影响

目的探讨宁神安脏饮对肝郁脾虚型失眠大鼠行为学变化和下丘脑伽γ-氨基丁酸(GABA)及谷氨酸(GLU)表达的影响。方法采用夹尾刺激+饮食失联+PCPA多因素制备肝郁脾虚型失眠大鼠模型。将80只大鼠随机分为正常组、模型组、宁神安脏饮组和艾司唑仑组,正常组及模型组给予等体积生理盐水灌胃,宁神安脏饮组大鼠按每次2.28 g/kg灌胃给药,艾司唑仑组大鼠每次按剂量0.18 mg/kg灌胃给药,分别于实验第0、7、14、21天检测各组大鼠的体重,于第21天进行各组大鼠糖水偏好实验、旷场实验及Morris水迷宫实验,测试各组大鼠的行为学表现;应用透射电镜观察下丘脑组织结构的变化,免疫组织化学方法观察失眠21d后各组大鼠下丘脑γ-氨基丁酸(GABA)和谷氨酸(GLU)阳性细胞数。结果与正常组比较,模型组大鼠一般状态、体重、糖水消耗和糖水偏好率、旷场活动能力明显降低,水迷宫平均逃避潜伏期明显升高(P<0.05),透射电镜观察脑组织线粒体、内质网水肿;经给药干预后,与模型组比较,宁神安脏饮组和艾司唑仑组可改善大鼠的一般状态、体重、糖水消耗和糖水偏好率、旷场活动能力,降低水迷宫平均逃避潜伏期(P<0.05),透射电镜观察下丘脑组织结构明显改善。免疫组化结果表明,与正常组比较,模型组下丘脑GABA和GLU的阳性细胞数降低(P<0.05);与模型组比,宁神安脏饮组和艾司唑仑组GABA和GLU的阳性细胞数均升高(P<0.05)。结论宁神安脏饮可明显改善肝郁脾虚型大鼠的行为学,激发大鼠自发活动能力和探究能力,改善脑组织超微结构,其作用机制可能与调节失眠大鼠下丘脑GABA和GLU的含量有关。

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.

Effects of somatostatin analog on splanchnic hemodynamics and plasma glucagon level in portal hypertensive rats

IM To investigate the effects of somatostatin analog on splanchnic hemodynamics and plasma glucagon level in portal hypertensive rats.METHODS Twentyeight male SpragueDawley rats were divided into two groups: intrahepatic portal hypertension (IHPH, n=14) by injection of CCl4 and prehepatic portal hypertension (PHPH, n=14) by stenosis of the portal vein. Animals of each group were divided into two subgroups: injection of octreotide and injection of normal saline. Seven agematched normal rats served as controls. The mean systemic arterial pressure (MSAP) and free portal venous pressure (FPP) were measured. The splanchnic blood flow was detected by injection of toad blood red cell labelled with 51Cr and 125I·T3. The concentration of plasma glucagon was determined by radioimmunoassay.RESULTS Octreotide significantly decreased both the splanchnic blood flow and FPP in portal hypertensive rats, and markedly increased splanchnic vascular and portal venous resistance. Octreotide did not significantly lower the plasma glucagon levels in both the peripheral and the portal veins.CONCLUSION The decreased splanchnic blood flow induced by octreotide in portal hypertensive rats results mainly from direct vasoconstriction but less from decreased plasma glucagon level.

强筋小麦龙麦26Glu-A3d基因遗传效应初步研究

龙麦26是东北春麦区强筋小麦育种的核心亲本,为进一步提高该品种品质潜力,拓宽其遗传基础,利用分子标记和6次选择性回交相结合的手段,将Glu-A3位点最优基因Glu-A3d导入龙麦26遗传背景之中,利用BC5F1、BC6F1群体和龙麦26的Glu-A3位点近等基因系为试材进行Glu-A3d基因遗传效应评价。结果表明,在强筋小麦品种龙麦26遗传背景下,导入Glu-A3d基因使籽粒蛋白、干面筋、面筋指数、吸水率、形成时间和稳定时间等指标3年平均分别提高0.07%、-2.13%、10.73%、0.13%、1.57%和4.97%。Zeleny沉降值和粉质仪的断裂时间2年平均分别提高3.05%和12.65%。以上结果表明,导入Glu-A3d基因使龙麦26品质性状均有不同程度提高。

