oxyntomodulin and Non-alcoholic-Fatty-Liver-Disease

This systematic review and meta-analysis was conducted to evaluate the efficacy and safety of 24 weeks of semaglutide treatment in patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).. PubMed, Embase, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov databases were searched for relevant studies. The primary outcome was the change in the serum alanine transaminase level. The secondary outcomes were changes in liver stiffness, liver function test parameters, metabolic parameters, and safety. Pooled mean differences and relative risks were calculated using random-effects models.. Six hundred studies were screened and eight were included (n = 2413). Semaglutide treatment showed a reduction in serum alanine transaminase [mean difference: 14.07 U/L (95% CI: 19.39 to -8.75); p < 0.001] and aspartate transaminase [mean difference: 6.89 U/L (95% CI: 9.14 to -4.63); p < 0.001] levels. There was a significant improvement in liver fat content [mean difference: 4.97% (95% CI: 6.65 to -3.29); p < 0.001] and liver stiffness [mean difference: 0.96 kPa (95% CI: 1.87 to -0.04); p = 0.04]. There were significant improvements in the glycated hemoglobin level and the lipid profile. However, the risk of serious adverse events [relative risk: 1.54 (95% CI: 1.02 to 2.34); p = 0.04] was high following semaglutide treatment as compared to placebo; the most common ones were gastrointestinal (nausea and vomiting, dyspepsia, decreased appetite, constipation, and diarrhea) and gallbladder-related diseases.. Treatment with 24 weeks of semaglutide could significantly improve liver enzymes, reduce liver stiffness, and improve metabolic parameters in patients with NAFLD/NASH. However, the gastrointestinal adverse effects could be a major concern.

Topics: Alanine Transaminase; Glucagon-Like Peptides; Humans; Liver; Non-alcoholic Fatty Liver Disease

Semaglutide, a peptidic GLP-1 receptor agonist, has been clinically approved for treatment of type 2 diabetes mellitus and is available in subcutaneous and oral dosage form. Diabetes, insulin resistance, and obesity are responsible for the pathological manifestations of non-alcoholic steatohepatitis (NASH). Similarly, insulin resistance in brain is also responsible for neurodegeneration and impaired cognitive functions.. Observations from phase-3 clinical trials like SUSTAIN and PIONEER indicated anti-obesity potential of semaglutide, which was established in STEP trials. Various pre-clinical and phase-2 studies have indicated the therapeutic potential of semaglutide in non-alcoholic steatohepatitis and neurodegenerative disorders like Parkinson's and Alzheimer's disease.. Significant weight reduction ability of semaglutide has been demonstrated in various phase-3 clinical trials, for which recently semaglutide became the first long-acting GLP-1 receptor agonist to be approved by the United States Food and Drug Administration for management of obesity. Various pre-clinical and clinical studies have revealed the hepatoprotective effect of semaglutide in NASH and neuroprotective effect in Parkinson's and Alzheimer's disease.. Many GLP-1 receptor agonists have shown hepatoprotective and neuroprotective activity in animal and human trials. As semaglutide is an already clinically approved drug, successful human trials would hasten its inclusion into therapeutic treatment of NASH and neurodegenerative diseases. Semaglutide improves insulin resistance, insulin signalling pathway, and reduce body weight which are responsible for prevention or progression of NASH and neurodegenerative diseases.

