Glucose-lowering agents and reduced risk of incident non-alcoholic fatty liver disease: new insights.
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ABSTRACT:
SUBMITTER: Mantovani A
PROVIDER: S-EPMC8847873 | biostudies-literature | 2022 Feb
REPOSITORIES: biostudies-literature
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Glucose-lowering agents and reduced risk of incident non-alcoholic fatty liver disease: new insights.
Mantovani Alessandro A Lombardi Rosa R Dalbeni Andrea A
Hepatobiliary surgery and nutrition 20220201 1
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Project description:Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease with a global prevalence of about 55% in people with type 2 diabetes mellitus (T2DM). T2DM, obesity and NAFLD are three closely inter-related pathological conditions. In addition, T2DM is one of the strongest clinical risk factors for the faster progression of NAFLD to non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. Increasing evidence suggests that newer classes of glucose-lowering drugs, such as peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors or sodium-glucose cotransporter-2 inhibitors, could reduce the rates of NAFLD progression. This narrative review aims to briefly summarize the recent results from randomized controlled trials testing the efficacy and safety of old and new glucose-lowering drugs for the treatment of NAFLD or NASH in adults both with and without coexisting T2DM.
| S-EPMC9597221 | biostudies-literature
Project description:One of the most common complications of childhood obesity is the non-alcoholic fatty liver disease (NAFLD), which is the most common form of liver disease in children. NAFLD is defined by hepatic fat infiltration > 5% hepatocytes, as assessed by liver biopsy, in the absence of excessive alcohol intake, viral, autoimmune and drug-induced liver disease. It encompasses a wide spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis, which, in turn, can evolve into cirrhosis and end stage liver disease. Obesity and insulin resistance are the main risk factors for pediatric NAFLD. In fact, NAFLD is strongly associated with the clinical features of insulin resistance especially the metabolic syndrome, prediabetes and type 2 diabetes mellitus (T2D). In particular, it has been clearly shown in obese youth that the prevalence of metabolic syndrome, pre-diabetes and type 2 diabetes increases with NAFLD severity progression. Evidence that not all of the obese patients develop NAFLD suggests that the disease progression is likely to depend on complex interplay between environmental factors and genetic predisposition. Recently, a non-synonymous SNP (rs738409), characterized by a C to G substitution encoding an isoleucine to methionine substitution at the amino acid position 148 in the patatin like phospholipase containing domain 3 gene (PNPLA3), has been associated with hepatic steatosis in a multiethnic cohort of adults as well as in children. Another important polymorphisms that acts with PNPLA3 to convey susceptibility to fatty liver in obese youths is the rs1260326 polymorphism in the glucokinase regulatory protein. The pharmacological approach in NAFLD children poorly adherent to or being unresponsive/partially responsive to lifestyle changes, is aimed at acting upon specific targets involved in the pathogenesis. There are some therapeutic approaches that are being studied in children. This article reviews the current knowledge regarding the pediatric fatty liver disease, the new insights and the future directions.
| S-EPMC4009477 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) represents the hepatic expression of the metabolic syndrome and is the most prevalent liver disease. NAFLD is associated with liver-related and extrahepatic morbi-mortality. Among extrahepatic complications, cardiovascular disease (CVD) is the primary cause of mortality in patients with NAFLD. The most frequent clinical expression of CVD is the coronary artery disease (CAD). Epidemiological data support a link between CAD and NAFLD, underlain by pathogenic factors, such as the exacerbation of insulin resistance, genetic phenotype, oxidative stress, atherogenic dyslipidemia, pro-inflammatory mediators, and gut microbiota. A thorough assessment of cardiovascular risk and identification of all forms of CVD, especially CAD, are needed in all patients with NAFLD regardless of their metabolic status. Therefore, this narrative review aims to examine the available data on CAD seen in patients with NAFLD, to outline the main directions undertaken by the CVD risk assessment and the multiple putative underlying mechanisms implicated in the relationship between CAD and NAFLD, and to raise awareness about this underestimated association between two major, frequent and severe diseases.