EFFECTS OF GLUCAGON ON ISLET β CELL FUNCTION IN PATIENTS WITH DIABETES MELLITUS

Objective To evaluate islet β cell response to intravenous glucagon （ a non-glucose secretagogue） stimulation in diabetes mellitus. Methods Nineteen patients with type 1 diabetes （T1 D） and 131 patients with type 2 diabetes （T2D） were recruited in this study. T2D patients were divided into two groups according to therapy： 36 cases treated with insulin and 95 cases treated with diet or oral therapy. The serum C-peptide levels were determined at fasting and six minutes after intra- venous injection of 1 mg of ghicagon. Results Both fasting and 6-minute post-ghicagon-stimulated C-peptide levels in T1D patients were significantly lower than those of T2D patients （0. 76±0. 36 ng/mL vs. 1.81±0. 78 ng/mL, P 〈 0.05 ; 0.88±0.42 ng/mL vs. 3.68±0. 98 ng/mL, P 〈 0. 05 ）. In T1D patients, the C-peptide level after injection of ghicagon was similar to the fasting level. In T2D, patients treated with diet or oral drug had a significantly greater fasting and stimulated C-peptide level than those patients received insulin therapy （2.45±0. 93 ng/mL vs. 1.61±0. 68 ng/mL, P 〈 0.05 ; 5.26±1.24 ng/mL vs. 2.15±0.76 ng/mL, P 〈 0.05 ）. The serum C-peptide level after ghicagon stimulation was positively correlated with C-peptide levels at fasting in all three groups （ r = 0.76, P 〈 0.05 ）. Conclusions The 6-minute ghicagon test is valuable in assessing the function of islet β cell in patients with diabetes mellitus. It is helpful for diagnosis and treatment of diabetes mellitus.

Effects of Electroacupuncture at Weiwanxiashu and Zusanli Points on Blood Glucose and Plasma Pancreatic Glucagon Contents in Diabetic Rabbits

The Effects of electroacupuncture (EA) at Weiwanxiashu (EX-B3) and Zusanli (ST 36) points on blood glucose (BG) and plasma pancreatic glucagon (PG) contents were dynamically observed in diabetic rabbits induced by Alloxan. It is found that acupuncture at Weiwanxiashu point can significantly lower the BG content and inhibit release of PG; no significant changes in BG and PG are found when acupuncture is given at Zusanli (ST 36) point alone, however BG and PG contents decrease more obviously when acupuncture employed at both Zusanli and Weiwanxiashu, suggesting that Zusanli has a marked synergetic action with Weiwanxiashu.

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 fat content 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. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

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-2 protects impaired intestinal mucosal barriers in obstructive jaundice rats

AIM: To observe the protective effect of glucagon-like peptide-2(GLP-2) on the intestinal barrier of rats with obstructive jaundice and determine the possible mechanisms of action involved in the protective effect.METHODS: Thirty-six Sprague-Dawley rats were randomly divided into a sham operation group, an obstructive jaundice group, and a GLP-2 group; each group consisted of 12 rats. The GLP-2 group was treated with GLP-2 after the day of surgery, whereas the other two groups were treated with the same concentration of normal saline. Alanine aminotransferase(ALT), total bilirubin, and endotoxin levels were recorded at 1, 3, 7, 10 and 14 d. Furthermore, on the 14 th day, body weight, the wet weight of the small intestine, pathological changes of the small intestine and the immunoglobulin A(Ig A) expressed by plasma cells located in the small intestinal lamina propria were recorded for each group.RESULTS: In the rat model, jaundice was obvious, and the rats' activity decreased 4-6 d post bile duct ligation. Compared with the sham operation group, the obstructive jaundice group displayed increased yellow staining of abdominal visceral serosa, decreased small intestine wet weight, thinning of the intestinal muscle layer and villi, villous atrophy, uneven height, fusion, partial villous epithelial cell shedding, substantial inflammatory cell infiltration and significantly reduced Ig A expression. However, no significant gross changes were noted between the GLP-2 and sham groups. With time, the levels of ALT, endotoxin and bilirubin in the GLP-2 group were significantly increased compared with the sham group(P < 0.01). The increasing levels of the aforementioned markers were more significant in the obstructive jaundice group than in the GLP-2 group(P < 0.01).CONCLUSION: GLP-2 reduces intestinal mucosal injuries in obstructive jaundice rats, which might be attributed to increased intestinal Ig A and reduced bilirubin and endotoxin.

Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity

Though the pathophysiology of clinical obesity is un-doubtedly multifaceted, several lines of clinical evidence implicate an important functional role for glucagon-like peptide 1(GLP-1) signalling. Clinical studies assessing GLP-1 responses in normal weight and obese subjects suggest that weight gain may induce functional deficits in GLP-1 signalling that facilitates maintenance of the obesity phenotype. In addition, genetic studies implicate a possible role for altered GLP-1 signalling as a risk factor towards the development of obesity. As reductions in functional GLP-1 signalling seem to play a role in clinical obesity, the pharmacological replenishment seems a promising target for the medical management of obesity in clinical practice. GLP-1 analogue liraglutide at a high dose(3 mg/d) has shown promising results in achieving and maintaining greater weight loss in obese individuals compared to placebo control, and currently licensed antiobesity medications. Generally well tolerated, provided that longer-term data in clinical practice supports the currently available evidence of superior short- and longterm weight loss efficacy, GLP-1 analogues provide promise towards achieving the successful, sustainable medical management of obesity that remains as yet, an unmet clinical need.