Topics: Alzheimer Disease; Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Hypoglycemic Agents; Insulin Resistance; Neurodegenerative Diseases; Non-alcoholic Fatty Liver Disease; Obesity; Parkinson Disease

Topics: Animals; Antioxidants; Fibroblast Growth Factors; Glucagon-Like Peptide Receptors; Glucagon-Like Peptides; Humans; Non-alcoholic Fatty Liver Disease; Receptor, Fibroblast Growth Factor, Type 1

There is an unmet medical need for an effective anti-fibrotic treatment for NASH with advanced fibrosis.. The authors review the current and novel agents for the treatment of NASH with fibrosis. They also consider the potential future strategies of combination therapies.. Farnesoid X receptor (FXR) agonist (obeticholic acid [OCA]) significantly ameliorated hepatic fibrosis in NASH stage 2/3 fibrosis in an interim analysis of phase 3 trial. Because OCA has several drawbacks such as itching and elevated low-density lipoprotein-cholesterol (LDL-C), non-bile acid FXR agonists are now under development. Selonsertib (apoptosis signaling kinase 1 inhibitor), emricasan (an irreversible pan-caspase inhibitor), and simtsuzumab (a monoclonal antibody against lysyl oxidase-like 2) were discontinued because of no efficacy over placebo. Peroxisome proliferator-activator receptor α/δ agonists, C-C motif chemokine receptor-2/5 antagonists, and thyroid β receptor agonist are ongoing in phase 3 trials. A variety of agents including fibroblast growth factor (FGF)-21 and FGF-19 agonists, as well as acetyl-CoA carboxylase inhibitors, are also expected. Among antidiabetic agents, semaglutide, a novel GLP-1 RA, is ongoing for NASH stage 1-3 fibrosis in a phase 2 trial. Furthermore, the combination of GLP-RA/glucagon receptor agonist and GLP-RA/gastrointestinal peptide agonist are promising future options.

Topics: Chenodeoxycholic Acid; Clinical Trials as Topic; Fibroblast Growth Factors; Glucagon-Like Peptides; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptors; Pioglitazone; Receptors, Cytoplasmic and Nuclear; Treatment Outcome; Vitamin E

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

The final goal in the management of patients with type 2 diabetes (T2D) is reduction in cardiovascular (CV) complications and total mortality. Various factors including hyperglycemia contribute to these complications and mortality directly and indirectly. In recent years, large-scale CV outcome trials with new antidiabetic medications, such as dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP1) receptor agonists, and sodium glucose cotransporter-2 (SGLT2) inhibitors, have been completed. Most clinical trials with DPP4 inhibitors have shown no inferiority compared with placebo treatments in terms of CV safety. However, they did not show benefits in terms of adverse CV events or mortality. CV outcome trials with GLP1 receptor agonists showed inconsistent results: lixisenatide did not show benefits in preventing major adverse CV events. In contrast, liraglutide and semaglutide (longer acting GLP1 receptor agonists) proved to be superior in terms of alleviating CV morbidity and mortality. Two large-scale CV outcome trials with SGLT2 inhibitors showed significant results: empagliflozin proved to be superior in preventing CV and all-cause mortality, and canagliflozin proved to be superior in preventing CV mortality but not all-cause mortality. So far, controlling cardiometabolic risk factors such as hemodynamic changes and weight loss by SGLT2 inhibitors are suggested to be the main mechanisms for these results. However, the risk-benefit profile for these new drugs will need further elucidation, and more studies are warranted to reveal the possible mechanisms. It will also be important to confirm these results from other ongoing trials with SGLT2 inhibitors.

Topics: Albuminuria; Atherosclerosis; Benzhydryl Compounds; Body Weight; Canagliflozin; Cardiovascular Diseases; Cardiovascular System; Glucagon; Glucagon-Like Peptides; Glucosides; Heart Failure; Hemodynamics; Humans; Hypoglycemic Agents; Ketones; Lipids; Liraglutide; Metabolic Syndrome; Metformin; Non-alcoholic Fatty Liver Disease; Osmosis; Risk Factors; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

