incretins and Non-alcoholic-Fatty-Liver-Disease

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that stimulate insulin secretion from pancreatic β cells in response to food ingestion. Modified GLP-1 and GIP peptides are potent agonists for their incretin receptors, and some evidence shows that the dual GLP-1 and GIP receptor agonist tirzepatide is effective in promoting marked weight loss. GLP-1 receptor agonists signal in the CNS to suppress appetite, increase satiety, and thereby decrease calorie intake, but many other effects of incretin signalling have been recognised that are relevant to the treatment of non-alcoholic fatty liver disease (NAFLD). This Review provides an overview of the literature supporting the notion that endogenous incretins and incretin-receptor agonist treatments are important not only for decreasing risk of developing NAFLD, but also for treating NAFLD and NAFLD-related complications. We discuss incretin signalling and related incretin-receptor agonist treatments, mechanisms in key relevant tissues affecting liver disease, and clinical data from randomised controlled trials. Finally, we present future perspectives in this rapidly developing field of research and clinical medicine.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Non-alcoholic Fatty Liver Disease

There are no drugs approved by regulatory agencies for the treatment of nonalcoholic fatty liver disease (NAFLD); incretin combination therapies are being developed for treatment of type 2 diabetes and research has moved to test their usefulness in NAFLD.. We reviewed the literature on the effectiveness of dual and triple peptides combining receptor agonists of the glucagon-like peptide 1, the glucose-dependent insulinotropic peptide, and glucagon to treat NAFLD and its associated metabolic diseases, and/or the cardiovascular risk intimately connected with the cluster of the metabolic syndrome. Other combination peptides involved the glucagon-like peptide 2 receptor, the fibroblast growth factor 21, the cholecystokinin receptor 2, and the amylin receptor.. Both dual and triple agonists are promising, based on animal, pharmacokinetic and proof-of concept studies, showing effectiveness both in the presence and the absence of diabetes on a few validated surrogate NAFLD biomarkers, but the majority of studies are still in progress. Considering the long natural history of NAFLD, final proof of their efficacy on primary clinical liver outcomes might be also derived from the analysis of large databases of National Healthcare Systems or Insurance companies, when used in diabetes for improving glycemic control, after careful propensity-score matching.

Topics: Animals; Biomarkers; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Non-alcoholic Fatty Liver Disease

In the last few decades, glucagon-like peptide-1 receptor (GLP-1R) agonists have changed current guidelines and improved outcomes for individuals with type 2 diabetes. However, the dual glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R agonist, tirzepatide, has demonstrated superior efficacy regarding improvements in HbA

Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Non-alcoholic Fatty Liver Disease; Obesity

Non-alcoholic steatohepatitis (NASH) is a progressive form of Non-alcoholic fatty liver disease (NAFLD), which slowly progresses toward cirrhosis and finally leads to the development of hepatocellular carcinoma. Obesity, insulin resistance, type 2 diabetes mellitus and the metabolic syndrome are major risk factors contributing to NAFLD. Targeting these risk factors is a rational option for inhibiting NASH progression. In addition, NASH could be treated with therapies that target the metabolic abnormalities causing disease pathogenesis (such as de novo lipogenesis and insulin resistance) as well with medications targeting downstream processes such as cellular damage, apoptosis, inflammation, and fibrosis. Glucagon-like peptide (GLP-1), is an incretin hormone dysregulated in both experimental and clinical NASH, which triggers many signaling pathways including fibroblast growth factor (FGF) that augments NASH pathogenesis. Growing evidence indicates that GLP-1 in concert with FGF-21 plays crucial roles in the conservation of glucose and lipid homeostasis in metabolic disorders. In line, GLP-1 stimulation improves hepatic ballooning, steatosis, and fibrosis in NASH. A recent clinical trial on NASH patients showed that the upregulation of FGF-21 decreases liver fibrosis and hepatic steatosis, thus improving the pathogenesis of NASH. Hence, therapeutic targeting of the GLP-1/FGF axis could be therapeutically beneficial for the remission of NASH. This review outlines the significance of the GLP-1/FGF-21 axis in experimental and clinical NASH and highlights the activity of modulators targeting this axis as potential salutary agents for the treatment of NASH.

Topics: Diabetes Mellitus, Type 2; Fibroblast Growth Factors; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin Resistance; Lipids; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease

GLP-1 is derived from intestinal L cells, which takes effect through binding to GLP-1R and is inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). Since its discovery, GLP-1 has emerged as an incretin hormone for its facilitation in insulin release and reduction of insulin resistance (IR). However, GLP-1 possesses broader pharmacological effects including anti-inflammation, neuro-protection, regulating blood pressure (BP), and reducing lipotoxicity. These effects are interconnected to the physiological and pathological processes of Alzheimer's disease (AD), hypertension, and non-alcoholic steatohepatitis (NASH). Currently, the underlying mechanism of these effects is still not fully illustrated and a better understanding of them may help identify promising therapeutic targets of AD, hypertension, and NASH. Therefore, we focus on the biological characteristics of GLP-1, render an overview of the mechanism of GLP-1 effects in diseases, and investigate the potential of GLP-1 analogues for the treatment of related diseases in this review.

Topics: Alzheimer Disease; Animals; Glucagon-Like Peptide 1; Humans; Hypertension; Incretins; Metabolic Networks and Pathways; Non-alcoholic Fatty Liver Disease

Topics: Adiposity; Adult; Anthropometry; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Randomized Controlled Trials as Topic; Treatment Outcome; Weight Loss

The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins-glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Incretins; Mice; Non-alcoholic Fatty Liver Disease; Obesity

The global epidemic of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) and the high prevalence among individuals with type 2 diabetes has attracted the attention of clinicians specialising in liver disorders. Many drugs are in the pipeline for the treatment of NAFLD/NASH, and several glucose-lowering drugs are now being tested specifically for the treatment of liver disease. Among these are nuclear hormone receptor agonists (e.g. peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists and liver X receptor agonists), fibroblast growth factor-19 and -21, single, dual or triple incretins, sodium-glucose cotransporter inhibitors, drugs that modulate lipid or other metabolic pathways (e.g. inhibitors of fatty acid synthase, diacylglycerol acyltransferase-1, acetyl-CoA carboxylase and 11β-hydroxysteroid dehydrogenase type-1) or drugs that target the mitochondrial pyruvate carrier. We have reviewed the metabolic effects of these drugs in relation to improvement of diabetic hyperglycaemia and fatty liver disease, as well as peripheral metabolism and insulin resistance.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lipid Metabolism; Liver; Molecular Targeted Therapy; Non-alcoholic Fatty Liver Disease; Pharmaceutical Preparations; Receptors, Cytoplasmic and Nuclear

