exenatide and Non-alcoholic-Fatty-Liver-Disease

In the present network meta-analysis (NMA), we aimed to compare the effectiveness of daily and weekly treatment with glucagon-like peptide-1 receptor agonists for patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM).. We used Stata 17.0 for the NMA. Eligible Randomized controlled trials (RCTs) were searched in PubMed, Cochrane, and Embase databases until December 2022. Two researchers independently screened the available studies. The Cochrane Risk of Bias tool was used to assess the risk of bias in the included studies. We used GRADEprofiler (version3.6) to analyze the evidence certainty. Primary outcomes such as liver fat content (LFC), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels, as well as secondary outcomes such as γ-glutamyltransferase (γGGT) and body weight, were evaluated. Then, each intervention was ranked by the surface under the cumulative ranking curve (SUCRA). As a supplement, we drew forest plots of subgroup using RevMan (version 5.4).. Fourteen RCTs involving 1666 participants were included in the present study. The NMA results showed that exenatide (bid) was the best treatment for improving LFC compared with other agents, liraglutide, dulaglutide, semaglutide (qw) and placebo), and the SUCRA values were 66.8%. Among five interventions (except exenatide (bid) and semaglutide (qw)) evaluated for AST outcome, and six interventions (except exenatide (bid)) evaluated for ALT outcome, semaglutide (qd) was the most effective drug (SUCRA (AST) = 100%, SUCRA (ALT) = 95.6%). The result of LFC in daily group was MD = -3.66, 95% CI [-5.56, -1.76] and in weekly GLP-1RAs group, it was MD = -3.51, 95% CI [-4, -3.02]. As to AST and ALT, the results in daily group versus weekly group were AST: MD = -7.45, 95% CI [-14.57, -0.32] versus MD= -0.58, 95% CI [-3.18, 2.01] and ALT: MD = -11.12, 95% CI [-24.18, 1.95] versus MD = -5.62, 95% CI [-15.25, 4]. The quality of evidence was assessed as moderate or low.. The daily GLP-1RAs may be more effective in primary outcomes. And the daily semaglutide may be the most effective treatment for NAFLD and T2DM among the six interventions.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Network Meta-Analysis; Non-alcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely related and mutually contribute to the disease's development. There are many treatment options available to patients. We provide a comprehensive overview of the evidence on the treatment effects of several potential interventions for NAFLD with T2DM.. This systematic review and network meta-analysis included searches of PubMed, Embase, Cochrane Library, and Web of Science from inception to June 30, 2023, for randomised controlled trials of treatment of NAFLD with T2DM. We performed Bayesian network meta-analyses to summarise effect estimates of comparisons between interventions. We applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) frameworks to rate all comparative outcomes' certainty in effect estimates, categorise interventions, and present the findings. This study was registered with PROSPERO, CRD42022342373.. Four thousand three hundred and sixty-nine records were retrieved from the database and other methods, of which 24 records were eligible for studies enrolling 1589 participants. Eight clinical indicators and 14 interventions were finally in focus. Referring to the lower surface under the cumulative ranking curves (SUCRA) and the league matrix table, exenatide and liraglutide, which are also glucagon-like peptide-1 receptor agonists (GLP-1RAs), showed excellent potential to reduce liver fat content, control glycemia, reduce body weight, and improve liver function and insulin resistance. Exenatide was more effective in reducing glycated haemoglobin (HbA. The high confidence mandates the confident application of these findings as guides for clinical practice. Dapagliflozin and pioglitazone are used for glycaemic control in patients with NAFLD combined with T2DM, and liraglutide is used for weight loss therapy in patients with abdominal obesity. The available evidence does not demonstrate the credibility of the effectiveness of other interventions in reducing liver fat content, visceral fat area, ALT, and insulin resistance. Future studies should focus on the clinical application of GLP-1Ras and the long-term prognosis of patients.

Topics: Bayes Theorem; Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Network Meta-Analysis; Non-alcoholic Fatty Liver Disease; Pioglitazone

Fatty liver is associated with obesity, type 2 diabetes, hyperlipidemia, hypertension, and metabolic syndrome. While there are no approved drugs for the treatment of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis, strategies to ameliorate fatty liver often target these related diseases. We sought to determine if any medications approved by the US Food and Drug Administration to treat diabetes are helpful in reducing weight and improving steatohepatitis in patients with NAFLD.. We conducted a systematic review of published and unpublished studies evaluating the comparative effectiveness and harms of diabetes medications for the treatment of NAFLD. We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials through 3rd quarter, 2019 using terms for included drugs and indications.. We screened 1591 citations and included 18 trials of diabetes drugs to treat NAFLD. Studies of metformin found no difference from placebo in steatosis, fibrosis, NAFLD activity score, or resolution of NASH. While weight and glucose control were improved with metformin, it did not substantially impact liver disease. Studies of pioglitazone in NASH patients found benefits in liver function, liver fat, and NASH resolution, though significant increases in weight may be cause for concern. Evidence for other thiazolinediones was more limited and had somewhat mixed results, but findings were generally consistent with those for pioglitazone: liver fat and function and glucose measures improved, but weight also increased. We found some evidence that liraglutide improves liver fat, liver function, and HbA1c and is effective at resolving NASH and reducing weight. Exenatide performed less well but also resulted in significant reductions in liver fat and weight.. Consistent with existing clinical practice guidelines, which recommend lifestyle intervention and treatment for comorbidities related to fatty liver disease as first-line treatment, trial evidence supports the efficacy of some diabetes drugs (especially pioglitazone) in patients with NAFLD or NASH, though weight gain with some diabetes drugs may warrant caution. Larger trials are needed to better characterize the efficacy and harms of diabetes pharmacotherapy in these patients.

Topics: Blood Glucose; Body Weight; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Pioglitazone; Randomized Controlled Trials as Topic; Rosiglitazone

Non-alcoholic fatty liver disease (NAFLD) is a continuum of disorders that can range from simple steatosis to non-alcoholic steatohepatitis (NASH). As a complex metabolic disorder, the pathophysiology of NAFLD is incompletely understood. Recently glucagon-like peptide (GLP)-1 and -2 signalling has been implicated in the pathogenesis of NAFLD. The role of these gut hormones in the hepatic abnormalities is complicated by lack of consensus on the presence of GLP-1 and GLP-2 receptors within the liver. Nevertheless, GLP-1 and GLP-2 receptor agonists have been associated with alterations in lipid metabolism and hepatic and systemic inflammation, pathological abnormalities characteristic of NAFLD. Treatment with GLP-1 analogues has been shown to reverse features of NAFLD including insulin resistance, and alterations in hepatic de novo lipogenesis and reactive oxygen species. In this review, we provide an overview of the role of GLP-1 and GLP-2 in lipid homeostasis and metabolic disease including NAFLD and NASH.

Topics: Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide-2 Receptor; Glucagon-Like Peptides; Humans; Insulin Resistance; Lipid Metabolism; Lipids; Lipogenesis; Lipoproteins; Liraglutide; Liver; Non-alcoholic Fatty Liver Disease; Peptides; Signal Transduction

This brief review describes the potential non-glycaemic effects and benefits of glucagon like peptide 1 receptor agonists (GLP1RA). It lists various indications in which this class of drugs has been used, and explains the rationale behind this use. The potential uses of GLP1RA extend across the entire spectrum of endocrinology and metabolism, from hypothalamic obesity to non-alcoholic steatohepatitis (NASH) to polycystic ovary syndrome (PCOS). The article also discusses and addresses endocrine-related concerns related to the GLP1RAs.

Topics: Bone and Bones; Central Nervous System; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Gonads; Humans; Hypothalamic Diseases; Incretins; Liraglutide; Liver; Male; Non-alcoholic Fatty Liver Disease; Obesity; Ovary; Peptides; Polycystic Ovary Syndrome; Psoriasis; Testis; Thyroid Gland; Venoms

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum that ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and to cirrhosis. The recommended treatment for this disease includes measures that target obesity and insulin resistance. The present review summarizes the role of newer anti-diabetic agents in treatment of NAFLD.. PubMed, MEDLINE and Ovid databases were searched to identify human studies between January 1990 and January 2013 using specified key words. Original studies that enrolled patients with a diagnosis of NAFLD or NASH and involved use of newer classes of anti-diabetic agents for a duration of at least 3 months were included.. Out of the screened articles, four met eligibility criteria and were included in our review. The classes of newer anti-diabetic medications described were dipeptidyl peptidase IV inhibitors and glucagon-like peptide-1 analogues.. Liraglutide and Exenatide showed improvement in transaminases as well as histology in patients with NASH. Sitagliptin showed improvement in transaminases but limited studies are there to access its effect on histology. Further studies are needed to support use of newer anti-diabetic medications in patients with NAFLD.