The rising prevalence of non-alcoholic fatty liver disease (NAFLD) parallels the global increase in the number of people diagnosed with obesity and metabolic syndrome. The gut-liver axis (GLA) plays an important role in the pathogenesis of NAFLD/non-alcoholic steatohepatitis (NASH). In this review, we discuss the clinical significance and underlying mechanisms of action of gut-derived secretory factors in NAFLD/NASH, focusing on recent human studies. Several studies have identified potential causal associations between gut-derived secretory factors and NAFLD/NASH, as well as the underlying mechanisms. The effects of gut-derived hormone-associated drugs, such as glucagon-like peptide-1 analog and recombinant variant of fibroblast growth factor 19, and other new treatment strategies for NAFLD/NASH have also been reported. A growing body of evidence highlights the role of GLA in the pathogenesis of NAFLD/NASH. Larger and longitudinal studies as well as translational research are expected to provide additional insights into the role of gut-derived secretory factors in the pathogenesis of NAFLD/NASH, possibly providing novel markers and therapeutic targets in patients with NAFLD/NASH.

Topics: Animals; Enteroendocrine Cells; Fibroblast Growth Factors; Glucagon-Like Peptides; Humans; Intercellular Signaling Peptides and Proteins; Neurotensin; Non-alcoholic Fatty Liver Disease

Non-alcoholic steatohepatitis (NASH) is associated with increased risk of liver-related and cardiovascular morbidity and mortality. Given the complex pathophysiology of NASH, combining therapies with complementary mechanisms may be beneficial. This trial evaluated the safety and efficacy of semaglutide, a glucagon-like peptide-1 receptor agonist, alone and in combination with the farnesoid X receptor agonist cilofexor and/or the acetyl-coenzyme A carboxylase inhibitor firsocostat in patients with NASH.. This was a phase II, open-label, proof-of-concept trial in which patients with NASH (F2-F3 on biopsy, or MRI-proton density fat fraction [MRI-PDFF] ≥10% and liver stiffness by transient elastography ≥7 kPa) were randomised to 24 weeks' treatment with semaglutide 2.4 mg once weekly as monotherapy or combined with once-daily cilofexor (30 or 100 mg) and/or once-daily firsocostat 20 mg. The primary endpoint was safety. All efficacy endpoints were exploratory.. A total of 108 patients were randomised to semaglutide (n = 21), semaglutide plus cilofexor 30 mg (n = 22), semaglutide plus cilofexor 100 mg (n = 22), semaglutide plus firsocostat (n = 22) or semaglutide, cilofexor 30 mg and firsocostat (n = 21). Treatments were well tolerated - the incidence of adverse events was similar across groups (73-90%) and most events were gastrointestinal in nature. Despite similar weight loss (7-10%), compared with semaglutide monotherapy, combinations resulted in greater improvements in liver steatosis measured by MRI-PDFF (least-squares mean of absolute changes: -9.8 to -11.0% vs. -8.0%), liver biochemistry, and non-invasive tests of fibrosis.. In patients with mild-to-moderate fibrosis due to NASH, semaglutide with firsocostat and/or cilofexor was generally well tolerated. In exploratory efficacy analyses, treatment resulted in additional improvements in liver steatosis and biochemistry vs. semaglutide alone. Given this was a small-scale open-label trial, double-blind placebo-controlled trials with adequate patient numbers are warranted to assess the efficacy and safety of these combinations in NASH.. NCT03987074.. Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis (NASH), are serious liver conditions that worsen over time if untreated. The reasons people develop NASH are complex and combining therapies that target different aspects of the disease may be more helpful than using single treatments. This trial showed that the use of 3 different types of drugs, namely semaglutide, cilofexor and firsocostat, in combination was safe and may offer additional benefits over treatment with semaglutide alone.