Non-alcoholic fatty liver disease is highly prevalent in patients with type 2 diabetes mellitus. Studies on glucagon-like peptide-1 receptor agonists for the treatment of non-alcoholic fatty liver disease have reported promising results. Despite this, there has been limited evidence of its efficacy in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus. This meta-analysis examined existing evidence on the efficacy of glucagon-like peptide-1 receptor agonists on the management of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus.. Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for articles discussing the efficacy of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. Values of standardized mean differences (SMD) and risk ratio (RR) were determined for continuous outcomes and dichotomous outcomes respectively.. 8 studies involving 1,454 patients from 5 randomized controlled trials and 3 cohort studies were included in the analysis. Our analysis found significant improvements in hepatic fat content, liver biochemistry, body composition, glucose parameters, lipid parameters, insulin sensitivity and inflammatory markers following glucagon-like peptide-1 receptor agonist treatment. Glucagon-like peptide-1 receptor agonists significantly decreased hepatic fat content compared to metformin and insulin-based therapies. Glucagon-like peptide-1 receptor agonists also improved fibrosis markers, but this did not reach statistical significance.. With a high prevalence of obesity and non-alcoholic fatty liver disease among patients with type 2 diabetes mellitus, glucagon-like peptide-1 receptor agonist treatment shows promise in improving both diabetes and non-alcoholic fatty liver disease phenotype.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lipid Metabolism; Liver; Non-alcoholic Fatty Liver Disease

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide (GLP-1) are the two incretin hormones secreted by the enteroendocrine system in response to nutrient ingestion. Compared with GLP-1, GIP is less well studied as a hormone or as a potential pharmacological treatment. Beyond its insulinotropic effects in the pancreas, GIP has important biological actions in many other tissues but its role in dietary fat metabolism and lipid storage in adipose tissue has been most studied. It is still unclear if such effects of GIP on adipose tissue/fat metabolism are protective or deleterious in the long term. Antagonising GIP actions through genetic and chemical disruption in mice models prevented diet induced obesity and improved insulin sensitivity. Whilst such effects of GIP antagonism are yet to be evaluated in humans, recent studies using combined GIP and GLP-1 agonists have shown weight reduction and improved glycaemic control in people with type 2 diabetes (T2D). Therapeutic manipulation of GIP physiology is intriguing in that both agonists and antagonists of GIP are being investigated to explore their potential weight-reducing and other metabolic benefits in people with obesity, T2D and non-alcoholic fatty liver disease (NAFLD). This review will discuss the physiological effects of GIP on fat metabolism in human adipose and other non-adipose tissues such as liver, pancreas, skeletal muscle and heart, describe where the actions of GIP may contribute to the pathophysiology of obesity, T2D and NAFLD and finally describe the therapeutic implications of GIP antagonism and agonism in these conditions.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Humans; Incretins; Lipid Metabolism; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Receptors, Gastrointestinal Hormone

Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide. Due to its association with obesity and diabetes and the fall in hepatitis C virus morbidity, cirrhosis in NAFLD is becoming the most frequent indication to liver transplantation, but the pathogenetic mechanisms are still not completely understood. The so-called gut-liver axis has gained enormous interest when data showed that its alteration can lead to NAFLD development and might favor the occurrence of non-alcoholic steatohepatitis (NASH). Moreover, several therapeutic approaches targeting the gut-pancreas-liver axis, e.g., incretins, showed promising results in NASH treatment. In this review, we describe the role of incretin hormones in NAFLD/NASH pathogenesis and treatment and how metagenomic/metabolomic alterations in the gut microbiota can lead to NASH in the presence of gut barrier modifications favoring the passage of bacteria or bacterial products in the portal circulation, i.e., bacterial translocation.

Topics: Animals; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Incretins; Liver; Non-alcoholic Fatty Liver Disease; Pancreas

Non-alcoholic fatty liver disease (NAFLD), affecting over 25% of the general population worldwide, is characterized by a spectrum of clinical and histological manifestations ranging from simple steatosis (>5% hepatic fat accumulation without inflammation) to non-alcoholic steatohepatitis (NASH) which is characterized by inflammation, and finally fibrosis, often leading to liver cirrhosis, and hepatocellular carcinoma. Up to 70% of patients with type 2 diabetes mellitus (T2DM) have NAFLD, and diabetics have much higher rates of NASH compared with the general non-diabetic population.. The aim of this study is to report recent approaches to NAFLD/NASH treatment in T2DM patients. To-date, there are no approved treatments for NAFLD (apart from lifestyle measures).. Current guidelines (2016) from 3 major scientific organizations suggest that pioglitazone and vitamin E may be useful in a subset of patients for adult NAFLD/NASH patients with T2DM. Newer selective PPAR-γ modulators (SPPARMs, CHRS 131) have shown to provide even better results with fewer side effects in both animal and human studies in T2DM. Newer antidiabetic drugs might also be useful, but detailed studies with histological outcomes are largely lacking. Nevertheless, prior animal and human studies on incretin mimetics, glucagon-like peptide-1 receptor agonists (GLP-1 RA) approved for T2DM treatment, have provided indirect evidence that they may also ameliorate NAFLD/NASH, whereas dipeptidyl dipeptidase-4 inhibitors (DDP-4i) were not better than placebo in reducing liver fat in T2DM patients with NAFLD. Sodium-glucoseco-transporter-2 inhibitors (SGLT2i) have been reported to improve NAFLD/NASH. Statins, being necessary for most patients with T2DM, may also ameliorate NAFLD/NASH, and could potentially reinforce the beneficial effects of the newer antidiabetic drugs, if used in combination, but this remains to be identified.. Newer antidiabetic drugs (SPPARMs, GLP-1 RA and SGLT2i) alone or in combination and acting alone or with potent statin therapy which is recommended in T2DM, might contribute substantially to NAFLD/NASH amelioration, possibly reducing not only liver-specific but also cardiovascular morbidity. These observations warrant long term placebo-controlled randomized trials with appropriate power and outcomes, focusing on the general population and more specifically on T2DM with NAFLD/NASH. Certain statins may be useful for treating NAFLD/NASH, while they substantially reduce cardiovascular disease risk.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Incretins; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. In some patients with NAFLD, isolated steatosis can progress to advanced stages with non-alcoholic steatohepatitis (NASH) and fibrosis, increasing the risk of cirrhosis and hepatocellular carcinoma. Furthermore, NAFLD is believed to be involved in the pathogenesis of common disorders such as type 2 diabetes and cardiovascular disease. In this Review, we highlight novel concepts related to diagnosis, risk prediction, and treatment of NAFLD. First, because NAFLD is a heterogeneous disease, the advanced stages of which seem to be strongly affected by comorbidities such as insulin resistance and type 2 diabetes, early use of reliable, non-invasive diagnostic tools is needed, particularly in patients with insulin resistance or diabetes, to allow the identification of patients at different disease stages. Second, although the strongest genetic risk alleles for NAFLD (ie, the 148Met allele in PNPLA3 and the 167Lys allele in TM6SF2) are associated with increased liver fat content and progression to NASH and cirrhosis, these alleles are also unexpectedly associated with an apparent protection from cardiovascular disease. If consistent across diverse populations, this discordance in NAFLD-related risk prediction between hepatic and extrahepatic disease might need to be accounted for in the management of NAFLD. Third, drug treatments assessed in NAFLD seem to differ with respect to cardiometabolic and antifibrotic efficacy, suggesting the need to better identify and tailor the most appropriate treatment approach, or to use a combination of approaches. These emerging concepts could contribute to the development of a multidisciplinary approach for endocrinologists and hepatologists working together in the management of NAFLD.