| S-EPMC9410285 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide, with an estimated prevalence of 25% in the Western World. NAFLD is a broad spectrum of disease states and while most people with NAFLD do not have progressive disease, 10-20% of patients develop histological features of inflammation (non-alcoholic steatohepatitis), fibrosis, cirrhosis and its complications. Despite this large disease burden of significant clinical impact, most people living with NAFLD are undiagnosed, disease course prediction is imprecise and there are no treatments licensed for this condition. In this review, we discuss some of the recent developments in NAFLD, focusing on disease definition and diagnosis, risk stratification and treatments.
| S-EPMC9234732 | biostudies-literature
Project description:AimsTo investigate the association between overweight/obesity and fatty liver index (FLI) on the odds of incident prediabetes/type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) in 2020 participants after 10 years follow up.MethodsAt baseline (in 2001) 2020 participants, males and females, aged 24-39 years, were stratified according to body mass index (BMI), normal weight (<25 kg/m2), overweight (≥25-<30 kg/m2), or obese (≥30 kg/m2) and FLI (as high FLI ≥60 or low FLI <60). We examined the incidence of prediabetes/type 2 diabetes and NAFLD (ultrasound assessed) over 10 years to 2011 to determine the relative impact of FLI and BMI.Results514 and 52 individuals developed prediabetes and type 2 diabetes during follow-up. Such individuals were older, with higher BMI, serum glucose, insulin, alanine aminotransferase (ALT) and triglyceride (TG) concentrations than those who did not develop prediabetes or type 2 diabetes (n = 1454). The additional presence of high FLI significantly increased the risk of developing prediabetes and type 2 diabetes above the risk of being overweight/obese. Compared with normal weight, low FLI participants, the odds of prediabetes were ∼2-fold higher and the odds of type 2 diabetes were 9-10-fold higher respectively in the overweight/obese, high FLI group. No difference was observed between normal weight, low FLI and overweight/obese and low FLI groups.ConclusionsAn increased FLI significantly increases the odds of incident prediabetes, type 2 diabetes and NAFLD in individuals with overweight/obese highlighting the contributory role of liver fat accumulation in the pathophysiology of prediabetes/type 2 diabetes.Key messagesObesity is a risk factor for non-alcoholic fatty liver disease (NAFLD), prediabetes and type 2 diabetes.Additionally, NAFLD is more prevalent in people with prediabetes and type 2 diabetes when compared to age- and BMI-matched individuals.The presence of a raised fatty liver index (FLI) confers a significantly increased risk of developing prediabetes, type 2 diabetes and NAFLD above that conferred by being overweight/obese.The degree of elevation of FLI can risk stratify for incident prediabetes and type 2 diabetes in people with obesity.
| S-EPMC8317942 | biostudies-literature
Project description:AimsHeart failure with preserved ejection fraction (HFpEF) and non-alcoholic fatty liver disease (NAFLD) are related conditions with an increasing incidence. The mechanism of their relationship remains undefined. Here, we aimed to explore the potential mechanisms, diagnostic markers, and therapeutic options for HFpEF and NAFLD.Methods and resultsHFpEF and NAFLD datasets were downloaded from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (DEGs) were screened for functional annotation. A protein-protein interaction network was constructed based on the STRING database, and hub genes were analysed using GeneMANIA annotation. ImmuCellAI (Immune Cell Abundance Identifier) was employed for analysis of immune infiltration. We also used validation datasets to validate the expression levels of hub genes and the correlation of immune cells. To screen for diagnostic biomarkers, we employed the least absolute shrinkage and selection operator and support vector machine-recursive feature elimination. Drug signature database was used to predict potential therapeutic drugs. Our analyses identified a total of 33 DEGs. Inflammation and immune infiltration played important roles in the development of both diseases. The data showed a close relationship between chemokine signalling pathway, cytokine-cytokine receptor interaction, calcium signalling pathway, neuroactive ligand-receptor interaction, osteoclast differentiation, and cyclic guanosine monophosphate-protein kinase G signalling pathway. We demonstrated that PRF1 (perforin 1) and IL2RB (interleukin-2 receptor subunit beta) proteins were perturbed by the diseases and may be the hub genes. The analysis showed that miR-375 may be a potential diagnostic marker for both diseases. Our drug prediction analysis showed that bosentan, eldecalcitol, ramipril, and probucol could be potential therapeutic options for the diseases.ConclusionsOur findings revealed common pathogenesis, diagnostic markers, and therapeutic agents for HFpEF and NAFLD. There is need for further experimental studies to validate our findings.