Topics: Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Liver; Non-alcoholic Fatty Liver Disease; Peptides; Pyrazines; Sitagliptin Phosphate; Transaminases; Treatment Outcome; Triazoles; Venoms

To assess the efficacy of exenatide (EXE) once weekly + dapagliflozin once daily (DAPA) versus each drug alone in reducing biomarkers of fatty liver/steatosis and fibrosis in a post hoc analysis of DURATION-8, a 104-week study in 695 patients with type 2 diabetes uncontrolled by metformin monotherapy.. We evaluated the impact of the study treatments on non-invasive markers of hepatic steatosis (fatty liver index [FLI] and non-alcoholic fatty liver disease [NAFLD] liver fat score), fibrosis (fibrosis-4 index [FIB-4]) and severe fibrosis (NAFLD fibrosis score), along with liver enzymes and insulin resistance, at weeks 28 and 52. All outcomes in this analysis were exploratory, with nominal P values reported.. At week 28, biomarkers of fatty liver/steatosis and fibrosis were reduced from baseline in all treatment groups. At week 28, EXE once weekly + DAPA effects for decrease in FLI were stronger than those of EXE once weekly + placebo (PLB; -2.92, 95% confidence interval [CI] -5.11, -0.73; P = 0.0092) or DAPA+PLB (-2.77 [95% CI -4.93, -0.62]; P = 0.0119), and stronger than those of EXE once weekly + PLB at week 52 (-3.23 [95% CI -5.79, -0.68]; P = 0.0134). FIB-4 showed reduction versus baseline only in the EXE once weekly + DAPA group at both week 28 (-0.06 [95% CI -0.11, -0.01]; P = 0.0135) and week 52 (-0.05 [95% CI -0.09, -0.004]; P = 0.0308).. The EXE once weekly + DAPA combination showed stronger effects than EXE once weekly + PLB or DAPA + PLB in ameliorating markers of hepatic steatosis and fibrosis in patients with type 2 diabetes. Prospective trials are needed to validate these findings.

Topics: Benzhydryl Compounds; Biomarkers; Diabetes Mellitus, Type 2; Exenatide; Fibrosis; Glucosides; Humans; Hypoglycemic Agents; Non-alcoholic Fatty Liver Disease; Prospective Studies

The aim of this study was to investigate the efficacy of exenatide and insulin glargine in patients with newly diagnosed type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD).. We performed a 24-week randomized controlled multicentre clinical trial. Seventy-six patients were randomly assigned 1:1 to receive exenatide or insulin glargine treatment. The endpoints included changes in liver fat content (LFC), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) measured by magnetic resonance spectroscopy, blood glucose, liver enzymes, lipid profile, body weight, and Fibrosis-4 index (FIB-4).. LFC, VAT, SAT, and FIB-4 were significantly reduced after exenatide treatment (ΔLFC, -17.55 ± 12.93%; ΔVAT, -43.57 ± 68.20 cm. Both exenatide and insulin glargine reduced LFC in patients with drug-naive T2DM and NAFLD; however, exenatide showed greater reductions in body weight, visceral fat area, liver enzymes, FIB-4, postprandial plasma glucose, and LDL-C.

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Prognosis

Diabetes mellitus type 2 (DMT2) and non-alcoholic fatty liver disease (NAFLD) are both characterized by decreased circulating adiponectin. Recently, glucagon-like peptide-1 receptor agonists have been shown to induce adiponectin's expression. However, their interaction on clinical grounds needs to be further elucidated.. DMT2 patients with abnormal aminotransferases were screened for NAFLD and subjected to liver biopsy (group A, n=17). A subgroup of patients (n=110), after assessed for eligibility criteria, was blindly randomized to receive either 6-month exenatide supplementation on glargine insulin (group B) or intense, self-regulated, insulin therapy alone (group C).. Baseline patient characteristics: 49(38.6%) males, aged 63.1 ± 7.5 years-old, BMI 32.9 ± 4.9 kg/m(2), HbA1c 8.1 ± 1.2% (65 ± 14 mmol/mol), median ALT 23 U/L (range 5-126), AST 20 U/L (7-72). Group A had biopsy-proven NAFLD with a median Activity Score of 5 and fibrosis stage 3. Presence of NAFLD was accompanied by a significant decline in adiponectin (p<0.001), which was negatively correlated with the degree of ALT in all groups (Spearman's correlation, rs=-0.644, p<0.001). In the subgroup intervention trial, adiponectin was significantly raised in both groups B and C (t-Student for paired samples, p=0.001) by Δ=+24.2% (interquartile range 14.8-53.2%). This elevation was not associated with the type of intervention but with weight loss, glycemic control and reduction of C-reactive protein (one-way ANCOVA).. Supplementation of exenatide to glargine insulin compared to standard insulin was: (i) effective in inducing weight loss, (ii) non-inferior in lowering HbA1c and (iii) non-inferior in increasing circulating adiponectin. Higher adiponectin was associated with lower ALT, suggesting a hepato-protective role for this cytokine.

Topics: Adiponectin; Aged; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Peptides; Prospective Studies; Venoms

The purpose of this study was to evaluate the advantages of exenatide treatment on obesity and non-alcoholic fatty liver disease (NAFLD) with elevated liver enzymes in patients with type 2 diabetes (T2D).. A total of 60 newly diagnosed patients with obesity, NAFLD with elevated liver enzymes and T2D were included in the study. The patients were randomly divided into two groups. The exenatide treatment group (n = 30) were treated with exenatide and insulin glargine, and the intensive insulin therapy group (n = 30) were treated with insulin aspart and insulin glargine for 12 weeks. Selected clinical characteristics were determined, and ultrasonography was performed at both baseline and 12 weeks following treatment.. At baseline, the clinical characteristics were matched between the two groups. After 12 weeks, fasting blood glucose (FBG), postprandial blood glucose (PBG), glycosylated haemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG) and total bilirubin levels were significantly decreased in the two groups (p < 0.001). Body weight and waist circumference were significantly decreased in the exenatide group but increased in the intensive insulin group (p < 0.001). The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyl transpeptidase (γGGT) in the exenatide group were significantly lower than in the intensive insulin group (p < 0.001). The mean body weight change correlated with the levels of ALT, AST and γGGT change (ALT, r = 0.761; AST, r = 0.733; γGGT, r = 0.752; p < 0.001). Moreover, the reversal rate of fatty liver was significantly higher in the exenatide group (93.3%) than the intensive insulin group (66.7%) (p < 0.01).. Exenatide has a better hepatic-protective effect than intensive insulin therapy and perhaps represents a unique option for adjunctive therapy for patients with obesity, non-alcoholic fatty liver disease with elevated liver enzymes and T2D.

Topics: Adult; Biomarkers; Body Mass Index; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Drug Therapy, Combination; Exenatide; Exercise; Female; Glycated Hemoglobin; Hepatic Insufficiency; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Peptides; Ultrasonography; Venoms; Waist Circumference; Weight Loss

To investigate the effects of exenatide on blood glucose, body weight and hepatic enzymes in patients with type 2 diabetes mellitus (T2DM) and concomitant non-alcoholic fatty liver disease (NAFLD).. One hundred and seventeen patients with T2DM and NAFLD were randomly divided into exenatide group and metformin group. Patients were treated with exenatide and metformin, respectively, for 12 weeks.. After 12 weeks of treatment, body weight, body mass index (BMI), waist-to-hip ratio, HbA1c, FPG, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were significantly reduced, and the AST/ALT ratio and adiponectin were markedly increased in both groups. BMI, waist-to-hip ratio, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were markedly lower, and AST/ALT ratio and adiponectin in the exenatide group were dramatically higher than in the metformin group.. Compared with metformin, exenatide is better to control blood glucose, reduces body weight and improves hepatic enzymes, attenuating NAFLD in patients with T2DM concomitant with NAFLD.

Topics: Adiponectin; Adult; Aged; Alanine Transaminase; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Exenatide; Fatty Liver; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Non-alcoholic Fatty Liver Disease; Peptides; Time Factors; Treatment Outcome; Venoms; Waist-Hip Ratio

Systemic fibroblast growth factor (FGF)21 levels and hepatic FGF21 production are increased in non-alcoholic fatty liver disease patients, suggesting FGF21 resistance. We examined the effects of exenatide on FGF21 in patients with type 2 diabetes and in a diet-induced mouse model of obesity (DIO).. Type 2 diabetes mellitus patients (n = 24) on diet and/or metformin were randomised (using a table of random numbers) to receive additional treatment consisting of pioglitazone 45 mg/day or combined therapy with pioglitazone (45 mg/day) and exenatide (10 μg twice daily) for 12 months in an open label parallel study at the Baylor Clinic.. Twenty-one patients completed the entire study and were included in the analysis. Pioglitazone treatment (n = 10) reduced hepatic fat as assessed by magnetic resonance spectroscopy, despite a significant increase in body weight (Δ = 3.7 kg); plasma FGF21 levels did not change (1.9  ±  0.6 to 2.2  ±  0.6 ng/ml [mean ± SEM]). However, combined pioglitazone and exenatide therapy (n = 11) was associated with a significant reduction of FGF21 levels (2.3  ±  0.5 to 1.1  ±  0.3 ng/ml) and a greater decrease in hepatic fat. Besides weight gain observed in the pioglitazone-treated patients, lower extremity oedema was observed as a side effect in two of the ten patients. Three patients who received pioglitazone and exenatide combination therapy complained of significant nausea that was self-limiting and did not require them to leave the study. In DIO mice, exendin-4 for 4 weeks significantly reduced hepatic triacylglycerol content, decreased hepatic FGF21 protein and mRNA, and enhanced phosphorylation of hepatic AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase, although no significant difference in weight and body fat was observed. Hepatic FGF21 correlated inversely with hepatic AMPK phosphorylation. In type 2 diabetes mellitus, combined pioglitazone and exenatide therapy is associated with a reduction in plasma FGF21 levels, as well as a greater decrease in hepatic fat than that achieved with pioglitazone therapy. In DIO mice, exendin-4 treatment reduces hepatic triacylglycerol and FGF21 protein, and enhances hepatic AMPK phosphorylation, suggesting an improvement of hepatic FGF21 resistance.. ClinicalTrials.gov NCT 01432405.

