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.

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

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 reactions.However,the pathogenesis of hypoglycaemic counterregulation is still unclear.Glucagon-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 reported.AIM To explore the impact of intestinal GLP-1 on impaired hypoglycaemic counterregulation in type 1 diabetic mice.METHODS 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)secretion.The 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 mice.RESULTS The expression levels of intestinal GLP-1 and its receptor(GLP-1R)were significantly increased in DH5 mice.Consecutive instances of excess of intestinal GLP-1 weakens the sympathetic-adrenal reflex,leading to dysfunction of adrenal counterregulation during hypoglycaemia.DH5 mice showed increased pancreaticδ-cell mass,cAMP levels inδcells,and plasma somatostatin concentrations,while cAMP levels in pancreaticαcells and plasma GCG levels decreased.Furthermore,GLP-1R expression in islet cells and plasma active GLP-1 levels were significantly increased in the DH5 group.Further experiments involving terminal ileal infusion and intraperitoneal injection in the model mice demonstrated that intestinal GLP-1 during recurrent hypoglycaemia hindered the secretion of the counterregulatory hormone GCG via the endocrine pathway.CONCLUSION Excessive intestinal GLP-1 is strongly associated with impaired counterregulatory responses to hypoglycaemia,leading to reduced appetite and compromised secretion of adrenaline,noradrenaline,and GCG during hypoglycaemia.

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.

Is it necessary to stop glucagon-like peptide-1 receptor agonists prior to endoscopic procedure? A retrospective study

BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are effective in diabetes and obesity,reducing hyperglycemia by increasing insulin release and delaying gastric emptying.However,they can cause gastroparesis,raising concerns about aspiration during procedures.Recent guidelines advise discontinuing GLP-1 RA before surgery to reduce the risk of pulmonary aspiration.AIM To evaluate the effect of GLP-1 RAs on gastric residual contents during endosco-pic procedures.METHODS A retrospective chart review at BronxCare Health System,New York,from January 2019 to October 2023,assessed gastric residue and aspiration in GLP-1 RA patients undergoing endoscopic procedures.Two groups were compared based on dietary status before the procedure.Data included demographics,symptoms of gastroparesis,opiate use,hemoglobin A1c,GLP-1 agonist indication,endo-scopic details,and aspiration occurrence.IBM SPSS was used for analysis,cal-culating means,standard deviations,and applying Pearson’s chi-square and t-tests for associations,with P<0.05 as being significant.RESULTS During the study,306 patients were included,with 41.2%on a clear liquid/low residue diet and 58.8%on a regular diet before endoscopy.Most patients(63.1%)were male,with a mean age of 60±12 years.The majority(85.6%)were on GLP-1 RAs for diabetes,and 10.1%reported digestive symptoms before endoscopy.Among those on a clear liquid diet,1.5%had residual food at endoscopy compared to 10%on a regular diet,which was statistically significant(P=0.03).Out of 31 patients with digestive symptoms,13%had residual food,all from the regular diet group(P=0.130).No complications were reported during or after the procedures.CONCLUSION The study reflects a significant rise in GLP-1 RA use for diabetes and obesity.A 24-hour liquid diet seems safe for endoscopic procedures without aspiration.Patients with upper gastrointestinal symptoms might have a higher residual food risk,though not statistically significant.Further research is needed to assess risks based on diabetes duration,gastroparesis,and GLP-1 RA dosing,aiming to minimize interruptions in therapy during procedures.

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 intestinal glucagon-like peptide-1 in hypoglycemia response impairment in type 1 diabetes

This study critically examines the novel findings presented by Jin et al,which explores the role of intestinal glucagon-like peptide-1(GLP-1)in impaired counterregulatory responses to hypoglycemia in mice with type 1 diabetes.The study identifies intestinal GLP-1 as a significant determinant in the physiological responses to hypoglycemia,offering new insights into its potential implications for diabetes management.The editorial synthesizes these findings,discusses their relevance in the context of current diabetes research,and outlines potential avenues for future investigation of intestinal GLP-1 as a therapeutic target.This analysis underscores the need for continued research into the complex mechanisms underlying impaired hypoglycemia responses and highlights the potential of targeting intestinal GLP-1 pathways in therapeutic strategies for type 1 diabetes.

