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

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World Journal of Gastroenterology 2024年第23期30卷 2964-2980页

作者： Jakub Rochoń Piotr Kalinowski Ksenia Szymanek-Majchrzak MichałGrąt Department of General Transplant and Liver SurgeryMedical University of WarsawWarsaw 02-097Poland Department of Medical Microbiology Medical University of WarsawWarsaw 02-004Poland

Metabolic dysfunction-associated fatty liver disease(MAFLD)is a hepatic manifestation of the metabolic *** is one of the most common liver diseases worldwide and shows increasing prevalence rates in most *** is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular *** microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver *** mechanisms involved in maintaining gut-liver axis homeostasis are *** critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gutliver axis *** increase in intestinal barrier permeability induces metabolic endotoxemia that leads to ***,alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and ***-like peptide-1 receptor agonists(GLP-1 RAs)are a class of drugs developed for the treatment of type 2 diabetes *** are also commonly used to combat obesity and have been proven to be effective in reversing hepatic *** 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 ***,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 *** 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.

关键词： Metabolic dysfunction-associated fatty liver disease Metabolic dysfunction-associated steatohepatitis Nonalcoholic fatty liver disease Non-alcoholic steatohepatitis Metabolic syndrome Obesity Gastrointestinal microbiota glucagon-like peptide-1 glucagon-like peptide-2 Bariatric surgery

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Intestinal glucagon-like peptide-1:A new player associated with impaired counterregulatory responses to hypoglycaemia in type 1 diabetic mice

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World Journal of Diabetes 2024年第8期15卷 1764-1777页

作者： Fang-Xin Jin Yan Wang Min-Ne Li Ru-Jiang Li Jun-Tang Guo Department of Histology and Embryology Key Laboratory of Universities in Shandong ProvinceShandong Second Medical UniversityWeifang 261053Shandong ProvinceChina Department of Pathological Physiology Shandong Second Medical UniversityWeifang 261053Shandong ProvinceChina

BACKGROUND Impaired hypoglycaemic counterregulation has emerged as a critical concern for diabetic patients who may be hesitant to medically lower their blood glucose levels due to the fear of potential hypoglycaemic ***,the pathogenesis of hypoglycaemic counterregulation is still ***-like peptide-1(GLP-1)and its analogues have been used as adjunctive therapies for type 1 diabetes mellitus(T1DM).The role of GLP-1 in counterregulatory dysfunction during hypoglycaemia in patients with T1DM has not been *** To explore the impact of intestinal GLP-1 on impaired hypoglycaemic counterregulation in type 1 diabetic *** T1DM was induced in C57BL/6J mice using streptozotocin,followed by intraperitoneal insulin injections to create T1DM models with either a single episode of hypoglycaemia or recurrent episodes of hypoglycaemia(DH5).Immunofluorescence,Western blot,and enzyme-linked immunosorbent assay were employed to evaluate the influence of intestinal GLP-1 on the sympathetic-adrenal reflex and glucagon(GCG)*** GLP-1 receptor agonist GLP-1(7-36)or the antagonist exendin(9-39)were infused into the terminal ileum or injected intraperitoneally to further investigate the role of intestinal GLP-1 in hypoglycaemic counterregulation in the model *** The expression levels of intestinal GLP-1 and its receptor(GLP-1R)were significantly increased in DH5 *** instances of excess of intestinal GLP-1 weakens the sympathetic-adrenal reflex,leading to dysfunction of adrenal counterregulation during ***5 mice showed increased pancreaticδ-cell mass,cAMP levels inδcells,and plasma somatostatin concentrations,while cAMP levels in pancreaticαcells and plasma GCG levels ***,GLP-1R expression in islet cells and plasma active GLP-1 levels were significantly increased in the DH5 *** experiments involving terminal ileal infusion and intraperitoneal injection in the model mice demonstra

关键词： glucagon-like peptide-1 Impaired hypoglycaemic counterregulation Type 1 diabetes Intestine Pancreas

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

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World Journal of Diabetes 2024年第5期15卷 818-822页

作者： Lorenzo Nesti Domenico Trico Department of Clinical and Experimental Medicine University of PisaPisa 56126Italy Laboratory of Metabolism Nutritionand AtherosclerosisUniversity of PisaPisa 56126Italy

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 ***,while evidence about atherosclerosis consistently suggests a cardioprotective potential with class effect,controversies remain on its impact on heart ***1 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 ***,weight loss alone achieved through GLP1 receptor agonists has failed in improving left ventricular *** 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 *** this class of therapies is going to change the history of heart failure is an ongoing debate.