Topics: Adult; Aged; Animals; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Therapy, Combination; Edema; Exenatide; Fatty Liver; Female; Fibroblast Growth Factors; Humans; Hypoglycemic Agents; Liver; Lower Extremity; Male; Metformin; Mice; Middle Aged; Nausea; Non-alcoholic Fatty Liver Disease; Obesity; Peptides; Pioglitazone; Thiazolidinediones; Venoms

Fatty liver is the earliest response to excessive ethanol consumption, which increases the susceptibility of the liver to develop advanced stage of liver disease. Our previous studies have revealed that chronic alcohol administration alters metabolic hormone levels and their functions. Of current interest to our laboratory is glucagon-like peptide 1 (GLP-1), a widely studied hormone known to reduce insulin resistance and hepatic fat accumulation in patients with metabolic-associated fatty liver disease. In this study, we examined the beneficial effects of exendin-4 (a GLP-1 receptor agonist) in an experimental rat model of ALD. Male Wistar rats were pair-fed the Lieber-DeCarli control or ethanol diet. After 4 weeks of this feeding regimen, a subset of rats in each group were intraperitoneally injected every other day with either saline or exendin-4 at a dose of 3 nmol/kg/day (total 13 doses) while still being fed their respective diet. At the end of the treatment, rats were fasted for 6 h and glucose tolerance test was conducted. The following day, the rats were euthanized, and the blood and tissue samples collected for subsequent analysis. We found that exendin-4 treatment had no significant effect on body weight gain among the experimental groups. Exendin-4-treated ethanol rats exhibited improved alcohol-induced alterations in liver/body weight and adipose/body weight ratio, serum ALT, NEFA, insulin, adiponectin and hepatic triglyceride levels. Reduction in indices of hepatic steatosis in exendin-4 treated ethanol-fed rats was attributed to improved insulin signaling and fat metabolism. These results strongly suggest that exendin-4 mitigates alcohol-associated hepatic steatosis by regulating fat metabolism.

Topics: Animals; Ethanol; Exenatide; Fatty Liver, Alcoholic; Glucagon-Like Peptide 1; Insulin; Male; Non-alcoholic Fatty Liver Disease; Obesity; Rats; Rats, Wistar

Excess hepatic lipid accumulation is the hallmark of non-alcoholic fatty liver disease (NAFLD), for which no medication is currently approved. However, glucagon-like peptide-1 receptor agonists (GLP-1RAs), already approved for treating type 2 diabetes, have lately emerged as possible treatments. Herein we aim to investigate how the GLP-1RA exendin-4 (Ex-4) affects the microRNA (miRNAs) expression profile using an in vitro model of steatosis. Total RNA, including miRNAs, was isolated from control, steatotic, and Ex-4-treated steatotic cells and used for probing a panel of 799 highly curated miRNAs using NanoString technology. Enrichment pathway analysis was used to find the signaling pathways and cellular functions associated with the differentially expressed miRNAs. Our data shows that Ex-4 reversed the expression of a set of miRNAs. Functional enrichment analysis highlighted many relevant signaling pathways and cellular functions enriched in the differentially expressed miRNAs, including hepatic fibrosis, insulin receptor, PPAR, Wnt/β-Catenin, VEGF, and mTOR receptor signaling pathways, fibrosis of the liver, cirrhosis of the liver, proliferation of hepatic stellate cells, diabetes mellitus, glucose metabolism disorder and proliferation of liver cells. Our findings suggest that miRNAs may play essential roles in the processes driving steatosis reduction in response to GLP-1R agonists, which warrants further functional investigation.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hep G2 Cells; Humans; Liver Cirrhosis; MicroRNAs; Non-alcoholic Fatty Liver Disease

There is a closely relationship between the development and progression of nonalcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD) and obesity and diabetes. NAFLD fibrosis scores should be routinely used to rule out patients with advanced fibrosis. High scores may help identify patients at higher risk of all causes andliverrelated morbidity and mortality. The aim of this study was to investigate the association between exenatide and fibrosis scores. The effect of exenatide treatment on fibrosis scores was evaluated in type 2 diabetes mellitus (DM) patients with MAFLD. Evaluation was made of 50 patients with type 2 DM and MAFLD. The NFS, FIB4 and APRI scores were calculated before and after 6 months of treatment. After 6 months of exenatide treatment, the NFS and APRI scores were determined to have decreased significantly. Exenatide was observed to control blood glucose, reduce body weight and improve fibrosis scores in MAFLD patients with type 2 diabetes.

Topics: Adult; Biomarkers; Blood Glucose; Decision Support Techniques; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Hypoglycemic Agents; Incretins; Liver; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Predictive Value of Tests; Retrospective Studies; Time Factors; Treatment Outcome; Weight Loss

To compare the efficacy of triple therapy (metformin/exenatide/pioglitazone) versus stepwise conventional therapy (metformin → glipizide → glargine insulin) on liver fat content and hepatic fibrosis in newly diagnosed, drug-naïve patients with type 2 diabetes.. Sixty-eight patients completed the 6-year follow-up and had an end-of-study (EOS) FibroScan to provide measures of steatosis (controlled attenuation parameter [CAP] in dB/m) and fibrosis (liver stiffness measurement [LSM] in kPa); 59 had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure liver fat.. At EOS, HbA1c was 6.8% and 6.0% in triple and conventional therapy groups, respectively (P = .0006). Twenty-seven of 39 subjects (69%) receiving conventional therapy had grade 2/3 steatosis (CAP, FibroScan) versus nine of 29 (31%) in triple therapy (P = .0003). Ten of 39 (26%) subjects receiving conventional therapy had stage 3/4 fibrosis (LSM) versus two of 29 (7%) in triple therapy (P = .04). Conventional therapy subjects had more liver fat (MRI-PDFF) than triple therapy (12.9% vs. 8.8%, P = .03). The severity of steatosis (CAP) (r = 0.42, P < .001) and fibrosis (LSM) (r = -0.48, P < .001) correlated inversely with the Matsuda Index of insulin sensitivity, but not with percentage body fat. Aspartate aminotransferase (AST) to Platelet Ratio Index (APRI), non-alcoholic fatty liver disease fibrosis score (NFS), plasma AST, and alanine aminotransferase (ALT) all decreased significantly with triple therapy, but only the decrease in plasma AST and ALT correlated with the severity of steatosis and fibrosis at EOS.. At EOS, subjects with type 2 diabetes treated with triple therapy had less hepatic steatosis and fibrosis versus conventional therapy; the severity of hepatic steatosis and fibrosis were both strongly and inversely correlated with insulin resistance; and changes in liver fibrosis scores (APRI, NFS, Fibrosis-4, and AST/ALT ratio) have limited value in predicting response to therapy.

Topics: Diabetes Mellitus, Type 2; Exenatide; Humans; Liver; Liver Cirrhosis; Metformin; Non-alcoholic Fatty Liver Disease; Pioglitazone; Prevalence

Obesity-induced inflammation mechanism is seen as a mechanism that may be the cause of insulin resistance and non-alcoholic fatty liver disease (NAFLD). Pathological destruction of insulin signaling molecules such as insulin receptor substrate proteins (IRS), especially due to the increase of cytokine signal suppressors (SOCS), has been demonstrated in experimental diabetes. The aim of this study was to determine the effects of metformin, pioglitazone, exenatide and exercise treatments used in type 2 diabetes on fatty liver and the role of Irs-1 and Socs3 molecules in this process in obese diabetic rats.. The study was conducted on 48 Wistar albino adult male rats weighing 180-220 g and randomly divided into 6 groups. The obese rat model with fatty liver was formed with a 60% fat diet for 4 weeks. Afterwards, drug treatment with metformin (Ob + D + M), pioglitazone (Ob + D + P), exenatide (Ob + D + ExA)) or exercise (Ob + D + ExE) was applied for 4 weeks to these obese groups, in which diabetes was induced by streptozocin (STZ). At the end of the experimental protocol, liver tissue samples were taken from all rat groups and histopathological and genetic analyses were performed.. The mean steatosis degrees of the Ob + D + ExA and Ob + D + ExE groups were statistically significantly decreased compared to the obese diabetic group (p < 0.001). The group with the lowest mean steatosis grade was the Ob + D + ExE. Decrease in SOCS-3 expression was significant in Ob + D + M and Ob + D + P groups than other groups (p < 0.05). Mean staining intensities of Ob + D + Ex group, Ob + D + ExE group and Ob + D + P group according to IRS-1 expression statistically significantly increased compared to obese diabetic group (p < 0.05). Average staining intensity of Ob + D + ExE group according to IRS-1 expression was significant than other groups.. Exercise and exenatide treatments seemed to be the prominent treatment methods by showing a statistically significant effect in decreasing the degree of steatosis, decreasing the Socs3 expression level and increasing the Irs-1 expression level.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Exenatide; Insulin Receptor Substrate Proteins; Insulin Resistance; Liver; Male; Metformin; Non-alcoholic Fatty Liver Disease; Obesity; Pioglitazone; Rats; Rats, Wistar