Topics: Antioxidants; Bariatric Surgery; Carcinoma, Hepatocellular; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Disease Progression; Dysbiosis; Gastrointestinal Microbiome; Genetic Predisposition to Disease; Humans; Incretins; Insulin Resistance; Lipase; Liver Cirrhosis; Liver Neoplasms; Membrane Proteins; Non-alcoholic Fatty Liver Disease; Obesity, Abdominal; Risk Assessment; Risk Reduction Behavior; Sodium-Glucose Transporter 2 Inhibitors

The prevalence of nonalcoholic liver disease (NAFLD) is increasing worldwide in conjunction with the epidemic increase in obesity and metabolic risk factors. Consequently, NAFLD has become a leading indication for liver transplantation. Although genetic factors play an important role in the pathogenesis of NAFLD, detrimental lifestyle trends favoring a calorically unrestricted diet rich in carbohydrates and unsaturated fat, prolonged sedentary periods or limited physical activity have major metabolic implications. In aggregate these physiological dysregulations constitute the main risk factors for the metabolic syndrome and NAFLD. The cornerstone of the treatment of NAFLD, is lifestyle changes, including modifications to diet and physical activity, to reduce body weight and liver fat, however adherence is notoriously poor and the epidemic of NAFLD continues to grow unimpeded. In the face of this unmet clinical need, the pharmacologic therapy of NAFLD has been expanding as the varied mechanistic pathways of NAFLD are elucidated. Beyond these approaches to treating NAFLD, the prevention of other liver diseases is additionally important. Chief among these is alcoholic liver disease, and heavy use is detrimental irrespective of underlying NAFLD. However, the impact of mild to moderate alcohol use in patients with mild or nonadvanced forms NAFLD is undefined. This article summarizes the results of the International Liver Transplantation Society consensus meeting on NAFLD in liver transplantation. It describes the available evidence and provides consensus guidance on the lifestyle and pharmacologic therapies of NAFLD, and the consensus position on alcohol use in patients with NAFLD.

Topics: Alcohol Drinking; Antioxidants; Bariatric Surgery; Comorbidity; Consensus Development Conferences as Topic; Diet, Carbohydrate Loading; Exercise; Healthy Lifestyle; Humans; Hypoglycemic Agents; Incretins; Liver Cirrhosis; Liver Diseases, Alcoholic; Liver Transplantation; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity; Patient Compliance; Practice Guidelines as Topic; Prevalence; Risk Factors; Weight Loss

Nonalcoholic-fatty-liver-disease/nonalcoholic steatohepatitis (NAFLD/NASH) is expected to become the leading liver disease worldwide. Typical liver-related complications are fibrosis, cirrhosis, and the development of hepatocellular cancer (HCC) with the need for liver transplantation. Up to now there is no approved pharmacotherapy. Indeed, this might be due to the complexity of this disease. While the cheapest therapeutic approach is still a lifestyle change leading to weight loss, the proportion of people achieving sufficient weight reduction without additional support is low. Newly developed drugs are expensive and lack a breakthrough in therapeutic success. One reason might be that drugs developed often derive from murine models. Unfortunately, there is little overlap between genes in human and mice that are responsible for the development of NAFLD/NASH. This review aims at summarizing latest developments as well as stress again that more translational research is necessary.. Therapy of NAFLD/NASH is easy and very complex at the same time, as the current main target is weight reduction. Since this is in fact not easily achieved and maintained by many affected individuals, pharmacotherapy to halt the progression of NAFLD/NASH is urgently warranted. More translational studies are needed to understand the metabolic mechanisms and interactions between the liver, gut, oxidative stress and the processes leading to NAFLD progression and HCC development, even in the absence of cirrhosis.

Topics: Animals; Bariatric Surgery; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Humans; Hypolipidemic Agents; Incretins; Life Style; Lipogenesis; Liver; Liver Cirrhosis; Liver Neoplasms; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Species Specificity; Translational Research, Biomedical; Weight Loss; Weight Reduction Programs

This review discusses completed phase II randomized clinical trials with high-quality published results for compounds that demonstrate effects on nonalcoholic steatohepatitis histology (obeticholic acid, elafibranor, and liraglutide). The authors also review the available preliminary data on cenicriviroc and selonsertib, with or without simtuzumab's phase II studies. Finally, the authors briefly discuss compounds that have been tested but did not achieve the primary end point of histologic improvement and appeared in high-quality published articles (cysteamine bitartrate and long-chain polyunsaturated fatty acids).