关键词： Atherosclerosis Cardiovascular system glucagon-like peptide-1 Heart failure Tirzepatide Type 2 diabetes Ventricular function Left

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Significance of serum glucagon-like peptide-1 and matrix Gla protein levels in patients with diabetes and osteoporosis

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World Journal of Clinical Cases 2022年第5期10卷 1527-1535页

作者： Fei-Fei Xie Yu-Fang Zhang Yan-Fang Hu Yun-Yun Xie Xiao-Ying Wang Shu-Zhen Wang Bao-Qiang Xie Department of Endocrinology Guangdong Provincial People’s Hospital Ganzhou Hospital(Ganzhou Municipal Hospital)Ganzhou 341000Jiangxi ProvinceChina

BACKGROUND Osteoporosis is a systemic bone disease characterized by decreased bone mass,impaired bone mass,and reduced bone strength that leads to increased bone fragility and *** 2 diabetes mellitus(T2DM)complicated with osteoporosis is a common systemic metabolic bone disease,and reduced bone mass and bone strength are considered the main clinical features;however,the pathogenesis of this disease has not been fully *** occurrence is considered related to sex,age,and genetic *** are many risk factors for diabetes complicated with ***,exploring these risk factors will help prevent *** To investigate the relationships among serum glucagon-like peptide-1(GLP-1)levels,matrix Gla protein(MGP)levels,and diabetes with *** Sixty patients with T2DM complicated with osteoporosis confirmed by the endocrinology department of our hospital were selected as the case *** T2DM patients with bone loss were selected as the control *** healthy participants were selected as the healthy *** general data,bone mineral density index,and bone metabolic markers of the three groups were *** relationships among GLP-1 levels,MGP levels,and the bone mineral density index of the case group were analyzed using linear correlation analysis and a logistic regression *** Differences in sex,smoking,and drinking among the case group,control group,and healthy group were not statistically significant(P>0.05).The mean age of the case group was older than those of the control and healthy groups(P1c level,hypertension rate,and coronary heart disease rate of the case and control groups were higher than those of the healthy group(P1 and MGP levels of the case group were lower than those of the control and healthy groups;these differences were statistically significant(P1 and MGP levels of the control gr

关键词： glucagon-like peptide-1 Matrix Gla protein Diabetes mellitus Osteoporosis Bone mineral density Systemic bone disease

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Improved systemic half-life of glucagon-like peptide-1-loaded carbonate apatite nanoparticles in rats

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World Journal of Diabetes 2022年第8期13卷 613-621页

作者： Nabilah Ibnat Rahela Zaman Mohammad Borhan Uddin Ezharul Chowdhury Chooi Yeng Lee School of Medicine and Health Sciences Monash University MalaysiaSubang Jaya 47500SelangorMalaysia School of Pharmacy Monash University MalaysiaSubang Jaya 47500SelangorMalaysia

BACKGROUND glucagon-like peptide-1(GLP1)is an endogenous peptide that regulates blood glucose *** its susceptibility to rapid metabolic degradation limits its therapeutic *** To prepare GLP1-encapsulated nanosize particle with controlled release property to improve the systemic half-life of *** GLP1 nanoparticles were prepared by complexation of GLP1 with carbonate apatite nanoparticles(CA NPs).The physicochemical properties of the CA NPs,the effects of GLP1-loaded CA NPs on cell viability,and the systemic bioavailability of GLP1 after CA NPs administration were *** The GLP1-loaded CA NPs was within 200 nm in size and stable in fetal bovine *** formulation did not affect the viability of human cell lines suggesting that the accumulation of CA NPs in target tissues is *** Sprague Dawley rats,the plasma GLP1 Levels as measured from the GLP1-loaded CA NPs-treated rats,were significantly higher than that of the control rats and free GLP1-treated rats at 1 h post-treatment(P<0.05),and the level remained higher than the other two groups for at least 4 *** The GLP1-loaded CA NPs improved the plasma half-life of *** systemic bioavailability of GLP1 is longer than other GLP1 nanoparticles reported to date.