To explore effective therapeutic strategy on nonalcoholic fatty liver disease (NAFLD), the amphiphilic oligochitosan derivative containing ursodeoxycholic acid (UDCA) was synthesized and named as UBC, which could self-assemble and encapsulate exenatide (Exe) to obtain Exe-UBC nano-vesicle. Exe-UBC could be uptaken by fatty-acid cultured cells and release UDCA and Exe responsive to the high esterase concentration. In vitro experiments demonstrated that Exe-UBC activated the expression level of SIRT1 with inhibited expression of PGC-1β and PPAR-γ and consequently exerted synergistic bioaction immediately on reducing lipidosis. After a month of Exe-UBC treated through intravenous injection, the body weight of high-fat diet feeding C57BL/6 mice recovered to ordinary level, and their lipid contents in the liver declined significantly. The recovery in hepatic function indexes like TG, AST, and ALT further revealed the superiority of Exe-UBC vesicles. These results suggested that the co-delivery of UDCA and Exe via Exe-UBC could be a potent platform for NAFLD treatment.

Topics: Animals; Chitosan; Diet, High-Fat; Exenatide; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Oligosaccharides; Sirtuin 1; Ursodeoxycholic Acid

Dysregulated hepatic steatosis may lead to chronic liver inflammation and nonalcoholic steatohepatitis (NASH). Recent studies have suggested that exendin-4, a glucagon-like peptide-1 agonist, may be a promising therapeutic for hepatic steatosis and NASH. However, the molecular mechanisms underlying the antihepatic steatosis actions of exendin-4 are not fully clear. Here, we demonstrate that autophagy is activated by either palmitic acid (PA) or oleic acid (OA) in HepG2 cells, and exendin-4 further enhances the autophagy-lysosomal pathway. We show that inhibition of autophagy by shLC3 attenuates exendin-4-mediated antisteatotic activity. Furthermore, expression of a key lysosomal marker, lysosome associated membrane protein 1 (LAMP1), is upregulated in OA + exendin-4-treated cells. The colocalization of LAMP1 and LC3 puncta further suggests that autophagic flux was enhanced by the cotreatment. Based on these findings, we conclude that autophagic flux might play an important role in the antisteatotic action of exendin-4.

Topics: Autophagy; Exenatide; Hep G2 Cells; Humans; Lysosomes; Non-alcoholic Fatty Liver Disease

Diabetes is the fifth leading cause of death in the People's Republic of China. The aim of the article is to compare the effects of nursing care on the laboratory findings and ultrasound results of diabetic patients with chronic liver diseases (CLD) who were treated with antiglycemic drugs.. Diabetic were patients treated with metformin hydrochloride in combination with gliclazide, pioglitazone hydrochloride, sitagliptin, exenatide or liraglutide. Non-alcoholic fatty liver disease (NAFLD) was evaluated by abdominal ultrasound, and fibrosis stages were evaluated at baseline and 8 months. All the patients were equally divided into two groups depending on the therapeutic approach.. The first group of patients additionally received nursing care, and the second group adhered to the prescribed therapy on their own. In total 90 patients, or 55.6%, had NAFLD at baseline, and its course was dependent upon changes in the weight (P = 0.009) and waist circumference (P = 0.012). The proportions of patients who demonstrated an ultrasonographic improvement in the control group were: 24 (56.8%) with gliclazide, 15 (41.3%) with pioglitazone hydrochloride, 28 (66.1%) with sitagliptin, 16 (79%) with exenatide and 15 (66.7%) with liraglutide (P = 0.2). For the group that received nursing care an ultrasonographic improvement was in: 29 (68.16%) with gliclazide, 18 (49.56%) with pioglitazone hydrochloride, 33 (79.32%) with sitagliptin, 19 (94.8%) with exenatide and 21 80.04% with liraglutide (P = 0.2).. Outcomes from the type 2 diabetes treatment paralleling of CLD were presented. Treatment of type 2 diabetes with pioglitazone hydrochloride, gliclazide, sitagliptin, liraglutide and exenatide was proven effective.

Topics: Diabetes Mellitus, Type 2; Exenatide; Gliclazide; Humans; Hypoglycemic Agents; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Pioglitazone; Sitagliptin Phosphate

The aim of this study was to evaluate the effects of a 6-month treatment regimen with exenatide on the lipid profile, high-sensitivity C-reactive protein (hsCRP), carotid intima media thickness (CIMT), visceral adiposity, and nonalcoholic fatty liver disease (NAFLD), all of which are important cardiovascular risk factors.. This study included 45 obese patients with type 2 diabetes mellitus (T2DM). Baseline clinical findings, laboratory parameters, and ultrasonography findings were recorded. An exenatide recipe was given twice daily to the patients and, after 6 months of therapy, the same variables were compared. The compared parameters were lipid profiles, hsCRP, aspartat aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, liver craniocaudal diameter, visceral fat volume, subcutaneous fat thickness, and CIMT. Liver diameter, visceral fat volume, subcutaneous fat thickness, and CIMT were measured by ultrasonography.. After therapy, statistically significant improvements were achieved in lipid profile, hsCRP, liver enzymes, body mass index, and waist and hip circumferences. Also, statistically significant decreases were obtained in liver craniocaudal diameter, subcutaneous fat thickness, visceral fat volume, and CIMT. The reduction of CIMT and liver diameter were not correlated with BMI and HbA1c reduction.. This study showed improvement in lipid profile and hsCRP levels with exenatide treatment. We also showed decrease in both visceral fat volume and subcutaneous fat thickness. We demonstrated significant decrease in liver enzymes with significant decrease in liver diameter. These findings support the use of exenatide in patients with NAFLD and T2DM. Additionally, this study showed that exenatide treatment given twice daily reduces CIMT in obese T2DM patients.

Topics: Adult; Anti-Obesity Agents; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Intra-Abdominal Fat; Lipids; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Obesity, Abdominal; Prospective Studies; Risk Factors; Subcutaneous Fat

The morbidity of nonalcoholic fatty liver disease (NAFLD) has increased consistently in recent years. Exenatide could reverse liver fibrosis and lower the occurrence of fatty liver. The aim of the study was to identify and characterize mRNA and miRNA expression to elucidate the mechanism of exenatide in the gerbil model.. Gerbils were fed a high-fat diet for 8 weeks to induce a fibrosis model; then, the gerbil models were treated with exenatide for 4 weeks. The total RNA extracted from the liver tissue samples was used to prepare the library and sequence on a HiSeq 2000. Bioinformatic methods were employed to analyze the sequence data to identify the mRNAs and miRNAs and to acquire the miRNA-mRNA regulatory network.. By RNA-seq, 2344 differentially expressed genes (DEGs) and 72 miRNAs were found in the model group. Compared with the model group, 591 DEGs and 19 miRNAs were found in the quercetin group, whereas 876 DEGs and 18 miRNAs were found in the treatment group. The miRNA-mRNA regulatory network was constructed in a gerbil model. Immunohistochemistry and RNA sequencing confirmed that the therapeutic effect of exenatide may be derived from extrahepatic signal transduction. The key differential genes are CYP3A, CYP4A11, ACAA1, ACSM, PHX1, MAO, FMO, UGT, ACOX2, ABAT, PIK3C and PLCG1. The key miRNAs are miR-15a, miR-27b, miR-532-3P, miR-627, miR-3596, miR-142-3P, Let-7e-5p, miR-214-5, miR-101-3p, miR-378d. New miRNAs, such as novel_127, novel_143, novel_15, novel_204 are associated with liver fibrosis, while novel_127, novel_15, and novel_54 are associated with reverse treated with exenatide.. Our research represents the first description of mRNA/miRNA profiles in a gerbil model of fatty liver fibrosis treated with exenatide, which may provide insights into the pathogenesis or treatment of the metabolic syndrome.

