Non-Alcoholic Fatty Liver Disease in Obese Youth With Insulin Resistance and Type 2 Diabetes.
Ontology highlight
ABSTRACT:
SUBMITTER: Scapaticci S
PROVIDER: S-EPMC8056131 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL) cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD). Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%-23% fat and 57%-65% carbohydrate lower liver fat compared to diets with 43%-55% fat and 27%-38% carbohydrate. Diets rich in saturated (SFA) as compared to monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance.
| S-EPMC4663582 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) are common conditions that regularly co-exist and can act synergistically to drive adverse outcomes. The presence of both NAFLD and T2DM increases the likelihood of the development of complications of diabetes (including both macro- and micro- vascular complications) as well as augmenting the risk of more severe NAFLD, including cirrhosis, hepatocellular carcinoma and death. The mainstay of NAFLD management is currently to reduce modifiable metabolic risk. Achieving good glycaemic control and optimising weight loss are pivotal to restricting disease progression. Once cirrhosis has developed, it is necessary to screen for complications and minimise the risk of hepatic decompensation. Therapeutic disease modifying options for patients with NAFLD are currently limited. When diabetes and NAFLD co-exist, there are published data that can help inform the clinician as to the most appropriate oral hypoglycaemic agent or injectable therapy that may improve NAFLD, however most of these data are drawn from observations in retrospective series and there is a paucity of well-designed randomised double blind placebo controlled studies with gold-standard end-points. Furthermore, given the heterogeneity of inclusion criteria and primary outcomes, as well as duration of follow-up, it is difficult to draw robust conclusions that are applicable across the entire spectrum of NAFLD and diabetes. In this review, we have summarised and critically evaluated the available data, with the aim of helping to inform the reader as to the most pertinent issues when managing patients with co-existent NAFLD and T2DM.
| S-EPMC4943559 | biostudies-literature
Project description:Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes. There are 12 samples in our study which belonged to 4 groups, and each group contains 3 different samples.
2015-01-23 | E-GEOD-65220 | biostudies-arrayexpress
Project description:OBJECTIVE:Increased hepatic expression of dipeptidyl peptidase 4 (DPP4) is associated with non-alcoholic fatty liver disease (NAFLD). Whether this is causative for the development of NAFLD is not yet clarified. Here we investigate the effect of hepatic DPP4 overexpression on the development of liver steatosis in a mouse model of diet-induced obesity. METHODS:Plasma DPP4 activity of subjects with or without NAFLD was analyzed. Wild-type (WT) and liver-specific Dpp4 transgenic mice (Dpp4-Liv-Tg) were fed a high-fat diet and characterized for body weight, body composition, hepatic fat content and insulin sensitivity. In vitro experiments on HepG2 cells and primary mouse hepatocytes were conducted to validate cell autonomous effects of DPP4 on lipid storage and insulin sensitivity. RESULTS:Subjects suffering from insulin resistance and NAFLD show an increased plasma DPP4 activity when compared to healthy controls. Analysis of Dpp4-Liv-Tg mice revealed elevated systemic DPP4 activity and diminished active GLP-1 levels. They furthermore show increased body weight, fat mass, adipose tissue inflammation, hepatic steatosis, liver damage and hypercholesterolemia. These effects were accompanied by increased expression of PPARγ and CD36 as well as severe insulin resistance in the liver. In agreement, treatment of HepG2 cells and primary hepatocytes with physiological concentrations of DPP4 resulted in impaired insulin sensitivity independent of lipid content. CONCLUSIONS:Our results give evidence that elevated expression of DPP4 in the liver promotes NAFLD and insulin resistance. This is linked to reduced levels of active GLP-1, but also to auto- and paracrine effects of DPP4 on hepatic insulin signaling.
| S-EPMC5641684 | biostudies-literature
Project description:Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes.
2015-01-23 | GSE65220 | GEO
Project description:Numerous studies have shown that C1q/TNF-related proteins (CTRPs) are involved in the pathophysiology of metabolic disorders, such as Non-alcoholic fatty liver disease (NAFLD) and Type 2 Diabetes (T2DM). There is a little information concerning CTRP13 in the context of NAFLD and T2DM. We evaluated the plasma levels of CTRP13 in healthy control and patients with NAFLD, T2DM and NAFLD+T2DM, and also correlations between CTRP13 plasma levels and clinical and subclinical features. Circulating CTRP13 was examined in 88 male (20 healthy control, 22 T2DM patients, 22 NAFLD patients and 22 NAFLD+T2DM patients). CTRP13 and adiponectin plasma levels were measured by ELISA method. CTRP13 serum levels were higher in the control group than the other groups (all p <0.001). CTRP13 had significant negative correlation with unfavorable anthropometric and metabolic factors including BMI, visceral fat, Insulin, HOMA-IR, TG, AST, ALT and ?-GT and have a positive correlation with plasma concentration of adiponectin. CTRP13 had a significant inverse correlation with cIMT (r = -0.345) and liver stiffness (LS) (r = -0.372) (both, p <0.001). Also, the multiple stepwise linear regression has shown that visceral fat is a significant predictor of CTRP13 serum levels (p <0.001). Multiple stepwise linear regression with LS as the dependent variable showed that ALT (p < 0.001) and SBP (p = 0.010) were two predictor factors for LS. Strikingly, multiple stepwise linear regression showed that CTRP13 (p = 0.006) and SBP (p = 0.007) were two independent predictors for cIMT. Lower CTRP13 in patients with T2DM, NAFLD and NAFLD + T2DM was associated with increased risk of the diseases. CTRP13 have negative associations with unfavorable metabolic factors and also is a negative predictor of cIMT. Our results suggested that CTRP13 could be an associated factor with NAFLD in patients with and without T2DM.