Topics: Antibodies, Monoclonal, Humanized; CCR5 Receptor Antagonists; Chalcones; Chenodeoxycholic Acid; Clinical Trials, Phase II as Topic; Cysteamine; Cystine Depleting Agents; Humans; Imidazoles; Incretins; Liraglutide; Non-alcoholic Fatty Liver Disease; Propionates; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Sulfoxides

Non-alcoholic fatty liver disease (NAFLD) is currently one of the leading forms of chronic liver disease, and its rising frequency worldwide has reached epidemic proportions. NAFLD, particularly its progressive variant NASH (non-alcoholic steatohepatitis), can lead to advanced fibrosis, cirrhosis, and HCC. The pathophysiologic mechanisms that contribute to the development and progression of NAFLD and NASH are complex, and as such myriad therapies are under investigation targeting different pathophysiological mechanisms. Incretin-based therapies, including GLP-1RAs and DPP-4 inhibitors and the inhibition of ASK1 pathway have provided two such novel mechanisms in the management of this disease, and will remain focus of this review.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; MAP Kinase Kinase Kinase 5; MAP Kinase Signaling System; Non-alcoholic Fatty Liver Disease; Reactive Oxygen Species; Treatment Outcome

Non-alcoholic fatty liver disease (NAFLD) is defined as hepatic steatosis exceeding 5% of hepatocytes with no other reason for hepatic fat accumulation. The association between NAFLD and type 2 diabetes is strong. Accordingly, up to 70% of obese patients with type 2 diabetes have NAFLD. The spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis with variable degrees of fibrosis and cirrhosis. Cirrhosis is the end-stage of chronic liver disease and is characterised by diffuse fibrosis and nodular regeneration of hepatocytes. Alcoholic liver disease and NAFLD are the most common aetiologies of cirrhosis. The WHO estimates that 70% of patients with cirrhosis have impaired glucose tolerance and 30% have manifest diabetes. The latter is termed hepatic diabetes and is associated with increased complications to cirrhosis and hepatocellular carcinoma. The objective of this thesis was to study the impact of liver dysfunction on incretin and glucagon (patho)physiology in relation to glucose metabolism. We hypothesised that NAFLD patients with normal glucose tolerance would develop reduced incretin effect and that NAFLD would worsen the incretin effect in patients with existing type 2 diabetes. Thus, in study I, we investigated the incretin effect and glucagon secretion in patients with NAFLD with and without type 2 diabetes compared to controls. We also hypothesised that the incretin effect would be disturbed in non-diabetic patients with more severe liver disease. Hence, the objective of study II was to investigate the incretin effect in patients with cirrhosis. Finally, the hypothesis in study III was that an impaired glucagonostatic effect of GLP-1 contributes to the hyperglucagonaemia of patients with liver disease. We therefore explored the glucagonostatic properties of GLP-1 in non-diabetic patients with NAFLD. The results of study I show that patients with NAFLD have normal secretion of GLP-1 and GIP and a reduced incretin effect. The groups with type 2 diabetes have the lowest incretion effect. We also find that NAFLD patients have high fasting glucagon concentrations regardless of their glucose (in)tolerance. We further demonstrated that patients with normal glucose tolerance and NAFLD have preserved glucagon suppression to both oral and intravenous glucose.  In study II, we find that non-diabetic patients with cirrhosis have elevated concentrations of GLP-1 and GIP and a reduced incretin effect. Patients with cirrhosis also have f

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Humans; Incretins; Insulin; Liver; Mice; Non-alcoholic Fatty Liver Disease

Given the high prevalence and rising incidence of non-alcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress. Medications in this group include peroxisome proliferator-activator receptor agonists (eg, pioglitazone, elafibranor, saroglitazar), medications targeting the bile acid-farnesoid X receptor axis (obeticholic acid), inhibitors of de novo lipogenesis (aramchol, NDI-010976), incretins (liraglutide) and fibroblast growth factor (FGF)-21 or FGF-19 analogues. A second approach is targeting the oxidative stress, inflammation and injury that follow the metabolic stress. Medications from this group include antioxidants (vitamin E), medications with a target in the tumour necrosis factor α pathway (emricasan, pentoxifylline) and immune modulators (amlexanox, cenicriviroc). A third group has a target in the gut, including antiobesity agents such as orlistat or gut microbiome modulators (IMM-124e, faecal microbial transplant, solithromycin). Finally, as the ongoing injury leads to fibrosis, the harbinger of liver-related morbidity and mortality, antifibrotics (simtuzumab and GR-MD-02) will be an important element of therapy. It is very likely that in the next few years several medications will be available to clinicians treating patients with NAFLD across the entire spectrum of disease.

Topics: Anti-Obesity Agents; Antioxidants; Chenodeoxycholic Acid; Dipeptidyl-Peptidase IV Inhibitors; Drug Discovery; Drug Repositioning; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunologic Factors; Incretins; Lipogenesis; Molecular Targeted Therapy; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear; Tumor Necrosis Factor-alpha

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease in Western societies. Despite its significance, there are no well-proven pharmacological treatments. Two novel classes of potential pharmacotherapies are the glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4I), collectively known as incretin-based therapies. These have several metabolic and anti-inflammatory actions that may be of benefit in NAFLD. The aim of this meta-analysis was to evaluate their efficacy via a structured retrieval and pooled analysis of relevant studies.. Studies were sourced from electronic databases and meeting abstracts. Main inclusion criteria were original studies investigating treatment of adults with NAFLD using GLP-1 RA/DPP-4I. Key outcomes were a change in serum alanine transaminase (ALT), as a marker of liver inflammation, and improvement in disease status measured by imaging or histology.. Initial searching retrieved 1357 peer-reviewed articles and abstracts. Four studies met all inclusion and exclusion criteria. There were a total of 136 participants with NAFLD and concomitant type 2 diabetes mellitus (T2DM). Meta-analysis (random-effects model) revealed a significant decrease in serum ALT following treatment (mean reduction 14.1 IU/L, 95% confidence intervals [CI] 8.3-19.8, P < 0.0001). In two studies with imaging and tissue data, treatment was found to significantly reduce steatosis, inflammation, and fibrosis.. The significant decrease in a key biochemical marker of hepatic inflammation following treatment with incretin-based therapies, as well as improvements in imaging and histology, suggests these agents may be effective options for managing NAFLD with comorbid T2DM.