Topics: Azetidines; Double-Blind Method; Fibrosis; Glucagon-Like Peptides; Humans; Isobutyrates; Isonicotinic Acids; Non-alcoholic Fatty Liver Disease; Oxazoles; Pyrimidines; Treatment Outcome

Glucagon-like peptide-1 receptor agonists may be a treatment option in patients with non-alcoholic fatty liver disease (NAFLD).. To investigate the effects of semaglutide on liver stiffness and liver fat in subjects with NAFLD using non-invasive magnetic resonance imaging (MRI) methods.. This randomised, double-blind, placebo-controlled trial enrolled subjects with liver stiffness 2.50-4.63 kPa by magnetic resonance elastography (MRE) and liver steatosis ≥10% by MRI proton density fat fraction (MRI-PDFF). The primary endpoint was change from baseline to week 48 in liver stiffness assessed by MRE.. Sixty-seven subjects were randomised to once-daily subcutaneous semaglutide 0.4 mg (n = 34) or placebo (n = 33). Change from baseline in liver stiffness was not significantly different between semaglutide and placebo at week 48 (estimated treatment ratio 0.96 (95% CI 0.89, 1.03; P = 0.2798); significant differences in liver stiffness were not observed at weeks 24 or 72. Reductions in liver steatosis were significantly greater with semaglutide (estimated treatment ratios: 0.70 [0.59, 0.84], P = 0.0002; 0.47 [0.36, 0.60], P < 0.0001; and 0.50 [0.39, 0.66], P < 0.0001) and more subjects achieved a ≥ 30% reduction in liver fat content with semaglutide at weeks 24, 48 and 72, (all P < 0.001). Decreases in liver enzymes, body weight and HbA. The change in liver stiffness in subjects with NAFLD was not significantly different between semaglutide and placebo. However, semaglutide significantly reduced liver steatosis compared with placebo which, together with improvements in liver enzymes and metabolic parameters, suggests a positive impact on disease activity and metabolic profile. ClinicalTrials.gov identifier: NCT03357380.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Elasticity Imaging Techniques; Glucagon-Like Peptides; Humans; Magnetic Resonance Imaging; Non-alcoholic Fatty Liver Disease

Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known.. We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.. In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed.. This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).

Topics: Adolescent; Adult; Aged; Amylases; Biopsy; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucagon-Like Peptides; Humans; Injections, Subcutaneous; Lipase; Liver; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Young Adult

Topics: Double-Blind Method; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Non-alcoholic Fatty Liver Disease; Placebos

Topics: Anti-Obesity Agents; Biopsy; Body Mass Index; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Monitoring; Female; Gastrointestinal Agents; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liver; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Treatment Outcome

To determine the effect of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors, on biomarkers of nonalcoholic steatohepatitis (NASH) and fibrosis in patients with type 2 diabetes mellitus (T2DM).. Patients with T2DM received either once weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks. Changes from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), keratin-18 (K-18), procollagen III (Pro-C3), and adiponectin were analyzed in a modified intention-to-treat population.. Significant (. In post hoc analyses, higher tirzepatide doses significantly decreased NASH-related biomarkers and increased adiponectin in patients with T2DM.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Biomarkers; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Immunoglobulin Fc Fragments; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Receptors, Gastrointestinal Hormone; Recombinant Fusion Proteins; Treatment Outcome