Topics: Animals; Exenatide; Gene Expression Profiling; Gene Regulatory Networks; Gerbillinae; Humans; Liver Cirrhosis; MicroRNAs; Non-alcoholic Fatty Liver Disease; RNA, Messenger

Exenatide is a glucagon-like polypeptide-1 analog, whose main clinical use is to treat type 2 diabetes. However, the mechanism of exenatide in mitigating non-alcoholic steatohepatitis (NASH) remains unclear. This study aimed to investigate the. Exenatide treatment inhibited the pyroptosis signaling pathway to attenuate NASH.. To the best of our knowledge, this report provides the first evidence showing that exenatide attenuated NASH by inhibiting the pyroptosis signaling pathway. Exenatide thus has important pathophysiological functions in NASH and may represent a useful new therapeutic target.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Exenatide; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Pyroptosis; Signal Transduction

The hallmark of non-alcoholic fatty liver disease (NAFLD) is the excessive hepatic lipid accumulation. Currently, no pharmacotherapy exists for NAFLD. However, the glucagon-like peptide-1 receptor agonists have recently emerged as potential therapeutics. Here, we sought to identify the long non-coding RNAs (LncRNAs) associated with the steatosis improvement induced by the GLP-1R agonist Exendin-4 (Ex-4) in vitro.. Steatosis was induced in HepG2 cells with oleic acid. The transcriptomic profiling was performed using total RNA extracted from untreated, steatotic, and Ex-4-treated steatotic cells. We validated a subset of differentially expressed LncRNAs with qRT-PCR and identified the most significantly enriched cellular functions associated with the relevant LncRNAs.. We confirm that Ex-4 improves steatosis in HepG2 cells. We found 379 and 180 differentially expressed LncRNAs between untreated and steatotic cells and between steatotic and Ex-4-treated steatotic cells, respectively. Interestingly, 22 upregulated LncRNAs in steatotic cells became downregulated with Ex-4 exposure, while 50 downregulated LncRNAs in steatotic cells became upregulated in the presence of Ex-4. Although some LncRNAs, such as MALAT1, H19, and NEAT1, were previously associated with NAFLD, the association of others with steatosis and the positive effect of Ex-4 is being reported for the first time. Functional enrichment analysis identified many critical pathways, including fatty acid and pyruvate metabolism, and insulin, PPAR, Wnt, TGF-β, mTOR, VEGF, NOD-like, and Toll-like receptors signaling pathways.. Our results suggest that LncRNAs may play essential roles in the mechanisms underlying steatosis improvement in response to GLP-1R agonists and warrant further functional studies.

Topics: Exenatide; Hep G2 Cells; Humans; Liver; Non-alcoholic Fatty Liver Disease; RNA, Long Noncoding

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Topics: Alstrom Syndrome; Animals; Blood Glucose; Calcium; Calcium Signaling; Diabetes Mellitus, Type 2; Disease Models, Animal; Endoplasmic Reticulum; Exenatide; Fluorescent Dyes; Fura-2; Glucagon-Like Peptide 1; Hepatocytes; Hypoglycemic Agents; Insulin; Insulin Resistance; Liver; Male; Mice; Mice, Transgenic; Non-alcoholic Fatty Liver Disease; Obesity; Palmitic Acid

To investigate the effect of exendin-4 on lipid deposition in hepatocytes and explore its possible mechanism for treatment of nonalcoholic fatty liver disease (NAFLD).. Human normal hepatocyte line LO2 and hepatoma cell line HepG2 were treated with palmitic acid (PA) to mimic hepatocyte steatosis or with combined treatments with PA+exendin-4 or PA+exendin-4+3BDO. Lipid deposition and proliferation of the two cell lines following treatment with PA or PA+exendin-4 were detected using Oil Red O staining and CCK8 assay, and the expression of p-mTOR, m-TOR, p-AKT, AKT and autophagy-related proteins LC3-Ⅰ/Ⅱ and p62 were detected with Western blotting; the expression of GLP-1R was detected with both Western blotting and immunofluorescence assay. The expression of LC3-Ⅰ/Ⅱ and p62 in the cells following treatment with PA+exendin-4 and PA+exendin-4+3BDO was detected with Western blotting.. Lipid deposition in the two cell lines increased significantly after PA treatment, but was alleviated by co-treatment with exendin-4. PA treatment significantly inhibited the proliferation of the two cell lines (. Exendin-4 may activate the AKT-mTOR signal pathway to promote autophagy

Topics: Autophagy; Exenatide; Humans; Non-alcoholic Fatty Liver Disease; Palmitic Acid; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease. This study aimed to evaluate the role of exenatide compared with metformin in halting the progression of fatty liver stimulated by a high-fat diet (HiFD) in rats.. Thirty male Wistar rats were allocated into 6 groups, 5 rats per each group. Group I: maintained on normal diet (normal group) for fourteen weeks. The other five groups were kept on HiFD throughout the experiment, HiFD was administered beside pharmacological treatments/or vehicle. Group II: (NAFLD control group), group III: received metformin (60 mg/kg/day, P.O.), group IV-VI: received exenatide (10, 20, and 40 μg/kg/day, S.C.) respectively for 7 weeks. At the end of the therapeutic period, fasting blood glucose was determined, and body weight was registered. Rats were sacrificed, and blood samples were taken to measure serum insulin, lipids, and liver enzymes. The liver index and homeostasis model of insulin resistance (HOMA-IR) index were calculated. Further, livers were dissected for histopathological examination and Western blot analysis.. NAFLD control group showed hyperglycemia, hyperinsulinemia, increased liver enzymes, hypertriglyceridemia, elevated hepatic lipid peroxides, and inflammatory mediators (interlukin 6, nuclear factor-κB, tumor necrosis factor-α and Toll-like receptor4) in addition to hepatic fatty degeneration. In a dose-dependent manner, exenatide significantly improved most of the above mentioned markers in comparsion with NAFLD at P≤0.05.. The current results suggest that exenatide is equivalent to metformin in controlling insulin resistance, body weight gain, improving liver function, suppressing inflammation, and attenuating NAFLD progression in male rats.

Topics: Animals; Body Weight; Diet, High-Fat; Disease Progression; Dose-Response Relationship, Drug; Exenatide; Hypoglycemic Agents; Inflammation; Insulin Resistance; Male; Metformin; NF-kappa B; Non-alcoholic Fatty Liver Disease; Rats; Rats, Wistar; Signal Transduction; Toll-Like Receptor 4

GLP-1 receptor agonists, such as exenatide, have been proven to attenuate nonalcoholic fatty liver disease (NAFLD) in vivo and in vitro. However, the efficiency of exenatide had interindividual differences. PNPLA3 is a major susceptibility gene for NAFLD and its I148M polymorphism increases the risk of all disorders of the NAFLD spectrum. Whether this variant contributes to variability in exenatide response is still unclear.. PNPLA3 148I knockin HepG2 cells were constructed using the Cas9/sgRNA system. Oil Red O staining combined with TG quantification was used to evaluate lipid accumulation. Western blotting and qRT-qPCR were conducted, respectively, to measure the protein and mRNA expression of lipid metabolic and endoplasmic reticulum (ER) stress-related inflammatory markers. PNPLA3 I148M was genotyped in type 2 diabetics using Sanger sequencing. The exenatide-induced changes in liver fat content and other clinical parameters were compared between PNPLA3 I148M genotypes.. Lipid deposition increased in both PNPLA3 148I/I and 148M/M HepG2 cells treated with palmitoleic acid, while cells with 148M/M had a higher TG content than those with 148I/I. Exendin-4 treatment was showed to be more significant in 148I/I cells than in 148M/M cells in terms of reducing the intrahepatic fat content, inhibiting SREBP-1c and ER stress-related inflammation, and activating AMPK-ACC lipid oxidation pathway. In patients with type 2 diabetes, 24-week treatment with exenatide improved liver fat content in patients carrying PNPLA3 148I/I better than in patients with 148M/M.. PNPLA3 I148M might modify the anti-NAFLD response to exenatide.

Topics: Diabetes Mellitus, Type 2; Exenatide; Genetic Predisposition to Disease; Genotype; Hep G2 Cells; Humans; Lipase; Liver; Membrane Proteins; Non-alcoholic Fatty Liver Disease

The intestinal microenvironment, a potential factor that contributes to the development of non-alcoholic fatty liver disease (NALFD) and type 2 diabetes (T2DM), has a close relationship with intestinal tight junctions (TJs). Here, we show that the disruption of intestinal TJs in the intestines of 16-week-old db/db mice and in high glucose (HG)-cultured Caco-2 cells can both be improved by sodium butyrate (NaB) in a dose-dependent manner in vitro and in vivo. Accompanying the improved intestinal TJs, NaB not only relieved intestine inflammation of db/db mice and HG and LPS co-cultured Caco-2 cells but also restored intestinal Takeda G-protein-coupled (TGR5) expression, resulting in up-regulated serum GLP-1 levels. Subsequently, the GLP-1 analogue Exendin-4 was used to examine the improvement of lipid accumulation in HG and free fatty acid (FFA) co-cultured HepG2 cells. Finally, we used 16-week-old db/db mice to examine the hepatoprotective effects of NaB and its producing strain Clostridium butyricum. Our data showed that NaB and Clostridium butyricum treatment significantly reduced the levels of blood glucose and serum transaminase and markedly reduced T2DM-induced histological alterations of the liver, together with improved liver inflammation and lipid accumulation. These findings suggest that NaB and Clostridium butyricum are a potential adjuvant treatment strategy for T2DM-induced NAFLD; their hepatoprotective effect was linked to the modulation of intestinal TJs, causing the restoration of glucose and lipid metabolism and the improvement of inflammation in hepatocytes.