Topics: Alanine Transaminase; Anti-Inflammatory Agents; Biomarkers; Comorbidity; Databases, Bibliographic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Non-alcoholic Fatty Liver Disease; Treatment Outcome

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

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been recognized as metabolic disorders characterized by fatty accumulation in the liver without alcohol consumption. The diseases can cause metabolic syndromes, consisting of obesity, diabetes mellitus (DM), dyslipidemia and hypertension. For the treatment of NAFLD/NASH, losing weight by exercise or diet remains the standard treatment, because no effective pharmacological therapy has yet been developed for NAFLD/NASH. Two incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), stimulate glucose-mediated insulin production in pancreatic β cells. Incretin has also been reported to have various extra-pancreatic effects, including the regulation of hepatic glucose production, appetite and satiety, as well as the stimulation of afferent sensory nerves. Therefore, incretin may have potential as a novel therapeutic agent for NAFLD/NASH.

Topics: Appetite; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Insulin-Secreting Cells; Liver; Neurons, Afferent; Non-alcoholic Fatty Liver Disease; Satiety Response; Sensory Receptor Cells

Nonalcoholic fatty liver disease is the most common cause of liver disease in the United States. There are no drug therapies approved for the treatment of nonalcoholic steatohepatitis (NASH). Multiple different pathways are involved in the pathogenesis and each can be the target of the therapy. It is possible that more than 1 target is involved in disease development and progression. Multiple clinical trials with promising agents are underway. Because NASH is a slowly progressive disease and treatment likely to be of prolonged duration, acceptance and approval of any agent will require information on long-term clinical benefits and safety.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Antioxidants; Caspase Inhibitors; Chenodeoxycholic Acid; Cholic Acids; Fatty Acids, Omega-3; Humans; Incretins; Insulin Resistance; Liraglutide; Liver X Receptors; Non-alcoholic Fatty Liver Disease; Pectins; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Non-alcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and is more prevalent in patients with type 2 diabetes mellitus (T2DM). Incretin-based antidiabetic agents (glucagonlike peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors) are used in the treatment of T2DM but it is unclear whether they may also play a role in the management of NAFLD. We systematically reviewed the PubMed and Scopus database up to October 2014 and also hand-searched the references of the retrieved articles for studies evaluating the effects of these agents on NAFLD. In animal studies, both GLP-1 receptor agonists and DPP-4 inhibitors reduced transaminase activity and steatosis but their effects on liver inflammation were inconsistent and fibrosis was not assessed. In clinical studies, both agents consistently reduced transaminase activity and steatosis as assessed non-invasively. There are very limited data on the effects of incretin-based treatments on liver histology. In conclusion, GLP-1 receptor agonists and DPP-4 inhibitors appear to hold promise in patients with NAFLD but larger controlled studies with histological and clinical endpoints are needed to evaluate their effects in this population.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Non-alcoholic Fatty Liver Disease

The aim of this review is to examine the evidence on the role of antidiabetic agents in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). In particular, metformin does not seem to have significant effects on liver histology. Glitazones improve steatosis and necro-inflammation, delay progression of fibrosis, and ameliorate glucose and lipid metabolism and subclinical inflammation. However, there is now evidence that prolonged treatment with these agents may offer no additional histological benefit and that metabolic improvement does not necessarily parallel histological improvement. Moreover, the long-term safety and efficacy of glitazones is an issue of continuing concern. Injectable glucagon-like peptide 1 (GLP-1) agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors are more recent antidiabetic agents with some promising preliminary resulst in NFLD. However, experience with their use is still very limited. In conclusion, no antidiabetic agent has hitherto been shown to exert a beneficial effect on hepatic fibrosis. However, pharmacological treatment could be considered in patients with non-alcoholic steatohepatitis (NASH) not responding to lifestyle intervention. Finally, larger long-term studies are needed to shed more light on the effect of antidiabetic treatment on NAFLD.

Topics: Administration, Oral; Biomimetic Materials; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease is considered a hepatic manifestation of metabolic syndrome (MS). The current treatment of non-alcoholic fatty liver disease (NAFLD) principally includes amelioration of MS components by lifestyle modifications but the lack of success in their implementation and sustainment arises the need for effective pharmacological agent in fatty liver treatment. Incretins are gut derived hormones secreted into the circulation in response to nutrient ingestion that enhances glucose-stimulated insulin secretion. Glucagon-like peptide-1 (GLP-1) is the most important incretin. Its receptor agonist and inhibitors of dipeptidyl peptidase-4 (DPP-4) are used in treatment of type 2 diabetes mellitus. DPP-4 serum activity and hepatic expression are shown to be elevated in several hepatic diseases. There are several experimental and clinical trials exploring the efficacy of incretin based therapies in NAFLD treatment. They suggest that GLP-1 analogues might have beneficial effect on hepatic steatosis acting as insulin sensitizers and directly by stimulating GLP-1 receptors expressed on hepatocytes. The use of DPP-4 inhibitors also results in hepatic fat reduction but the mechanism of action remains unclear. There is growing evidence that incretin based therapies have beneficial effects on hepatocytes, however further study analysis are needed to assess the long term effect of incretin based therapies on NAFLD.

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Liver; Non-alcoholic Fatty Liver Disease; Receptors, Glucagon; Treatment Outcome

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

Topics: Animals; Antioxidants; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Incretins; Insulin Resistance; Lipid Metabolism; Liver; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Receptors, Glucagon; Signal Transduction; Treatment Outcome

Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They function to stimulate insulin secretion while suppressing glucagon secretion. GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus (T2DM), and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases. As we know, along with change in lifestyles, the prevalence of non-alcoholic fatty liver disease (NAFLD) in China is rising more than that of viral hepatitis and alcoholic fatty liver disease, and NAFLD has become the most common chronic liver disease in recent years. Recent studies further suggest that GLP-1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels, cutting down the fat content to promote fat redistribution, directly decreasing fatty degeneration of the liver, reducing the degree of liver fibrosis and improving inflammation. This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials.