Liraglutide, a daily injectable glucagon-like peptide-1 receptor (GLP-1r) agonist, has been shown to reduce liver fat content (LFC) in humans. Data regarding the effect of dulaglutide, a once-weekly GLP-1r agonist, on human LFC are scarce. This study examined the effect of dulaglutide on LFC in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).. Effect of dulaglutide on liver fat (D-LIFT) was a 24 week, open-label, parallel-group, randomised controlled trial to determine the effect of dulaglutide on liver fat at a tertiary care centre in India. Adults (n = 64), who had type 2 diabetes and MRI-derived proton density fat fraction-assessed LFC of ≥6.0% at baseline, were randomly assigned to receive dulaglutide weekly for 24 weeks (add-on to usual care) or usual care, based on a predefined computer-generated number with a 1:1 allocation that was concealed using serially numbered, opaque, sealed envelopes. The primary endpoint was the difference of the change in LFC from 0 (baseline) to 24 weeks between groups. The secondary outcome measures included the difference of the change in pancreatic fat content (PFC), change in liver stiffness measurement (LSM in kPa) measured by vibration-controlled transient elastography, and change in liver enzymes.. Eighty-eight patients were screened; 32 were randomly assigned to the dulaglutide group and 32 to the control group. Overall, 52 participants were included for per-protocol analysis: those who had MRI-PDFF data at baseline and week 24. Dulaglutide treatment resulted in a control-corrected absolute change in LFC of -3.5% (95% CI -6.6, -0.4; p = 0.025) and relative change of -26.4% (-44.2, -8.6; p = 0.004), corresponding to a 2.6-fold greater reduction. Dulaglutide-treated participants also showed a significant reduction in γ-glutamyl transpeptidase (GGT) levels (mean between-group difference -13.1 U/l [95% CI -24.4, -1.8]; p = 0.025) and non-significant reductions in aspartate aminotransferase (AST) (-9.3 U/l [-19.5, 1.0]; p = 0.075) and alanine aminotransferase (ALT) levels (-13.1 U/l [-24.4, 2.5]; p = 0.10). Absolute changes in PFC (-1.4% [-3.2, 0.3]; p = 0.106) and LSM (-1.31 kPa [-2.99, 0.37]; p = 0.123) were not significant when comparing the two groups. There were no serious drug-related adverse events.. When included in the standard treatment for type 2 diabetes, dulaglutide significantly reduces LFC and improves GGT levels in participants with NAFLD. There were non-significant reductions in PFC, liver stiffness, serum AST and serum ALT levels. Dulaglutide could be considered for the early treatment of NAFLD in patients with type 2 diabetes.. ClinicalTrials.gov NCT03590626 FUNDING: The current study was supported by an investigator-initiated study grant from Medanta-The Medicity's departmental research fund and a grant from the Endocrine and Diabetes Foundation (EDF), India. Graphical abstract.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Liver; Liver Function Tests; Non-alcoholic Fatty Liver Disease; Recombinant Fusion Proteins

Topics: Fibrosis; Glucagon-Like Peptides; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease

Topics: Fibrosis; Glucagon-Like Peptides; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease

Topics: Glucagon-Like Peptides; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease

The weight loss following Semaglutide treatment, a GLP-1 receptor agonist, might be responsible for some effects observed on the nonalcoholic fatty liver disease of obese mice.. Two groups of C57BL/6 male mice (n = 30/group) were fed the diets Control (C) or high-fat (HF) for 16 weeks. Then, separated into six new groups for an additional four weeks (n = 10/group) and treated with Semaglutide (S, 40 µg/kg) or paired feeding (PF) with S groups (C; C-S; C-PF; HF; HF-S; HF-PF).. Semaglutide reduced energy consumption leading to weight loss. Simultaneously it improved glucose intolerance, glycated hemoglobin, insulin resistance/sensitivity, plasma lipids, and gastric inhibitory polypeptide. Semaglutide and paired feeding mitigated liver steatosis and adipose differentiation-related protein (Plin2) expression. Semaglutide also improved hormones and adipokines, reduced lipogenesis and inflammation, and increased beta-oxidation. Semaglutide lessened liver glucose uptake and endoplasmic reticulum (ER) stress. Among the 14 genes analyzed, 13 were modified by Semaglutide (93 %, six genes were changed exclusively by Semaglutide, and seven other genes were affected by the combination of Semaglutide and paired feeding). In seven genes, the paired diet showed no effect (50% of the genes tested). No marker was affected exclusively by paired feeding.. Semaglutide and the consequent weight loss reduced obese mice liver inflammation, insulin resistance, and ER stress. However, weight loss alone did show few or no action on some significant study findings, like liver steatosis, leptin, insulin, resistin, and amylin. Furthermore, hepatic inflammation mediated by MCP-1 and partially by TNF-alpha and IL6 were also not reduced by weight loss. Furthermore, weight loss alone did not lessen hepatic lipogenesis as determined by the findings of SREBP-1c, CHREBP, PPAR-alpha, and SIRT1. Semaglutide was implicated in improving glucose uptake and lessening ER stress by reducing GADD45, independent of weight loss.