Topics: Animals; Blood Glucose; Butyric Acid; Caco-2 Cells; Cholesterol; Clostridium butyricum; Colon; Cytokines; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Hep G2 Cells; Humans; Hypoglycemic Agents; Inflammation; Intestines; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Receptors, G-Protein-Coupled; Tight Junctions; Triglycerides

Obesity and associated metabolic comorbidities represent a growing public health problem. In this study, we demonstrate the use of a newly created fusion gene of exendin-4 and α1-antitrypsin to control obesity and obesity-associated metabolic disorders including insulin resistance, fatty liver and hyperglycemia. The fusion gene encodes a protein with exendin-4 peptide placed at the N-terminus of human α-1 antitrypsin, and is named EAT. Hydrodynamic transfer of the EAT gene to mice prevents high-fat diet-induced obesity, insulin resistance and fatty liver development. In diet-induced obese mice, expression of EAT gene induces weight loss, improves glucose homeostasis, and attenuates hepatic steatosis. In ob/ob mice, EAT gene transfer suppresses body weight gain, maintains metabolic homeostasis, and completely blocks fatty liver development. Six-month overexpression of the EAT fusion gene in healthy mice does not lead to any detectable toxicity. Mechanistic study reveals that the resulting metabolic benefits are achieved by a reduced food take and down-regulation of transcription of pivotal genes responsible for lipogenesis and lipid droplet formation in the liver and chronic inflammation in visceral fat. These results validate the feasibility of gene therapy in preventing and restoring metabolic homeostasis under diverse pathologic conditions, and provide evidence in support of a new strategy to control obesity and related metabolic diseases.

Topics: Adiposity; alpha 1-Antitrypsin; Animals; Anti-Obesity Agents; Diet, High-Fat; Exenatide; Gene Expression Regulation; Genetic Vectors; Glucose; Insulin Resistance; Leptin; Male; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Protein Engineering; Recombinant Fusion Proteins; Weight Gain

Exenatide (Exe) is a glucagon-like peptide (GLP)-1 receptor agonist that enhances insulin secretion and is associated with induction of satiety with weight loss. As mitochondrial dysfunction and lipotoxicity are central features of nonalcoholic steatohepatitis (NASH), we tested whether Exe improved mitochondrial function in this setting. We studied C57BL/6J mice fed for 24 weeks either a control- or high-fructose, high-trans-fat (TFD)-diet (i.e., a NASH model previously validated by our laboratory). For the final 8 weeks, mice were treated with Exe (30 µg/kg/day) or vehicle. Mitochondrial metabolism was assessed by infusion of [13C3]propionate, [3,4-13C2]glucose and NMR-based 13C-isotopomer analysis. Exenatide significantly decreased fasting plasma glucose, free fatty acids and triglycerides, as well as adipose tissue insulin resistance. Moreover, Exe reduced 23% hepatic glucose production, 15% tri-carboxylic acid (TCA) cycle flux, 20% anaplerosis and 17% pyruvate cycling resulting in a significant 31% decrease in intrahepatic triglyceride content (P = 0.02). Exenatide improved the lipidomic profile and decreased hepatic lipid byproducts associated with insulin resistance and lipotoxicity, such as diacylglycerols (TFD: 111 ± 13 vs Exe: 64 ± 13 µmol/g protein, P = 0.03) and ceramides (TFD: 1.6 ± 0.1 vs Exe: 1.3 ± 0.1 µmol/g protein, P = 0.03). Exenatide lowered expression of hepatic lipogenic genes (Srebp1C, Cd36) and genes involved in inflammation and fibrosis (Tnfa, Timp1). In conclusion, in a diet-induced mouse model of NASH, Exe ameliorates mitochondrial TCA cycle flux and significantly decreases insulin resistance, steatosis and hepatocyte lipotoxicity. This may have significant clinical implications to the potential mechanism of action of GLP-1 receptor agonists in patients with NASH. Future studies should elucidate the relative contribution of direct vs indirect mechanisms at play.

Topics: Adipose Tissue; Animals; Blood Glucose; Citric Acid Cycle; Diet, High-Fat; Exenatide; Fatty Acids, Nonesterified; Fibrosis; Gene Expression Profiling; Glucagon-Like Peptide 1; Hepatocytes; Hypoglycemic Agents; Inflammation; Insulin Resistance; Lipid Metabolism; Lipidomics; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mitochondria; Non-alcoholic Fatty Liver Disease; Triglycerides

Exendin-4, a glucagon-like peptide-1 receptor agonist has been shown to have curative effects on hepatic steatosis in murine models.. The present study aimed to elucidate the effect of Exendin-4 on hepatic receptor for advanced glycation end products (RAGE) mRNA expression in non-alcoholic steatohepatitis (NASH) rat model induced by high-fat diet.. NASH was induced by high-fat diet intake, and Exendin-4 was given in two different doses. After 12 weeks, liver enzyme levels, hepatic triglycerides, antioxidant enzymes and malondialdehyde (MDA) levels, and mRNA RAGE was detected using RT-PCR.. Exendin-4 in high dose reduced significantly liver enzymes activity, hepatic triglycerides, MDA levels and hepatic mRNA RAGE expression levels with significantly higher antioxidant enzymes activity.. Our results give further insights into the mechanisms underlying the curative role of Exendin-4 in NASH, suggesting that interference with RAGE may be a useful therapeutic approach to NASH.

Topics: Animals; Biomarkers; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Induction; Exenatide; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Insulin Resistance; Lipid Peroxidation; Liver; Male; Non-alcoholic Fatty Liver Disease; Organ Size; Oxidative Stress; Oxidoreductases; Peptides; Random Allocation; Rats, Wistar; Receptor for Advanced Glycation End Products; Triglycerides; Venoms

Topics: Animals; Exenatide; Glucagon; Glucagon-Like Peptide 1; Liver; Male; Mice; Non-alcoholic Fatty Liver Disease; Peptides; Receptors, Glucagon; Venoms

Non-alcoholic fatty liver disease (NAFLD) is a common disease associated with metabolic syndrome and can lead to life-threatening complications like hepatic carcinoma and cirrhosis. Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist antidiabetic drug, has the capacity to overcome insulin resistance and attenuate hepatic steatosis but the specific underlying mechanism is unclear. This study was designed to investigate the underlying molecular mechanisms of exenatide therapy on NAFLD. We used in vivo and in vitro techniques to investigate the protective effects of exenatide on fatty liver via fat mass and obesity associated gene (FTO) in a high-fat (HF) diet-induced NAFLD animal model and related cell culture model. Exenatide significantly decreased body weight, serum glucose, insulin, insulin resistance, serum free fatty acid, triglyceride, total cholesterol, low-density lipoprotein, aspartate aminotransferase, and alanine aminotransferase levels in HF-induced obese rabbits. Histological analysis showed that exenatide significantly reversed HF-induced lipid accumulation and inflammatory changes accompanied by decreased FTO mRNA and protein expression, which were abrogated by PI3K inhibitor LY294002. This study indicated that pharmacological interventions with GLP-1 may represent a promising therapeutic strategy for NAFLD.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Blood Glucose; Body Weight; Chromones; Diet, High-Fat; Disease Models, Animal; Eating; Enzyme Inhibitors; Exenatide; Fatty Liver; Gene Expression Regulation; In Vitro Techniques; Insulin; Male; Malondialdehyde; Morpholines; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Peptides; Phosphatidylinositol 3-Kinases; Protective Agents; Rabbits; Superoxide Dismutase; Venoms

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.. 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.. Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fatty acid transport protein 4 (FATP4), a hepatic FFA influx-related 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) mRNA (lipogenesis-related gene) and acyl-coenzyme A oxidase 1 (ACOX1) mRNA (β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein mRNA (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 mRNA level.. 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.

Topics: Acyl-CoA Oxidase; Animals; Biomarkers; Disease Models, Animal; Exenatide; Fatty Acid Transport Proteins; Fatty Acids, Nonesterified; Gene Expression Regulation; Glucagon-Like Peptide 1; Inflammation Mediators; Liver; Macrophages; Male; Mice, Inbred NOD; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Peptides; Sterol Regulatory Element Binding Protein 1; Time Factors; Triglycerides; Venoms

To compare the effect of different hypoglycemic drugs on laboratory and ultrasonographic markers of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes not controlled on metformin alone.. Prospective study of diabetic patients treated with metformin in combination with gliclazide, pioglitazone, sitagliptin, exenatide, or liraglutide. NAFLD was assessed by abdominal ultrasound and NAFLD fibrosis score was calculated at baseline and 6 months.. Fifty-eight patients completed 6 months of follow-up: 15 received gliclazide, 13 pioglitazone, 15 sitagliptin, 7 exenatide, and 8 liraglutide. NAFLD affected 57.8% of patients at baseline, and its ultrasonographic course varied depending on changes in weight (P=.009) and waist circumference (P=.012). The proportions of patients who experienced ultrasonographic improvement in the different treatment groups were: 33.3% with gliclazide, 37.5% with pioglitazone, 45.5% with sitagliptin, 80% with exenatide, and 33% with liraglutide (P=.28).. Qualitative ultrasonographic NAFLD improvement in diabetic patients treated with metformin in combination with other hypoglycemic drugs is associated to change over time in weight and waist circumference. Long-term clinical trials are needed to assess whether incretin therapies result in better liver outcomes than other hypoglycemic therapies.