关键词： glucagon-like peptide-1 Metabolic syndrome Nanoparticles Plasma half-life Rat

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Correlation between gut microbiota and glucagon-like peptide-1 in patients with gestational diabetes mellitus

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World Journal of Diabetes 2022年第10期13卷 861-876页

作者： Yun-Yi Liang Ling-Yu Liu Yan Jia Yi Li Jie-Na Cai Yi Shu Jing-Yi Tan Pei-Yi Chen Hong-Wei Li Hui-Hua Cai Xiang-Sheng Cai Health Management Center The Sixth Affiliated HospitalSchool of MedicineSouth China University of TechnologyFoshan 528000Guangdong ProvinceChina The First Affiliated Hospital Henan University of Chinese MedicineZhengzhou 450000Henan ProvinceChina Shenzhen Hospital University of Chinese Academy of SciencesShenzhen 518001Guangdong ProvinceChina Clinical Laboratory Puning People’s HospitalPuning 515300Guangdong ProvinceChina Institute of Biotherapy Southern Medical UniversityGuangzhou 510515Guangdong ProvinceChina Department of Obstetrics and Gynecology Guangdong Provincial People's HospitalGuangzhou 510080Guangdong ProvinceChina

BACKGROUND Gestational diabetes mellitus(GDM)places both the mother and offspring at high risk of *** evidence suggests that the gut microbiota plays a role in the pathogenesis of ***,it is still unclear whether the gut microbiota is related to blood biochemical traits,particularly glucagon-like peptide-1(GLP-1),in GDM *** To explore the correlation between the gut microbiota and blood biochemical traits,particularly GLP-1,in GDM *** The V4 region of the 16S ribosomal ribonucleic acid(rRNA)gene was sequenced based on the fecal samples of 35 pregnant women with GDM and was compared to that of 25 pregnant women with normal glucose tolerance(NGT).RESULTS The results showed that Ruminococcaceae_UCG-002,Ruminococcaceae_UCG-005,Clostridium_sensu_stricto_1,and Streptococcus were more abundant in the NGT group than in the GDM *** and Lachnoclostridium were more abundant in the GDM group than in the NGT ***’s correlation analysis was performed to identify the relationships between microbiota genera and blood biochemical ***,Roseburia,Faecalibacterium,and Ruminococcaceae_UCG-002 were significantly negatively correlated with ***_UCG-002 was significantly negatively correlated with hemoglobin *** was significantly positively correlated with ***,Oscillibacter,and Bifidobacterium were significantly positively correlated with GLP-1.A random forest model showed that 20 specific genera plus glucose provided the best discriminatory power,as indicated by the area under the receiver operating characteristic curve(0.94).CONCLUSION The results of this study reveal novel relationships between the gut microbiome,blood biochemical traits,particularly GLP-1,and GDM *** findings suggest that some genera are crucial for controlling blood glucose-related indices and may be beneficial for GDM *** in the microbial composition of the

关键词： Gut microbiome glucagon-like peptide-1 Gestational diabetes mellitus Glucose

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

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Neural Regeneration Research 2011年第6期6卷 457-461页

作者： Jin Wu Lan Zhang Zhongwei Sun Gang Huang Jing Huang Bing Mei Shanghai Key Laboratory of Brain Functional Genomics Key Laboratory of Brain Functional Genomics Ministry of Education East China Normal University Shanghai 200062 China School of Life Science East China Normal University Shanghai 200062 China

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.

关键词： glucagon-like peptide-1 mutated glucagon-like peptide-1 differentiation PC12 cells

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Uncoupling protein 2 regulates glucagon-like peptide-1 secretion in L-cells

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World Journal of Gastroenterology 2012年第26期18卷 3451-3457页

作者： Yan Chen Zheng-Yang Li Yan Yang Hong-Jie Zhang De-partment of Gastroenterology First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029Jiangsu ProvinceChina