Topics: Animals; Disease Models, Animal; Endoplasmic Reticulum; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Nutritional Support; Obesity; Weight Loss

Non-alcoholic steatohepatitis (NASH) has emerged as a major challenge for public health because of high global prevalence and lack of evidence-based therapies. Most animal models of NASH lack sufficient validation regarding disease progression and pharmacological treatment. The Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mouse demonstrate clinical translatability with respect to disease etiology and hallmarks of NASH. This study aimed to evaluate disease progression and responsiveness to clinically effective interventions in GAN DIO-NASH mice. Disease phenotyping was performed in male C57BL/6J mice fed the GAN diet high in fat, fructose, and cholesterol for 28-88 weeks. GAN DIO-NASH mice with biopsy-confirmed NASH and fibrosis received low-caloric dietary intervention, semaglutide (30 nmol/kg/day, s.c.) or lanifibranor (30 mg/kg/day, p.o.) for 8 and 12 weeks, respectively. Within-subject change in nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) and fibrosis stage was evaluated using automated deep learning-based image analysis. GAN DIO-NASH mice showed clear and reproducible progression in NASH, fibrosis stage, and tumor burden with high incidence of hepatocellular carcinoma. Consistent with clinical trial outcomes, semaglutide and lanifibranor improved NAS, whereas only lanifibranor induced regression in the fibrosis stage. Dietary intervention also demonstrated substantial benefits on metabolic outcomes and liver histology. Differential therapeutic efficacy of semaglutide, lanifibranor, and dietary intervention was supported by quantitative histology, RNA sequencing, and blood/liver biochemistry. In conclusion, the GAN DIO-NASH mouse model recapitulates various histological stages of NASH and faithfully reproduces histological efficacy profiles of compounds in advanced clinical development for NASH. Collectively, these features highlight the utility of GAN DIO-NASH mice in preclinical drug development.

Topics: Animals; Benzothiazoles; Biopsy; Diet; Disease Models, Animal; Disease Progression; Glucagon-Like Peptides; Humans; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Sulfonamides

Dulaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), has been shown to reduce body weight and liver fat content in patients with type 2 diabetes. Family with sequence similarity 3 member A (FAM3A) plays a vital role in regulating glucose and lipid metabolism. The aim of this study was to determine the mechanisms by which dulaglutide protects against hepatic steatosis in HepG2 cells treated with palmitic acid (PA).. HepG2 cells were pretreated with 400 μM PA for 24 hours, followed by treatment with or without 100 nM dulaglutide for 24 hours. Hepatic lipid accumulation was determined using Oil red O staining and triglyceride (TG) assay, and the expression of lipid metabolism-associated factor was analyzed using quantitative real time polymerase chain reaction and Western blotting.. Dulaglutide significantly decreased hepatic lipid accumulation and reduced the expression of genes associated with lipid droplet binding proteins, de novo lipogenesis, and TG synthesis in PA-treated HepG2 cells. Dulaglutide also increased the expression of proteins associated with lipolysis and fatty acid oxidation and FAM3A in PA-treated cells. However, exendin-(9-39), a GLP-1R antagonist, reversed the expression of FAM3A, and fatty acid oxidation-associated factors increased due to dulaglutide. In addition, inhibition of FAM3A by siRNA attenuated the reducing effect of dulaglutide on TG content and its increasing effect on regulation of fatty acid oxidation.. These results suggest that dulaglutide could be used therapeutically for improving nonalcoholic fatty liver disease, and its effect could be mediated in part via upregulation of FAM3A expression through a GLP-1R-dependent pathway.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Immunoglobulin Fc Fragments; Non-alcoholic Fatty Liver Disease; Palmitic Acid; Recombinant Fusion Proteins; Signal Transduction