Glucagon-like peptide-1 agonists:Role of the gut in hypoglycemia unawareness,and the rationale in type 1 diabetes

Type 1 diabetes is increasing and the majority of patients have poor glycemic control.Although advanced technology and nanoparticle use have greatly enhanced insulin delivery and glucose monitoring,weight gain and hypoglycemia remain major challenges and a constant source of concern for patients with type 1 diabetes.Type 1 diabetes shares some pathophysiology with type 2 diabetes,and an overlap has been reported.The above observation created great interest in glucagon-like peptide-1 receptor agonists(GLP-1)as adjuvants for type 1 diabetes.Previous trials confirmed the positive influence of GLP-1 agonists onβcell function.However,hypoglycemia unawareness and dysregulated glucagon response have been previously reported in patients with recurrent hypoglycemia using GLP-1 agonists.Jin et al found that the source of glucagon dysregulation due to GLP-1 agonists resides in the gut.Plausible explanations could be gut nervous system dysregulation or gut microbiota disruption.This review evaluates the potential of GLP-1 agonists in managing type 1 diabetes,particularly focusing on their impact on glycemic control,weight management,and glucagon dysregulation.We provide a broader insight into the problem of type 1 diabetes mellitus management in the light of recent findings and provide future research directions.

Glucagon-like peptide-1 receptor agonists:Exploring the mechanisms from glycemic control to treatment of multisystemic diseases

This editorial takes a deeper look at the insights provided by Soresi and Giannitrapani,which examined the therapeutic potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)for metabolic dysfunction-associated fatty liver disease.We provide supplementary insights to their research,highlighting the broader systemic implications of GLP-1RAs,synthesizing the current understanding of their mechanisms and the trajectory of research in this field.GLP-1RAs are revolutionizing the treatment of type 2 diabetes mellitus and beyond.Beyond glycemic control,GLP-1RAs demonstrate cardiovascular and renal protective effects,offering potential in managing diabetic kidney disease alongside renin–angiotensin–aldosterone system inhibitors.Their role in bone metabolism hints at benefits for diabetic osteoporosis,while the neuroprotective properties of GLP-1RAs show promise in Alzheimer's disease treatment by modulating neuronal insulin signaling.Additionally,they improve hormonal and metabolic profiles in polycystic ovary syndrome.This editorial highlights the multifaceted mechanisms of GLP-1RAs,emphasizing the need for ongoing research to fully realize their therapeutic potential across a range of multisystemic diseases.

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.

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 receptor agonists and myocardial metabolism in atrial fibrillation

Atrial fibrillation(AF)is the most common cardiac arrhythmia.Many medical conditions,including hypertension,diabetes,obesity,sleep apnea,and heart failure(HF),increase the risk for AF.Cardiomyocytes have unique metabolic characteristics to maintain adenosine triphosphate production.Significant changes occur in myocardial metabolism in AF.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)have been used to control blood glucose fluctuations and weight in the treatment of type 2 diabetes mellitus(T2DM)and obesity.GLP-1RAs have also been shown to reduce oxidative stress,inflammation,autonomic nervous system modulation,and mitochondrial function.This article reviews the changes in metabolic characteristics in cardiomyocytes in AF.Although the clinical trial outcomes are unsatisfactory,the findings demonstrate that GLP-1 RAs can improve myocardial metabolism in the presence of various risk factors,lowering the incidence of AF.

The Association between GLP-1 Receptor-Based Agonists and the Incidence of Asthma in Patients with Type 2 Diabetes and/or Obesity:A Meta-Analysis

Objective Recent studies have indicated potential anti-inflammatory effects of glucagon-like peptide-1 receptor agonists(GLP-1RAs)on asthma,which is often comorbid with type 2 diabetes mellitus(T2DM)and obesity.Therefore,we conducted a meta-analysis to assess the association between the administration of glucagon-like peptide-1(GLP-1)receptor-based agonists and the incidence of asthma in patients with T2DM and/or obesity.Methods PubMed,Web of Science,Embase,the Cochrane Central Register of Controlled Trials,and Clinicaltrial.gov were systematically searched from inception to July 2023.Randomized controlled trials(RCTs)of GLP-1 receptor-based agonists(GLP-1RA,GLP-1 based dual and triple receptor agonist)with reports of asthma events were included.Outcomes were computed as risk ratios(RR)using a fixedeffects model.Results Overall,39 RCTs with a total of 85,755 participants were included.Compared to non-GLP-1 receptor-based agonist users,a trend of reduced risk of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments,although the difference was not statistically significant[RR=0.91,95%confidence interval(CI):0.68 to 1.24].Further Subgroup analyses indicated that the use of light-molecular-weight GLP-1RAs might be associated with a reduced the risk of asthma when compared with non-users(RR=0.65,95%CI:0.43 to 0.99,P=0.043).We also performed sensitivity analyses for participant characteristics,study design,drug structure,duration of action,and drug subtypes.However,no significant associations were observed.Conclusion Compared with non-users,a modest reduction in the incidence of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments.Further investigations are warranted to assess the association between GLP-1 receptor-based agonists and the risk of asthma.