Topics: Animals; Anti-Inflammatory Agents; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Hepatitis; Humans; Incretins; Lipids; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Obesity; Receptors, Glucagon; Risk Factors; Signal Transduction; Treatment Outcome

Nonalcoholic fatty liver disease (NAFLD) is a serious public health problem. It is now estimated to affect 30% of adults and about 10% of children in the U.S. Hispanics are disproportionably affected with not only higher rates of NAFLD but also more severe disease. Treatment options are currently limited.. In this review, we will focus on a series of novel findings related to the pathobiology of liver damage in nonalcoholic steatohepatitis (NASH) that are attractive targets for development of novel therapeutic strategies for human NASH. In particular, we will discuss four different areas due to their novelty and growing importance including microparticles, the inflammasomes, gut-liver axis and dietary lipids.. There is an urgent need to develop novel safe and effective therapies for the growing NAFLD epidemic. The data discussed in this article provide strong rational to think out of the box when considering novel therapeutic targets for patients with NAFLD.

Topics: Animals; Bile Acids and Salts; Cell-Derived Microparticles; Dietary Fats; Fatty Liver; Humans; Incretins; Inflammasomes; Non-alcoholic Fatty Liver Disease

Dipeptidyl peptidase-4 (DPP-4) is a membrane-associated peptidase, also known as CD26. DPP-4 has widespread organ distribution throughout the body and exerts pleiotropic effects via its peptidase activity. A representative target peptide is glucagon-like peptide-1, and inactivation of glucagon-like peptide-1 results in the development of glucose intolerance/diabetes mellitus and hepatic steatosis. In addition to its peptidase activity, DPP-4 is known to be associated with immune stimulation, binding to and degradation of extracellular matrix, resistance to anti-cancer agents, and lipid accumulation. The liver expresses DPP-4 to a high degree, and recent accumulating data suggest that DPP-4 is involved in the development of various chronic liver diseases such as hepatitis C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Furthermore, DPP-4 occurs in hepatic stem cells and plays a crucial role in hepatic regeneration. In this review, we described the tissue distribution and various biological effects of DPP-4. Then, we discussed the impact of DPP-4 in chronic liver disease and the possible therapeutic effects of a DPP-4 inhibitor.

Topics: Carcinoma, Hepatocellular; Dipeptidyl Peptidase 4; End Stage Liver Disease; Extracellular Matrix; Fatty Liver; Gene Expression Regulation, Enzymologic; Hepatitis C; Humans; Incretins; Insulin Resistance; Lipid Metabolism; Liver Neoplasms; Non-alcoholic Fatty Liver Disease

Effects of glucagonlike peptide 1 (GLP1) on liver cells are very intensively studied. In the metabolism of saccharides GLP1 stimulates synthesis of glycogen and reduces glucose production -  thus acting like insulin. In the lipid metabolism it enhances fatty acid oxidation and lipid transport from hepatocytes while reducing de novo lipogenesis -  effects more similar to glucagon action. Some studies suggest beneficial effects of GLP1 on oxidative stress, endoplasmic reticulum stress, production of inflammatory mediators and dysfunction of biliary secretion. Current results suggest that drugs affecting incretin system could be used in the treatment of certain liver diseases (e.g. NAFLD and NASH) in the future. In the following article we mention the known effects of GLP 1 on liver functions and liver metabolism and we point out its possible future therapeutic use in the treatment of liver diseases.

Topics: Animals; Glucagon; Glucagon-Like Peptide 1; Hepatocytes; Humans; Hypoglycemic Agents; Incretins; Insulin; Lipid Metabolism; Liver Diseases; Non-alcoholic Fatty Liver Disease; Oxidative Stress

Topics: Diabetes Mellitus, Type 2; Fatty Liver; Humans; Incretins; Liver; Non-alcoholic Fatty Liver Disease

Recent research has led to an interest in the role of the gut and liver in type 2 diabetes mellitus (T2DM).. To review the role of the gastrointestinal system in glucose homoeostasis, with particular focus on the effects of incretin hormones, hepatic steatosis and bile acids.. PubMed and Google Scholar were searched using terms such as incretin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4), hepatic steatosis, bile acid and gastric bypass. Additional relevant references were identified by reviewing the reference lists of articles.. Perturbations of incretin hormones and bile acid secretion contribute to the pathogenesis of T2DM, leading to their potential as therapeutic targets. The incretin hormones (GIP and GLP-1) are deactivated by DPP-4. GLP-1 agonists and DPP-4 inhibitors improve glycaemic control in patients with T2DM. Hepatic steatosis, along with insulin resistance, may precede the development of T2DM, and may benefit from anti-diabetes medications. Bile acids play an important role in glucose homoeostasis, with effects mediated via the farnesoid X receptor (FXR) and the cell surface receptor TGR5. The bile acid sequestrant colesevelam has been shown to be effective in improving glycaemic control in patients with T2DM. Altered gastrointestinal anatomy after gastric bypass surgery may also affect enterohepatic recirculation of bile acids and contribute to improved glycaemic control.. Research in recent years has led to new pathways and processes with a role in glucose homoeostasis, and new therapeutic targets and options for type 2 diabetes mellitus.

Topics: Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Type 2; Fatty Liver; Gastric Bypass; Gastrointestinal Tract; Homeostasis; Humans; Incretins; Non-alcoholic Fatty Liver Disease

Regulatory role of the brain in energy expenditure, appetite, glucose metabolism, and central effects of insulin has been prominently studied. Certain neurons in the hypothalamus increase or decrease appetite via orexigenes and anorexigenes, regulating energy balance and food intake. Hypothalamus is the site of afferent and efferent stimuli between special nuclei and beta- and alpha cells, and it regulates induction/inhibition of glucose output from the liver. Incretines, produced in intestine and in certain brain cells (brain-gut hormones), link to special receptors in the hypothalamus. Central role of insulin has been proved both in animals and in humans. Insulin gets across the blood-brain barrier, links to special hypothalamic receptors, regulating peripheral glucose metabolism. Central glucose sensing, via "glucose-excited" and "glucose-inhibited" cells have outstanding role. Former are active in hyperglycaemia, latter in hypoglycaemia, via influencing beta- and alpha cells, independently of traditional metabolic pathways. Evidence of brain insulin resistance needs centrally acting drugs, paradigm changes in therapy and prevention of metabolic syndrome, diabetes, cardiovascular and oncological diseases.