Topics: Azetidines; Dancing; Glucagon-Like Peptides; Humans; Isobutyrates; Isonicotinic Acids; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Oxazoles; Pyrimidines

Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has been extensively studied, the role of its underlying pathogenesis remains unclear, and there is currently no approved therapeutic strategy for NAFLD. The purpose of this study was to observe the beneficial effects of Semaglutide on NAFLD in vivo and in vitro, as well as its potential molecular mechanisms.. Semaglutide was used to treat type 2 diabetes mellitus (T2DM) combined with NAFLD mice for 12 weeks. Hepatic function and structure were evaluated by liver function, blood lipids, liver lipids, H&E staining, oil red staining and Sirius staining. The expression of α/β hydrolase domain-6 (ABHD6) was measured by qPCR and Western blotting in vivo and in vitro. Then, dual-luciferase reporter assay was performed to verify the regulation of the upstream miR-5120 on ABHD6.. Our data revealed that Semaglutide administration significantly improved liver function and hepatic steatosis in T2DM combined with NAFLD mice. Furthermore, compared with controls, up-regulation of ABHD6 and down-regulation of miR-5120 were found in the liver of T2DM+NAFLD mice and HG+FFA-stimulated Hepa 1-6 hepatocytes. Interestingly, after Semaglutide intervention, ABHD6 expression was significantly decreased in the liver of T2DM+NAFLD mice and in HG+FFA-stimulated Hepa 1-6 hepatocytes, while miR-5120 expression was increased. We also found that miR-5120 could regulate the expression of ABHD6 in hepatocytes, while Semaglutide could modulate the expression of ABHD6 through miR-5120. In addition, GLP-1R was widely expressed in mouse liver tissues and Hepa 1-6 cells. Semaglutide could regulate miR-5120/ABHD6 expression through GLP-1R.. Our data revealed the underlying mechanism by which Semaglutide improves hepatic steatosis in T2DM+NAFLD, and might shed new light on the pathological role of miR-5120/ABHD6 in the pathogenesis of T2DM+NAFLD.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Liver; Mice; Mice, Inbred C57BL; MicroRNAs; Monoacylglycerol Lipases; Non-alcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is commonly observed in patients with type 2 diabetes (T2D). Semaglutide, a glucagon-like peptide 1 receptor agonist, may have a therapeutic role by targeting common mechanisms involved in the pathophysiology of T2D and NAFLD. The study aimed to assess the effectiveness of Semaglutide on NAFLD in patients with T2D.. Forty-eight patients were treated with subcutaneous Semaglutide in add-on to metformin for 52 weeks. After the baseline visit (T0), follow-up was scheduled quarterly (T3, and T6) and then at 12 months of therapy (T12). During each visit, body composition was analyzed by phase-sensitive bio-impedance, and NAFLD was diagnosed and staged by Ultrasound (US) imaging. Surrogate biomarkers of NAFLD were also calculated and followed over time.. A significant decrease in anthropometric and glucometabolic parameters, insulin resistance, liver enzymes, and laboratory indices of hepatic steatosis was observed during treatment. Similarly, fat mass and visceral adipose tissue (VAT) decreased over time more than skeletal muscle and free-fat mass. US-assessed VAT thickness and the 12-point steatosis score also declined at T3 up to T12. Liver steatosis improved in most patients (70%), showing a reduction by at least one class in the semiquantitative US staging.. Besides glucose control and body composition improvements, Semaglutide was effective in ameliorating the clinical appearance and severity of NAFLD in T2D patients.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Non-alcoholic Fatty Liver Disease; Prospective Studies

Topics: Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Non-alcoholic Fatty Liver Disease

Topics: Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Non-alcoholic Fatty Liver Disease