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.

Combining GLP-1 receptor agonists and SGLT-2 inhibitors for cardiovascular disease prevention in type 2 diabetes:A systematic review with multiple network meta-regressions

BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.AIM To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.METHODS The systematic review was conducted according to PRISMA recommendations.The protocol was registered on PROSPERO(ID:42022385007).A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment.Effect modification of prior myocardial infarction(MI)and heart failure(HF)was also explored to provide clinical insight as to when the INTRODUCTION The macro-and micro-vascular benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are independent of their glucose-lowering effects[1].In patients with type 2 diabetes(T2D),the major cardiovascular outcome trials(CVOT)showed that dipeptidyl peptidase-4 inhibitors(DPP-4I)did not improve cardiovascular outcomes[2],whereas cardiovascular benefit of GLP-1RA or SGLT-2I was significant[3,4].Further subgroup analyses indicated that the background cardiovascular risk should be considered when examining the cardiovascular outcomes of these newer glucose-lowering medications.For instance,prevention of major adverse cardiovascular events(MACE)was only seen in those patients with baseline atherosclerotic cardiovascular disease[3,4].Moreover,a series of CVOT conducted in patients with heart failure(HF)have demonstrated that(compared with placebo)SGLT-2I significantly reduced risk of hospitalization for HF or cardiovascular death,irrespective of their history of T2D[5-8].However,similar cardiovascular benefits were not observed in those with myocardial infarction(MI)[9,10].Cardiovascular co-morbidities are not only approximately twice as common but are also associated with dispropor-tionately worse cardiovascular outcomes in patients with T2D,compared to the general population[11].Therefore,it is of clinical importance to investigate whether the combination treatment of GLP-1RA and SGLT-2I could achieve greater cardiovascular benefit,particularly when considering patients with cardiovascular co-morbidities who may not gain sufficient cardiovascular protection from the monotherapies.This systematic review with multiple network meta-regressions was mainly aimed to explore whether combining GLP-1RA and SGLT-2I can provide additional cardiovascular benefit in T2D.Cardiovascular outcomes of these newer antidiabetic medications were also estimated under effect modification of prior cardiovascular diseases.This was to provide clinical insight as to when the combination treatment might be prioritized.

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 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.

Potential roles of glucagon-like peptide-1-based therapies in treating non-alcoholic fatty liver disease

Glucagon-like peptide-1(GLP-1)-based therapies have demonstrated efficacy and safety in treating type 2 diabetes, which shares a similar pathophysiological mechanism with non-alcoholic fatty liver disease(NAFLD). Recent studies showed that glucose-induced GLP-1 secretion was decreased in patients with NAFLD and that the level of dipeptidyl peptidase-4, which inactivates intact GLP-1, was upregulated. Moreover, the expression of the GLP-1 receptor was downregulated in livers from patients with NAFLD, indicating an association of defective GLP-1 signalling with NAFLD. Notably, GLP-1-based therapies are reported to be effective in improving hepatic endpoints in patients with NAFLD, such as reducing hepatic fat content, hepatic steatosis and plasma transaminase levels, and preventing fibrosis. GLP-1-based therapies are beneficial for body weight control and glycaemic normalisation, which are important for the management of NAFLD. Moreover, clinical and preclinical studies showed that GLP-1-based agents might directly exert their actions on the liver through activation of functional GLP-1 receptors in hepatocytes.The possible mechanisms involve regulating gene expression that is associated with insulin resistance and lipid metabolism, and suppressing oxidative stress in the liver cells, thus preventing the development and progression of NAFLD. Based on these promising data, large-scale randomised controlled trials are warranted to assess the efficacy and safety of GLP-1-based therapies in treating NAFLD.

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.

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

AIM:To investigate whether uncoupling protein 2(UCP2) affects oleic acid-induced secretion of glucagonlike peptide-1(GLP-1) in L-cells.METHODS: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 acid.Localization of UCP2 and GLP-1 in NCI-H716 cells was assessed by immunofluorescence labeling.NCI-H716 cells were transiently transfected with a small interfering RNA(siRNA) that targets UCP2(siUCP2) or with a nonspecific siRNA using Lipofectamine 2000.The concentrations of bioactive GLP-1 in the medium were measured by enzyme linked immunosorbent assay.RESULTS:Both GLP-1 and UCP2 granules were expressed mainly in the cytoplasm of NCI-H716 cells.NCI-H716 cells that secreted GLP-1 also expressed UCP2.Time-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.Furthermore,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 acid.UCP2 plays an important role in L-cell secretion that is induced by free fatty acids.