Topics: Animals; Appetite Depressants; Appetite Regulation; Blood Glucose; Brain; Ceramides; Cognition; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hypothalamus; Incretins; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Metabolic Syndrome; Neuropeptides; Non-alcoholic Fatty Liver Disease; Oligopeptides; Orexins; Pyrrolidonecarboxylic Acid

Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis.. This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1·8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119.. Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4·3 [95% CI 1·0-17·7]; p=0·019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]).. Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies.. Wellcome Trust, National Institute of Health Research, and Novo Nordisk.

Topics: Adolescent; Adult; Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Incretins; Injections, Subcutaneous; Liraglutide; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Treatment Outcome; Young Adult

We evaluated whether patients with histologically verified nonalcoholic fatty liver disease (NAFLD) have an impaired incretin effect and hyperglucagonaemia.. Four groups matched for age, sex and body mass index were studied: (i) 10 patients with normal glucose tolerance and NAFLD; (ii) 10 patients with type 2 diabetes and NAFLD; (iii) eight patients with type 2 diabetes and no liver disease; and (iv) 10 controls. All participants underwent a 50-g oral glucose tolerance test (OGTT) and an isoglycaemic intravenous glucose infusion (IIGI). We determined the incretin effect by relating the beta cell secretory responses during the OGTT and IIGI. Data are presented as medians (interquartile range), and the groups were compared by using the Kruskal-Wallis test.. Controls exhibited a higher incretin effect [55% (43-73%)] compared with the remaining three groups (P < 0.001): 39% (44-71%) in the nondiabetic NAFLD patients, 20% (-5-50%) in NAFLD patients with type 2 diabetes, and 2% (-8-6%) in patients with type 2 diabetes and no liver disease. We found fasting hyperglucagonaemia in NAFLD patients with [7.5 pmol L(-1) (6.8-15 pmol L(-1))] and without diabetes [7.5 pmol L(-1) (5.0-8.0 pmol L(-1))]. Fasting glucagon levels were lower but similar in patients with type 2 diabetes and no liver disease [4.5 pmol L(-1) (3.0-6.0 pmol L(-1))] and controls [3.4 pmol L(-1) (1.8-6.0 pmol L(-1) )]. All groups had similar glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide responses.. Patients with NAFLD have a reduced incretin effect and fasting hyperglucagonaemia, with the latter occurring independently of glucose (in)tolerance.

Topics: Adult; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Incretins; Insulin; Male; Middle Aged; 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 test specific mono-agonists to the glucagon-like peptide-1 receptor (GLP-1R), glucagon receptor (GCGR) and glucose-dependent insulinotropic peptide receptor (GIPR), individually and in combination, in a mouse model of diet-induced non-alcoholic steatohepatitis (NASH) and fibrosis in order to decipher the contribution of their activities and potential additive effects to improving systemic and hepatic metabolism.. We induced NASH by pre-feeding C57BL/6J mice a diet rich in fat, fructose and cholesterol for 36 weeks. This was followed by 8 weeks of treatment with the receptor-specific agonists 1-GCG (20 μg/kg twice daily), 2-GLP1 (3 μg/kg twice daily) or 3-GIP (30 μg/kg twice daily), or the dual (1 + 2) or triple (1 + 2 + 3) combinations thereof. A dual GLP-1R/GCGR agonistic peptide, 4-dual-GLP1/GCGR (30 μg/kg twice daily), and liraglutide (100 μg/kg twice daily) were included as references.. Whereas low-dose 1-GCG or 3-GIP alone did not influence body weight, liver lipids and histology, their combination with 2-GLP1 provided additional weight loss, reduction in liver triglycerides and improvement in histological disease activity score. Notably, 4-dual-GLP-1R/GCGR and the triple combination of selective mono-agonists led to a significantly stronger reduction in the histological non-alcoholic fatty liver disease activity score compared to high-dose liraglutide, at the same extent of body weight loss.. GCGR and GIPR agonism provide additional, body weight-independent improvements on top of GLP-1R agonism in a murine model of manifest NASH with fibrosis.

Topics: Animals; Glucagon-Like Peptide-1 Receptor; Incretins; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Receptors, Glucagon

Nonalcoholic fatty liver disease (NAFLD) is seriously affecting the general health due to its high prevalence and associated risk of liver-related consequences and extrahepatic chronic complications. New drugs are urgently needed for the treatment of NAFLD. The purpose of this meta-analysis is to assess the efficacy of incretin-based therapies in patients with NAFLD.. We will search 4 databases for relative studies: PubMed, Cochrane Library, Embase, and Web of Science databases and identified all reports of randomized controlled trials (RCTs) published from inception to July 2020. Two authors will independently scan the searched articles, extract the data from included articles, and assess the risk of bias by Cochrane tool of risk of bias. Disagreements will be resolved by discussion among authors. All analysis will be performed based on the Cochrane Handbook for Systematic Reviews of Interventions. Fixed-effects model or random-effects model will be used to calculate pooled estimates of weighted mean difference (WMD) with 95% confidence intervals (CIs) or odds ratio (OR) with 95% CIs.. This systematic review aims to examine the effect of incretin-based therapies on liver histology, liver fat content, liver enzymes, and adverse events in patients with NAFLD.. These findings will provide guidance to clinicians and patients on the use of incretin-based therapies for NAFLD.

Topics: Humans; Incretins; Meta-Analysis as Topic; Non-alcoholic Fatty Liver Disease; Systematic Reviews as Topic

Topics: Diabetes Mellitus; Humans; Incretins; Liver Cirrhosis; Metformin; Non-alcoholic Fatty Liver Disease

Type 2 diabetes (T2DM) associated with non-alcoholic fatty liver disease (NAFLD) increases cardiovascular risk. Complex and subtle connections are established between hepatic dysfunction and adipose tissue hyperactivity. This relationship is mediated by insulin resistance, dyslipidemia and inflammation. Recently incretins have been involved in this connection including GLP-1 (glucagon-like peptide-1). The aim of this study is to establish interactions between the GLP-1 plasma levels and metabolic syndrome clusters and adipocytokines profile (leptin, adiponectin, resistin, TNFα and IL-6) in diabetic subjects with or without NAFLD. The study was undertaken on 320 adult subjects divided into four groups: NAFLD, DT2, NAFLD+DT2 and control. In all subjects, the metabolic syndrome clusters was investigated according to the NCEP/ATPIII criteria. Insulin resistance was evaluated by the Homa-IR model. The metabolic parameters were determined on Cobas® automated biochemical analysis. The adipocytokines are determined by immunoassay method on Elisa human reader - Biotek ELX 800. The NAFLD has been confirmed by abdominal ultrasound and by histology. Feeding and fasting plasma GLP-1 was assessed by Elisa method. The data revealed that insulin resistance (Homa-IR) is present in all groups. Homa-IR is negatively associated with plasma GLP-1 depletion in the NAFLD, DT2 and NAFLD+DT2 groups. Adiponectin levels are decreased in all groups as for GLP-1. At the opposite, leptin, resistin, TNFα and IL-6 levels show an inverse correlation with GLP-1. This study suggests that plasma GLP-1 can be considered as a transition and evolution biomarker between NAFLD and T2D. GLP-1 accurately reflects metabolic and inflammatory status, both in subjects with NAFLD only or with T2D only, before the diabetes - steatosis stage.