| S-EPMC5148106 | 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:Background: Non-alcoholic fatty liver disease (NAFLD) is not uncommon in non-obese subjects, referred to as non-obese NAFLD. It is not fully determined whether non-obese NAFLD is associated with increased risks of type 2 diabetes (T2D) and coronary artery disease (CAD) in Chinese. This study aimed to examine the association between NAFLD and risks of T2D and CAD in a non-obese Chinese population. Methods: The present cohort study included two stages. In the first cross-sectional study, 16,093 non-obese subjects with a body max index (BMI) < 25.0 kg/m2 were enrolled from The Second Xiangya Hospital, China, from 2011 to 2014. Hepatic steatosis was evaluated by ultrasonography examination. Logistic regression analyses were used to examine the association of non-obese NAFLD with T2D and CAD at baseline. In the subsequent 5-year follow-up study, 12,649 subjects free of T2D and CAD at baseline were included, and the incidence of T2D and CAD were observed. Cox proportional hazard regression analyses were performed to determine the risk of incident T2D and CAD with NAFLD. Results: At baseline, the prevalence of NAFLD, T2D and CAD were 10.7% (1,717/16,093), 3.3% (529/16,093) and 0.7% (113/16,093), respectively. The univariate logistic regression analyses showed NAFLD associated with both T2D and CAD. Moreover, in a multivariate logistic regression model, NAFLD remained independently associated with T2D (OR: 2.7, 95% CI: 2.2-3.3, p < 0.001). However, no significant association was found between NAFLD and CAD by the multivariate logistic regression analyses (OR: 1.1, 95% CI: 0.6-1.8, p = 0.854). During a 5-year follow-up period, 177 (1.4%) patients developed T2D, and 134 (1.1%) developed CAD, respectively. In univariate Cox regression models, NAFLD associated with both T2D and CAD. Moreover, the multivariate Cox regression analysis revealed that NAFLD independently associated with an increased risk of T2D (HR: 2.3, 95% CI: 1.7-3.2, p < 0.001). However, the association between NAFLD and incident CAD was lost in the multivariate Cox regression analysis (HR = 1.5, 95% CI: 1.0-2.4, p = 0.059). Conclusions: NAFLD was an independent risk factor for T2D in non-obese subjects. However, no significant association was observed between non-obese NAFLD and incident CAD after adjusting other traditional cardiovascular risk factors, suggesting these factors might mediate the increased incidence of CAD in non-obese NAFLD patients.
| S-EPMC8417689 | biostudies-literature
Project description:Activation of inflammatory pathways is known to accompany development of obesity-induced non-alcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes. In addition to caspase-1, the neutrophil serine proteases proteinase 3, neutrophil elastase and cathepsin G are able to process the inactive pro-inflammatory mediators IL-1? and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In the present study, we investigated whether proteinase 3 is involved in obesity-induced development of insulin resistance and NAFLD. We investigated the development of NAFLD and insulin resistance in mice deficient for neutrophil elastase/proteinase 3 and neutrophil elastase/cathepsin G and in wild-type mice treated with the neutrophil serine proteinase inhibitor human alpha-1 antitrypsin. Expression profiling of metabolically relevant tissues obtained from insulin resistant mice showed that expression of proteinase 3 was specifically upregulated in the liver, whereas neutrophil elastase, cathepsin G and caspase-1 were not. Neutrophil elastase/proteinase 3 deficient mice showed strongly reduced levels of lipids in the liver after fed a high fat diet. Moreover, these mice were resistant to high fat diet-induced weight gain, inflammation and insulin resistance. Injection of proteinase 3 exacerbated insulin resistance in caspase-1(-/-) mice, indicating that proteinase 3 acts independently of caspase-1. Treatment with alpha-1 antitrypsin during the last 10 days of a 16 week high fat diet reduced hepatic lipid content and decreased fasting glucose levels. We conclude that proteinase 3 is involved in NAFLD and insulin resistance and that inhibition of proteinase 3 may have therapeutic potential.
| S-EPMC5004724 | biostudies-literature
Project description:ObjectiveInsulin resistance and altered hepatic mitochondrial function are central features of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), but the etiological role of these processes in disease progression remains unclear. Here we investigated the molecular links between insulin resistance, mitochondrial remodeling, and hepatic lipid accumulation.MethodsHepatic insulin sensitivity, endogenous glucose production, and mitochondrial metabolic fluxes were determined in wild-type, obese (ob/ob) and pioglitazone-treatment obese mice using a combination of radiolabeled tracer and stable isotope NMR approaches. Mechanistic studies of pioglitazone action were performed in isolated primary hepatocytes, whilst molecular hepatic lipid species were profiled using shotgun lipidomics.ResultsLivers from obese, insulin-resistant mice displayed augmented mitochondrial content and increased tricarboxylic acid cycle (TCA) cycle and pyruvate dehydrogenase (PDH) activities. Insulin sensitization with pioglitazone mitigated pyruvate-driven TCA cycle activity and PDH activation via both allosteric (intracellular pyruvate availability) and covalent (PDK4 and PDP2) mechanisms that were dependent on PPAR? activity in isolated primary hepatocytes. Improved mitochondrial function following pioglitazone treatment was entirely dissociated from changes in hepatic triglycerides, diacylglycerides, or fatty acids. Instead, we highlight a role for the mitochondrial phospholipid cardiolipin, which underwent pathological remodeling in livers from obese mice that was reversed by insulin sensitization.ConclusionOur findings identify targetable mitochondrial features of T2D and NAFLD and highlight the benefit of insulin sensitization in managing the clinical burden of obesity-associated disease.
| S-EPMC7811046 | biostudies-literature