Topics: Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Lipids; Liraglutide; Liver Function Tests; Male; Metabolic Syndrome; Metformin; Middle Aged; Non-alcoholic Fatty Liver Disease; Peptides; Pilot Projects; Pioglitazone; Prospective Studies; Sitagliptin Phosphate; Thiazolidinediones; Venoms; Waist Circumference

The CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), a major transcriptional regulator of endoplasmic reticulum (ER) stress-mediated apoptosis, is implicated in lipotoxicity-induced ER stress and hepatocyte apoptosis in non-alcoholic fatty liver disease (NAFLD). We have previously demonstrated that the glucagon-like peptide-1 (GLP-1) agonist, liraglutide, protects steatotic hepatocytes from lipotoxicity-induced apoptosis by improved handling of free fatty acid (FFA)-induced ER stress. In the present study, we investigated whether CHOP is critical for GLP-1-mediated restoration of ER homeostasis and mitigation of hepatocyte apoptosis in a murine model of NASH (non-alcoholic steatohepatitis). Our data show that despite similar caloric intake, CHOP KO (CHOP(-/-)) mice fed a diet high in fat, fructose, and cholesterol (HFCD) for 16 weeks developed more severe histological features of NASH compared with wild-type (WT) controls. Severity of NASH in HFCD-fed CHOP(-/-) mice correlated with significant decrease in peroxisomal β-oxidation, and increased de novo lipogenesis and ER stress-mediated hepatocyte apoptosis. Four weeks of liraglutide treatment markedly attenuated steatohepatitis in HFCD-fed WT mice by improving insulin sensitivity, and suppressing de novo lipogenesis and ER stress-mediated hepatocyte apoptosis. However, in the absence of CHOP, liraglutide did not improve insulin sensitivity, nor suppress peroxisomal β-oxidation or ER stress-mediated hepatocyte apoptosis. Taken together, these data indicate that CHOP protects hepatocytes from HFCD-induced ER stress, and has a significant role in the mechanism of liraglutide-mediated protection against NASH pathogenesis.

Topics: Animals; Apoptosis; Blood Glucose; Cells, Cultured; Cholesterol; Diet, High-Fat; Dietary Carbohydrates; Disease Models, Animal; Endoplasmic Reticulum Stress; Exenatide; Hepatocytes; Insulin Resistance; Lipid Metabolism; Liraglutide; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Peptides; Protective Agents; Transcription Factor CHOP; Venoms

Non-alcoholic fatty liver disease (NAFLD) is associated with increased plasma homocysteine level, which is caused by down-regulation of hepatic cystathionine beta-synthase (CBS) activity. CBS catalyzes the first step in the transsulfuration of homocysteine to cysteine, which contributes ∼50% of the cysteine required for hepatic biosynthesis of glutathione (GSH), the most abundant antioxidant in cells. As the glucagon-like peptide-1 (GLP-1) receptor agonists (e.g. exendin-4) effectively reverse hepatic steatosis, the effect of exendin-4 on both homocysteine and redox status was investigated in the livers of rats fed with high-fat diet (HFD). It was found that HFD down-regulated CBS protein expression, which was probably due to induction of rno-miR-376c expression in the liver. The level of GSH was markedly reduced, whereas the level of malonydialdehyde, an indicator of lipid peroxidation, was significantly increased in the livers of rats fed with HFD. Exendin-4 treatment increased hepatic CBS protein and GSH levels, and reduced malonydialdehyde level in hyperlipidemic rats. Our findings suggest that GLP-1 receptor agonists have beneficial effects on redox homeostasis in NAFLD.

Topics: Animals; Cystathionine beta-Synthase; Diet, High-Fat; Down-Regulation; Exenatide; Glutathione; Homeostasis; Homocysteine; Male; Malondialdehyde; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction; Peptides; Rats; Rats, Sprague-Dawley; RNA, Messenger; Venoms

Topics: Alanine Transaminase; Aspartate Aminotransferases; Biomarkers; Body Mass Index; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Peptides; Triglycerides; Venoms; Waist Circumference

The aetiology of inflammation in the liver and vessel wall, leading to non-alcoholic steatohepatitis (NASH) and atherosclerosis, respectively, shares common mechanisms including macrophage infiltration. To treat both disorders simultaneously, it is highly important to tackle the inflammatory status. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces hepatic steatosis and has been suggested to reduce atherosclerosis; however, its effects on liver inflammation are underexplored. Here, we tested the hypothesis that exendin-4 reduces inflammation in both the liver and vessel wall, and investigated the common underlying mechanism.. Female APOE*3-Leiden.CETP mice, a model with human-like lipoprotein metabolism, were fed a cholesterol-containing Western-type diet for 5 weeks to induce atherosclerosis and subsequently treated for 4 weeks with exendin-4.. Exendin-4 modestly improved dyslipidaemia, but markedly decreased atherosclerotic lesion severity and area (-33%), accompanied by a reduction in monocyte adhesion to the vessel wall (-42%) and macrophage content in the plaque (-44%). Furthermore, exendin-4 reduced hepatic lipid content and inflammation as well as hepatic CD68⁺ (-18%) and F4/80⁺ (-25%) macrophage content. This was accompanied by less monocyte recruitment from the circulation as the Mac-1⁺ macrophage content was decreased (-36%). Finally, exendin-4 reduced hepatic chemokine expression in vivo and suppressed oxidized low-density lipoprotein accumulation in peritoneal macrophages in vitro, effects dependent on the GLP-1 receptor.. Exendin-4 reduces inflammation in both the liver and vessel wall by reducing macrophage recruitment and activation. These data suggest that exendin-4 could be a valuable strategy to treat NASH and atherosclerosis simultaneously.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apolipoprotein E3; Atherosclerosis; Cholesterol Ester Transfer Proteins; Diet, Atherogenic; Disease Models, Animal; Drug Implants; Dyslipidemias; Endothelium, Vascular; Exenatide; Fatty Liver; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypolipidemic Agents; Liver; Macrophage Activation; Macrophages; Mice; Mice, Transgenic; Non-alcoholic Fatty Liver Disease; Peptides; Random Allocation; Receptors, Glucagon; Venoms

To investigate the metabolic changes in skeletal muscle and/or adipose tissue in glucagon-like peptide-1-induced improvement of nonalcoholic fatty liver disease (NAFLD).. Male Wistar rats were fed either a control diet (control group) or a high-fat diet (HFD). After 4 wk, the HFD-fed rats were subdivided into two groups; one group was injected with exenatide [HFD-Ex(+) group] and the other with saline [HFD-Ex(-) group] every day for 12 wk. The control group received saline and were fed a control diet. Changes in weight gain, energy intake, and oxygen consumption were analyzed. Glucose tolerance tests were performed after 8 wk of treatment. Histological assessments were performed in liver and adipose tissue. RNA expression levels of lipid metabolism related genes were evaluated in liver, skeletal muscle, and adipose tissue.. Exenatide attenuated weight gain [HFD-Ex(-) vs HFD-Ex(+)] and reduced energy intake, which was accompanied by an increase in oxygen consumption and a decrease in the respiratory exchange ratio [HFD-Ex(-) vs HFD-Ex(+)]. However, exenatide did not affect glucose tolerance. Exenatide reduced lipid content in the liver and adipose tissue. Exenatide did not affect the expression of lipid metabolism-related genes in the liver or skeletal muscle. In adipose tissue, exenatide significantly upregulated lipolytic genes, including hormone-sensitive lipase, carnitine palmitoyltransferase-1, long-chain acyl-CoA dehydrogenase, and acyl-CoA oxidase 1 [HFD-Ex(-) vs HFD-Ex(+)]. Exenatide also upregulated catalase and superoxide dismutase 2 [HFD-Ex(-) vs HFD-Ex(+)].. In addition to reducing appetite, enhanced lipid use by exenatide in adipose tissue may reduce hepatic lipid content in NAFLD, most likely by decreasing lipid influx into the liver.