Topics: Adipokines; Adult; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Incretins; Insulin Resistance; Liver; Male; Metabolic Networks and Pathways; Metabolic Syndrome; Middle Aged; Non-alcoholic Fatty Liver Disease

Topics: Body Weight; Diabetes Mellitus, Type 2; Humans; Incretins; Insulin Glargine; Lipids; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

Topics: Female; Humans; Incretins; Liraglutide; Male; Non-alcoholic Fatty Liver Disease

We previously reported that incretin-based drugs, such as dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide-1 (GLP-1) analogs, improved glycemic control and liver inflammation in non-alcoholic fatty liver disease (NAFLD) patients with type 2 diabetes mellitus (T2DM). However, the effect on alanine aminotransferase (ALT) normalization was still limited.. The aim of this study is to elucidate the effectiveness of sodium-glucose co-transporter 2 (SGLT-2) inhibitors as second-line treatments for NAFLD patients with T2DM who do not respond to incretin-based therapy.. We retrospectively enrolled 130 consecutive Japanese NAFLD patients with T2DM who were treated with GLP-1 analogs or DPP-4 inhibitors. Among them, 70 patients (53.8 %) had normal ALT levels. Of the remaining 60 patients (46.2 %) who did not have normal ALT levels, 24 (40.0 %) were enrolled in our study and were administered SGLT-2 inhibitors in addition to GLP-1 analogs or DPP-4 inhibitors. We compared changes in laboratory data including ALT levels and body weight at the end of the follow-up.. Thirteen patients were administered a combination of SGLT-2 inhibitors with DPP-4 inhibitors, and the remaining 11 patients were administered a combination of SGLT-2 inhibitors with GLP-1 analogs. The median dosing period was 320 days. At the end of the follow-up, body weight (from 84.8 to 81.7 kg, p < 0.01) and glycosylated hemoglobin levels (from 8.4 to 7.6 %, p < 0.01) decreased significantly. Serum ALT levels also decreased significantly (from 62 to 38 IU/L, p < 0.01) with an improvement in the FIB-4 index (from 1.75 to 1.39, p = 0.04). Finally, 14 patients (58.3 %) achieved normalization of serum ALT levels.. Administration of SGLT-2 inhibitors led to not only good glycemic control, but also to a reduction in body weight, normalization of ALT levels, and a reduction in the FIB-4 index even in patients who did not respond to incretin-based therapy.

Topics: Alanine Transaminase; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Glucosides; Humans; Incretins; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Retrospective Studies; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Weight Loss

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

Topics: Female; Humans; Incretins; Liraglutide; Male; Non-alcoholic Fatty Liver Disease

Topics: Female; Humans; Incretins; Liraglutide; Male; Non-alcoholic Fatty Liver Disease

Topics: Female; Humans; Incretins; Liraglutide; Male; Non-alcoholic Fatty Liver Disease

Bile acids or its derivatives may influence non-alcoholic fatty liver disease development through multiple mechanisms. Intestinal L-cells secrete glucagon-like peptide-1 (GLP-1) and can be activated by bile acids (BA) influencing insulin resistance and hepatic steatosis development and progression. The aim of the present study was to assess the effects of cholic acid (CA) or ursodeoxycholic acid (UDCA) administration on portal and systemic levels of GLP-1 in genetically obese mice with established hepatic steatosis. Eight-week-old ob/ob mice were fed CA or UDCA during 4 weeks. Systemic and portal GLP-1 levels were measured as well as glucose tolerance test, serum and biliary parameters, hepatic triglyceride content, liver histology, and hepatic gene expression of relevant genes related to bile secretion. Eight-week-old ob/ob mice exhibited marked obesity, hyperinsulinemia, and fasting hyperglycemia. Administration of both CA and UDCA was associated to decreased hepatic triglyceride content and complete reversion of histological steatosis. BA-fed animals did not exhibit significant differences in glucose tolerance. In addition, neither CA nor UDCA administration significantly influenced portal or systemic GLP-1 levels. CA and UDCA strongly ameliorated established fatty liver in ob/ob mice independently of the GLP-1 incretin pathway. Thus, the anti-steatotic action of these bile acids is likely related to direct hepatic effects.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase; Cholic Acid; Gene Expression; Glucagon-Like Peptide 1; Glucose Tolerance Test; Incretins; Liver; Male; Mice; Mice, Obese; Non-alcoholic Fatty Liver Disease; Organic Anion Transporters, Sodium-Dependent; Receptors, Cytoplasmic and Nuclear; Symporters; Triglycerides; Ursodeoxycholic Acid

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been recognized as a metabolic disorder characterized by fatty accumulation of the liver without alcohol consumption. The progression of the diseases has been considered to link to metabolic syndrome, consisting of obesity, diabetes mellitus(DM), dyslipidemia and hypertension. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide(GIP) function as incretin and stimulate glucose-mediated insulin production by pancreatic beta cells. Incretin was also reported to have various kinds of extrapancreatic effects including the regulation of hepatic glucose production, the inhibition of pancreatic exocrine secretion, cardioprotective and cardiotropic effects, the regulation of appetite and satiety, and stimulation of afferent sensory nerves. Therefore, incretins are also expected as therapeutic agents for NFLD and NASH.

Topics: Fatty Liver; Glucagon-Like Peptide-1 Receptor; Hepatocytes; Humans; Incretins; Lipid Metabolism; Non-alcoholic Fatty Liver Disease; Receptors, Glucagon