| S-EPMC9871724 | biostudies-literature
Project description:Industrialized society-caused dysregular human behaviors and activities such as overworking, excessive dietary intake, and sleep deprivation lead to perturbations in the metabolism and the development of metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide, affects around 30% and 25% of people in Western and Asian countries, respectively, which leads to numerous medical costs annually. Insulin resistance is the major hallmark of NAFLD and is crucial in the pathogenesis and for the progression from NAFLD to non-alcoholic steatohepatitis (NASH). Excessive dietary intake of saturated fats and carbohydrate-enriched foods contributes to both insulin resistance and NAFLD. Once NAFLD is established, insulin resistance can promote the progression to the more severe state of liver endangerment like NASH. Here, we review current and potential studies for understanding the complexity between insulin-regulated glycolytic and lipogenic homeostasis and the underlying causes of NAFLD. We discuss how disruption of the insulin signal is associated with various metabolic disorders of glucoses and lipids that constitute both the metabolic syndrome and NAFLD.
| S-EPMC6359196 | biostudies-literature
Project description:IntroductionNon-alcoholic fatty liver disease (NAFLD) is characterized by excess accumulation of triglycerides within the liver. However, whether the circulating levels of triglycerides and cholesterol transported in triglyceride-rich lipoproteins (remnant cholesterol, remnant-C) are related to the occurrence of NAFLD has not yet been studied. This study aims to assess the association of triglycerides and remnant-C with NAFLD in a Chinese cohort of middle aged and elderly individuals.MethodsAll subjects in the current study are from the 13,876 individuals who recruited in the Shandong cohort of the REACTION study. We included 6,634 participants who had more than one visit during the study period with an average follow-up time of 43.34 months. The association between lipid concentrations and incident NAFLD were evaluated by unadjusted and adjusted Cox proportional hazard models. The potential confounders were adjusted in the models including age, sex, hip circumference (HC), body mass index (BMI), systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), diabetes status and cardiovascular disease (CVD) status.ResultsIn multivariable-adjusted Cox proportional hazard model analyses, triglycerides (hazard ratio[HR], 95% confidence interval [CI]:1.080,1.047-1.113;p<0.001), high-density lipoprotein cholesterol (HDL-C) (HR, 95% CI: 0.571,0.487-0.670; p<0.001), and remnant-C (HR, 95% CI: 1.143,1.052-1.242; p=0.002), but not total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C), were associated with incident NAFLD. Atherogenic dyslipidemia (triglycerides>1.69 mmol/L, HDL-C<1.03 mmol/L in men or<1.29 mmol/L in women) was also associated with NAFLD (HR, 95% CI: 1.343,1.177-1.533; p<0.001). Remnant-C levels were higher in females than in males and increased with increasing BMI and in participants with diabetes and CVD compared with those without diabetes or CVD. After adjusting for other factors in the Cox regression models, we found that serum levels of TG and remnant-C, but not TC or LDL-C, were associated with NAFLD outcomes in women group, non-cardiovascular disease status, non-diabetes status and middle BMI categories (24 to 28 kg/m2).DiscussionIn the middle aged and elderly subset of the Chinese population, especially those who were women, non-CVD status, non-diabetes status and middle BMI status (24 to 28 kg/m2), levels of triglycerides and remnant-C, but not TC or LDL-C, were associated with NAFLD outcomes independent of other risk factors.