AIM:To investigate whether uncoupling protein 2(UCP2) affects oleic acid-induced secretion of glucagonlike peptide-1(GLP-1) in ***:mRNA and protein expression of UCP2 were analyzed in human NCI-H716 cells,which serve as a model for enteroendocrine L-cells,by quantitative reverse transcription-polymerase chain reaction and Western blotting before and after treatment with oleic *** of UCP2 and GLP-1 in NCI-H716 cells was assessed by immunofluorescence ***-H716 cells were transiently transfected with a small interfering RNA(siRNA) that targets UCP2(siUCP2) or with a nonspecific siRNA using Lipofectamine *** concentrations of bioactive GLP-1 in the medium were measured by enzyme linked immunosorbent ***:Both GLP-1 and UCP2 granules were expressed mainly in the cytoplasm of NCI-H716 ***-H716 cells that secreted GLP-1 also expressed ***-course experiments revealed that release of GLP-1 from NCI-H716 cells into the medium reached a maximum at 120 min and remained stable until at least 180 min after treatment with oleic acid(the level of GLP-1 increased about 2.3-fold as compared with the level of GLP-1 in the control cells,P < 0.05).In an experiment to determine dose dependence,stimulation of NCI-H716 cells with ≤ 8 mmol oleic acid led to a concentration-dependent release of GLP-1 into the medium;10 mmol oleic acid diminished the release of ***,GLP-1 secretion induced by oleic acid from NCI-H716 cells that were transfected with siUCP2 decreased to 41.8%,as compared with NCI-H716 cells that were transfected with a non-specific siRNA(P < 0.01).CONCLUSION:UCP2 affected GLP-1 secretion induced by oleic ***2 plays an important role in L-cell secretion that is induced by free fatty acids.

关键词： glucagon-like peptide-1 L-cell NCI-H716cells Oleic acid Uncoupling protein 2

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Effects and mechanism of glucagon-like peptide-1 on injury of rats cardiomyocytes induced by hypoxia-reoxygenation

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Chinese Medical Journal 2008年第21期121卷 2134-2138页

作者： XIE Yun WANG Shao-xin SHA Wei-wei ZHOU Xue WANG Wei-tin HAN Li-pin LI Dai-qing YU De-min Department of Diabetic Neurology Metabolic Disease Hospital Tianjin Medical University Tianjin 300070 China Department Of Endocrinology Beijing Changping District Hosoital Beijing 102200 China Department of Endocrinology Chinese People's Liberation Army 252 Hospital Baoding Hebei 071000 China

Background Although the insulinotropic role of glucagon-like peptide-1 （GLP-1） in type 2 diabetes mellitus has been substantiated, its role in cardioprotection remains largely unknown. This study aimed to determine the effects of GLP-1 on injury of rats cardiac myocytes induced by hypoxia-reoxygenation （H/R） and the possible mechanisms. Methods The cultured neonatal rats cardiac myocytes were randomly divided into seven groups： the normal control group, the H/R group, the GLP-1＋H/R group, the GLP-1＋H/R＋UO126 （the p42/44 mitogen-activated protein kinase （MAPK） inhibitor） group, the GLP-1＋H/R＋LY294002 （phosphatidylinositol 3-kinase （PI3K） inhibitor） group, the H/R＋UO126 group, and the H/R＋LY294002 group. The lactate dehydrogenase （LDH） activity, apoptosis rate of cardiac myocytes, and caspase-3 activity were detected after the injury of H/R. Results Compared with the normal control group, the activity of LDH, cardiac myocyte apoptosis rate, and caspase-3 activity all increased significantly in the H/R group （P 〈0.01）. Compared with the H/R group, these three indices all decreased in the H/R＋GLP-1 group （P 〈0.01）. However, the changes of LDH activity, apoptosis rate, and caspase-3 activity were inhibited by LY294002 and UO126 respectively. Conclusions GLP-1 can directly act on cardiac myocytes and protect them from H/R injury mainly by inhibiting their apoptosis. Its mechanism may be through the PI3K-Akt pathway and the MAPK signaling pathway.

关键词： glucagon-like peptide-1 hypoxia-reoxygenation apoptosis caspase-3 MAP kinase PI3K/Akt

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Solid phase synthesis of fatty acid modified glucagon-like peptide-1(7-36) amide under thermal and controlled microwave irradiation

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Chinese Chemical Letters 2010年第1期21卷 27-30页

作者： Ni, Shuai Han Zhang, Hui Bin Huang, Wen Long Zhou, Jin Pei Qian, Hai China Pharmaceut Univ Ctr Drug Discovery Nanjing 210009 Peoples R China

Fatty acid modified glucagon-like peptide-1(7-36) amide was synthesized efficiently on Rink-Amide-MBHA resin by microwave-assisted solid phase *** method of thermal and controlled microwave irradiation provided impressive enhancements in product yield,selectivity,and reaction *** coupling time was dramatically decreased to 6 min,and the desired products were obtained in high yield and purity.

关键词： glucagon-like peptide-1 GLP-1 Microwave Solid phase Fatty acid modification

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