Topics: Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Non-alcoholic Fatty Liver Disease

Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment.. To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD.. Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight.. Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change.. Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Biomarkers; Body Weight; Cardiovascular Diseases; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Inflammation; Liver; Male; Middle Aged; Multicenter Studies as Topic; Non-alcoholic Fatty Liver Disease; Obesity; Randomized Controlled Trials as Topic; Retrospective Studies; Weight Reduction Programs; Young Adult

To evaluate the effects of dulaglutide vs placebo on liver and glycaemic/metabolic measurements in a population with Type 2 diabetes and in a subgroup with non-alcoholic fatty liver/non-alcoholic steatohepatitis.. In the overall population at 6 months, dulaglutide significantly reduced alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels vs placebo [least squares mean treatment differences: -1.7 IU/l (95% CI -2.8, -0.6), P=0.003; -1.1 IU/l (95% CI -2.1, -0.1), P=0.037; -6.6 IU/l (95% CI -12.4, -0.8), P=0.025, respectively]. In the subgroup with non-alcoholic fatty liver/non-alcoholic steatohepatitis (alanine aminotransferase levels greater than or equal to the upper limit of normal), mean baseline liver enzyme values were 38.0 IU/l, 27.8 IU/l and 43.9 IU/l for alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase, respectively. In this population, more pronounced reductions from baseline in alanine aminotransferase were observed with dulaglutide vs placebo (-8.8 IU/l vs -6.7 IU/l). In the subgroup of people with alanine aminotransferase levels less than the upper limit of normal, changes from baseline in alanine aminotransferase did not significantly differ between treatment groups (0.0 IU/l vs 0.7 IU/l).. Once-weekly dulaglutide improved alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels compared with placebo in a pattern consistent with liver fat reductions. Our results add further weight to the notion that glucagon-like peptide-1 receptor agonists may provide benefit in lowering liver fat in addition to their other metabolic actions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Aspartate Aminotransferases; Diabetes Mellitus, Type 2; Down-Regulation; Female; gamma-Glutamyltransferase; Glucagon-Like Peptides; Humans; Immunoglobulin Fc Fragments; Lipid Metabolism; Liver; Liver Function Tests; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Recombinant Fusion Proteins; Retrospective Studies; Young Adult

Topics: Glucagon-Like Peptides; Humans; Lipids; Non-alcoholic Fatty Liver Disease

Topics: Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Lipids; Non-alcoholic Fatty Liver Disease

Palmitic acid is an important risk factor for the pathogenesis of non-alcoholic steatohepatitis (NASH), but changes in palmitic acid intestinal absorption in NASH are unclear. The aim of this study was to clarify changes in palmitic acid intestinal absorption and their association with the pathogenesis of NASH.. A total of 106 participants were recruited to the study, of whom 33 were control subjects (control group), 32 were patients with NASH Brunt stage 1-2 [early NASH (e-NASH)], and 41 were patients with NASH Brunt stage 3-4 [advanced NASH (a-NASH)].. Overall,. Significantly upregulated palmitic acid absorption by activation of its transporters was evident in patients with NASH, and clinical progression of NASH was related to palmitic acid absorption. These dietary changes are associated with the onset and progression of NASH.

Topics: Adult; Aged; Apolipoprotein B-48; Apolipoproteins A; Breath Tests; Carbon Radioisotopes; Carrier Proteins; Case-Control Studies; Caveolin 1; CD36 Antigens; Chylomicrons; Endoribonucleases; Fatty Acid Transport Proteins; Fatty Acid-Binding Proteins; Female; Glucagon-Like Peptides; Humans; Insulin Resistance; Intestinal Absorption; Jejunum; Liver Cirrhosis; Male; Membrane Proteins; Middle Aged; Monomeric GTP-Binding Proteins; Non-alcoholic Fatty Liver Disease; Palmitic Acids; Protein Serine-Threonine Kinases; RNA, Messenger