incretins and Liver-Cirrhosis

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

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

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

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

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

Hepatic stellate cells (HSC) play a key role in the development of chronic liver disease (CLD). Liraglutide, well-established in type 2 diabetes, showed anti-inflammatory and anti-oxidant properties. We evaluated the effects of liraglutide on HSC phenotype and hepatic microvascular function using diverse pre-clinical models of CLD. Human and rat HSC were in vitro treated with liraglutide, or vehicle, and their phenotype, viability and proliferation were evaluated. In addition, liraglutide or vehicle was administered to rats with CLD. Liver microvascular function, fibrosis, HSC phenotype and sinusoidal endothelial phenotype were determined. Additionally, the effects of liraglutide on HSC phenotype were analysed in human precision-cut liver slices. Liraglutide markedly improved HSC phenotype and diminished cell proliferation. Cirrhotic rats receiving liraglutide exhibited significantly improved liver microvascular function, as evidenced by lower portal pressure, improved intrahepatic vascular resistance, and marked ameliorations in fibrosis, HSC phenotype and endothelial function. The anti-fibrotic effects of liraglutide were confirmed in human liver tissue and, although requiring further investigation, its underlying molecular mechanisms suggested a GLP1-R-independent and NF-κB-Sox9-dependent one. This study demonstrates for the first time that liraglutide improves the liver sinusoidal milieu in pre-clinical models of cirrhosis, encouraging its clinical evaluation in the treatment of chronic liver disease.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Hepatic Stellate Cells; Humans; Incretins; Liraglutide; Liver; Liver Cirrhosis; Male; Microvessels; Rats, Wistar

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

The impaired glucose tolerance in cirrhosis is poorly understood. We evaluated the influence of gastrointestinal-mediated glucose disposal and incretin effect in patients with cirrhosis.. Non-diabetic patients with Child-Pugh A or B cirrhosis (n = 10) and matched healthy controls (n = 10) underwent a 50-g oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion. We presented data as median ± interquartile range and compared groups using non-parametric analysis of variance.. Patients with cirrhosis were glucose intolerant compared with healthy controls (4-h OGTTAUC : 609 ± 458 vs 180 ± 155 min × mmol/L; P = 0.005), insulin resistant (homeostatic model assessment for insulin resistance: 3.7 ± 4.9 vs 2.6 ± 1.4; P = 0.014) and had fasting hyperglucagonemia (8 ± 3 vs 3 ± 4 pmol/L; P = 0.027). Isoglycemia was achieved using 35 ± 12 g of intravenous glucose in patients with cirrhosis compared with 24 ± 10 g in healthy controls (P = 0.003). The gastrointestinal-mediated glucose disposal was markedly lower in patients with cirrhosis (30 ± 23 vs 52 ± 20%; P = 0.003). Despite higher levels of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide patients with cirrhosis had reduced incretin effect (35 ± 44 vs 55 ± 30%; P = 0.008).. Impaired gastrointestinal-mediated glucose disposal and reduced incretin effect may contribute to the glucose intolerance seen in patients with cirrhosis.

Topics: Adult; Aged; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Incretins; Insulin Resistance; Liver Cirrhosis; Male; Middle Aged

In this work Author presents a case report of a female patient of 65 years old who had suffered from type 2 diabetes mellitus and from concomitant cryptogenic cirrhosis. She was treated with liraglutide, an analogue of human GLP-1, obtaining an optimal metabolic control associated with an improved clinical condition for the cirrhosis.

Topics: Aged; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide; Liver; Liver Cirrhosis

Topics: Blood Glucose; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Incretins; Liver Cirrhosis; Portasystemic Shunt, Transjugular Intrahepatic