| S-EPMC10198261 | biostudies-literature
Project description:The aim of the current study was to evaluate the association between changes in non-alcoholic fatty liver disease (NAFLD) over time and risk of incident diabetes mellitus (DM). In total, 3047 subjects without underlying DM were followed up for 14 years from the Anseong-Ansan cohort. NAFLD status was determined biennially using the hepatic steatosis index (HSI), and subjects were clustered into seven groups according to changes in HSI, body mass index (BMI), and homeostatic model assessment of insulin resistance (HOMA-IR): none, persistent, transient, transient resolved, resolved, incident, and recurrent NAFLD (Groups 1-7, respectively). Predictive abilities were compared between the dynamics of HSI and single time points. Regarding the changes in HSI, the risk of incident DM was highest in Group 2 (hazard ratio [HR] 2.710; P < 0.001), followed by Groups 7 (HR 2.062; P < 0.001) and 3 (HR 1.559; P = 0.027). The predictive ability for DM was powerful in order of HOMA-IR, HSI and BMI. The dynamics of NAFLD were less predictive of incident DM than single time-point NAFLD. In conclusion, NAFLD is more useful than BMI in predicting incident DM. However, NAFLD status at single time points can better predict incident DM than dynamic changes in HSI.
| S-EPMC8847663 | biostudies-literature
Project description:Background/aimsSome studies showed that probiotics could improve the composition and structure of gut microbiota. Changes in the gut microbiota may alter bile acid (BAs) composition and kinetics, improving non-alcoholic fatty liver disease (NAFLD). However, it still needs to be clarified how probiotics improve both the metabolism of BAs and NAFLD. This study aimed to reveal the regulatory mechanisms of cholesterol-lowering (CL) probiotics on NAFLD from aspects involved in BA metabolism in FXR gene knockout (FXR-/-) mice.MethodsFXR-/- male mice were randomly divided into three groups based on different interventions for 16 weeks, including normal diet (ND), high-fat diet (HFD), and probiotic intervention in the HFD (HFD+P) group. 16s rDNA sequencing and ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) were utilized to analyze the changes in gut microbiota and fecal bile acids in mice.ResultsWe found that the intervention of the CL probiotics improved liver lipid deposition and function in HFD-induced NAFLD mice by decreasing the levels of total cholesterol (TC; p = 0.002) and triglyceride (TG; p = 0.001) in serum, as well as suppressing liver inflammation, such as interleukin-1 beta (IL-1β; p = 0.002) and tumor necrosis factor-alpha (TNF-α; p < 0.0001). 16S rDNA sequencing and metabolomic analyses showed that probiotics effectively reduced the abundance of harmful gut microbiota, such as Firmicutes (p = 0.005), while concomitantly increasing the abundance of beneficial gut microbiota in NAFLD mice, such as Actinobacteriota (p = 0.378), to improve NAFLD. Compared with the ND group, consuming an HFD elevated the levels of total BAs (p = 0.0002), primary BAs (p = 0.017), and secondary BAs (p = 0.0001) in mice feces, while the intervention with probiotics significantly reduced the increase in the levels of fecal total bile acids (p = 0.013) and secondary bile acids (p = 0.017) induced by HFD.ConclusionThe CL probiotics were found to improve liver function, restore microbiota balance, correct an abnormal change in the composition and content of fecal bile acids, and repair the damaged intestinal mucosal barrier in mice with NAFLD, ultimately ameliorating the condition. These results suggested that CL probiotics may be a promising and health-friendly treatment option for NAFLD.
| S-EPMC10397539 | biostudies-literature