Topics: Adipose Tissue; Animals; Appetite Regulation; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Energy Intake; Energy Metabolism; Exenatide; Gene Expression Regulation, Enzymologic; Lipolysis; Liver; Male; Mitochondria; Muscle, Skeletal; Non-alcoholic Fatty Liver Disease; Oxygen Consumption; Peptides; Rats, Wistar; Time Factors; Up-Regulation; Venoms; Weight Gain

GLP-1 and incretin mimetics, such as exenatide, have been shown to attenuate hepatocyte steatosis in vivo and in vitro, but the specific underlying mechanism is unclear. SIRT1, an NAD(+)-dependent protein deacetylase, has been considered as a crucial regulator in hepatic lipid homeostasis by accumulated studies. Here, we speculate that SIRT1 might mediate the effect of the GLP-1 receptor agonist exenatide (exendin-4) on ameliorating hepatic steatosis. After 8 weeks of exenatide treatment in male SIRT1(+/-) mice challenged with a high-fat diet and their wild-type (WT) littermates, we found that lipid deposition and inflammation in the liver, which were improved dramatically in the WT group, diminished in SIRT1(+/-) mice. In addition, the protein expression of SIRT1 and phosphorylated AMPK was upregulated, whereas lipogenic-related protein, including SREBP-1c and PNPLA3, was downregulated in the WT group after exenatide treatment. However, none of these changes were observed in SIRT1(+/-) mice. In HepG2 cells, exendin-4-reversed lipid deposition induced by palmitate was hampered when SIRT1 was silenced by SIRT1 RNA interference. Our data demonstrate that SIRT1 mediates the effect of exenatide on ameliorating hepatic steatosis, suggesting the GLP-1 receptor agonist could serve as a potential drug for nonalcoholic fatty liver disease (NAFLD), especially in type 2 diabetes combined with NAFLD, and SIRT1 could be a therapeutic target of NAFLD.

Topics: Animals; Diabetes Mellitus, Type 2; Exenatide; Fatty Liver; Glucagon-Like Peptide-1 Receptor; Male; Mice; Non-alcoholic Fatty Liver Disease; Peptides; Receptors, Glucagon; RNA Interference; Sirtuin 1; Venoms

Glucagon‑like peptide‑1 (GLP‑1) is involved in the development of non‑alcoholic steatohepatitis (NASH), which is characterized by fatty acid imbalance. The aim of this study was to investigate the effects of the GLP‑1 receptor (GLP‑1R) agonist, exendin‑4 (Ex‑4), on hepatic fatty acid metabolism and its key enzyme, Δ‑5‑desaturase, in a murine model of NASH. NASH was induced in db/db mice fed a methionine‑choline deficient (MCD) diet. Ex‑4 (n=4) or saline [control (CON); n=4] was administered intraperitoneally for 8 weeks. Steatohepatitis activity was evaluated by non‑alcoholic fatty liver disease (NAFLD) activity score. Hepatic fatty acid composition and Δ‑5‑desaturase index were analyzed by gas chromatography. Ex‑4 treatment significantly reduced body weight and the NAFLD activity score. Hepatic concentrations of long‑chain saturated fatty acids (SFAs) were significantly higher in the Ex‑4 group compared to the CON group (23240±955 vs. 31710±8436 µg/g•liver, P<0.05).Ex‑4 significantly reduced hepatic n‑3 polyunsaturated fatty acid (PUFA)/n‑6 PUFA ratio compared to the CON group (13.83±3.15 vs. 8.73±1.95, P<0.05). In addition, the hepatic Δ‑5‑desaturase index was significantly reduced in the Ex‑4 group compared to the CON group (31.1±12.4 vs. 10.5±3.1, P<0.05). In conclusion, the results showed that Ex‑4 improved steatohepatitis in a murine model of NASH. Furthermore, Ex‑4 altered hepatic long‑chain saturated and PUFA composition and reduced the Δ‑5‑desaturase index. Thus, Ex‑4 may improve NASH by regulating hepatic fatty acid metabolism.

Topics: Animals; Body Weight; Delta-5 Fatty Acid Desaturase; Disease Models, Animal; Exenatide; Fatty Acid Desaturases; Fatty Acids; Glucagon-Like Peptide-1 Receptor; Liver; Male; Mice; Models, Biological; Non-alcoholic Fatty Liver Disease; Peptides; Receptors, Glucagon; Triglycerides; Venoms

Ischemia-reperfusion injury (IRI) is a common clinical consequence of hepatic surgery, cardiogenic shock, and liver transplantation. A steatotic liver is particularly vulnerable to IRI, responding with extensive hepatocellular injury. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in IRI, although its role in IRI of a steatotic liver is unclear. The role of autophagy was investigated in high-fat diet (HFD)-fed mice exposed to IRI in vivo and in steatotic hepatocytes exposed to hypoxic IRI (HIRI) in vitro. Two inhibitors of autophagy, 3-methyladenine and bafilomycin A1, protected the steatotic hepatocytes from HIRI. Exendin 4 (Ex4), a glucagon-like peptide 1 analog, also led to suppression of autophagy, as evidenced by decreased autophagy-associated proteins [microtubule-associated protein 1A/1B-light chain 3 (LC3) II, p62, high-mobility group protein B1, beclin-1, and autophagy-related protein 7], reduced hepatocellular damage, and improved mitochondrial structure and function in HFD-fed mice exposed to IRI. Decreased autophagy was further demonstrated by reversal of a punctate pattern of LC3 and decreased autophagic flux after IRI in HFD-fed mice. Under the same conditions, the effects of Ex4 were reversed by the competitive antagonist exendin 9-39. The present study suggests that, in IRI of hepatic steatosis, treatment of hepatocytes with Ex4 mitigates autophagy, ameliorates hepatocellular injury, and preserves mitochondrial integrity. These data suggest that therapies targeting autophagy, by Ex4 treatment in particular, may ameliorate the effects of IRI in highly prevalent steatotic liver.

Topics: Adenine; Animals; Autophagy; Cells, Cultured; Exenatide; Hepatocytes; Humans; Macrolides; Male; Mice; Mice, Inbred C57BL; Mitochondria, Liver; Non-alcoholic Fatty Liver Disease; Peptides; Reperfusion Injury; Venoms

The aim of this study was to examine the effects of a new sustained-release (SR) microsphere formulation of exenatide, DA-3091, on body weight gain and hepatic injury in high fat diet (HFD)-induced obese mice and high sucrose diet (HSD)-induced non-alcoholic fatty liver disease (NAFLD) mice. Then, we determined whether DA-3091 has the potency as a drug for the treatment of metabolic disease. In obese mice, after 8-week treatment, the body weight gain was significantly more suppressed by both 1 mg/kg and 2 mg/kg of DA-3091, monthly subcutaneous administered, than by 10 mg/kg/day of sibutramin, a drug against obesity. In NAFLD mice, a significant reduction in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, representative markers of hepatic injury, was observed after biweekly subcutaneous administration of 1 mg/kg and 2 mg/kg of DA-3091 for 8 weeks. A significant reduction in hepatic lipid accumulation was observed in DA-3091 treated groups as well. Based on these results, it is demonstrated that DA-3091 has the potency as a drug for the treatment of metabolic disease.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Glucose; Body Weight; Cholesterol; Delayed-Action Preparations; Dietary Fats; Endotoxins; Exenatide; Fatty Liver; Hypoglycemic Agents; Liver; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Microspheres; Non-alcoholic Fatty Liver Disease; Obesity; Organ Size; Peptides; Prodrugs; Sucrose; Venoms

High-fat dietary intake and low physical activity lead to insulin resistance, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Recent studies have shown an effect of glucagon-like peptide-1 (GLP-1) on hepatic glucose metabolism, although GLP-1 receptors (GLP-1r) have not been found in human livers. The aim of this study was to investigate the presence of hepatic GLP-1r and the effect of exenatide, a GLP-1 analogue, on hepatic signalling.. The expression of GLP-1r was evaluated in human liver biopsies and in the livers of high-fat diet-treated rats. The effect of exenatide (100 nM) was evaluated in hepatic cells of rats fed 3 months with the high-fat diet.. GLP-1r is expressed in human hepatocytes, although reduced in patients with NASH. Similarly, in rats with NASH resulted from 3 months of the high-fat diet, we found a decreased expression of GLP-1r and peroxisome proliferator-activated receptor γ (PPARγ), and reduced peroxisome proliferator-activated receptor α (PPARα) activity. Incubation of hepatocytes with exenatide increased PPARγ expression, which also exerted an insulin-sensitizing action by reducing JNK phosphorylation. Moreover, exenatide increased protein kinase A (PKA) activity, Akt and AMPK phosphorylation and determined a PKA-dependent increase of PPARα activity.. GLP-1 has a direct effect on hepatocytes, by activating genes involved in fatty acid β-oxidation and insulin sensitivity. GLP-1 analogues could be a promising treatment approach to improve hepatic insulin resistance in patients with NAFLD/NASH.

Topics: AMP-Activated Protein Kinases; Animals; Biopsy; Cyclic AMP-Dependent Protein Kinases; Dietary Fats; Disease Models, Animal; Exenatide; Fatty Acids; Fatty Liver; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Hep G2 Cells; Hepatocytes; Humans; Hypoglycemic Agents; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Liver; Male; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction; Peptides; Phosphorylation; PPAR alpha; PPAR gamma; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Signal Transduction; Time Factors; Venoms

Topics: Animals; Dietary Fats; Exenatide; Fatty Liver; Glucagon-Like Peptide-1 Receptor; Hepatocytes; Humans; Hypoglycemic Agents; Liver; Male; Non-alcoholic Fatty Liver Disease; Peptides; Receptors, Glucagon; Signal Transduction; Venoms