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BACKGROUND The prevalence of metabolic (dysfunction)-associated fatty liver disease (MAFLD) increases together with the epidemic of childhood obesity. An important mechanism in the phenomenon appears to be insulin resistance (IR), the assessment of which in children is problematic. The homeostatic model assessment of IR (HOMA-IR), commonly used for this, is not standardized and appears not to correlate with IR in the pediatric population. Therefore, our study aimed to evaluate potential substitute indices of IR, including the triglyceride-glucose index (TyG), triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C), modified TyG indices: TyG-waist circumference (TyG-WC) and TyG-body mass index (TyG-BMI) as surrogate markers of MAFLD in obese children suspected to have liver disease. MATERIAL AND METHODS The retrospective study included 264 obese children admitted to the Department to diagnose suspected liver disease. MAFLD was diagnosed according to the International Expert Consensus Statement. Anthropometric measurements and laboratory tests were made and the indices were calculated. Receiver operating characteristics analysis was performed to calculate the power of the indices. RESULTS MAFLD was diagnosed in 184 patients (70%). Obese children with MAFLD showed significantly higher activity of liver enzymes and concentration of total cholesterol, TG, WC, and waist-to-hip ratio compared to non-hepatopathic obese controls (n=80). The most important indices in identifying MAFLD were: TyG (AUC=0.641, p<0.001, cut-off =8.41, sensitivity=57.4%, specificity=68.8%), and TG/HDL-C (AUC=0.638, p<0.001, cut-off=2.5, sensitivity=48.6%, specificity=76.3%). TyG-BMI and HOMA-IR were not useful predictors. CONCLUSIONS TyG and TG/HDL-C can be considered as potential surrogate biomarkers in predicting MAFLD in obese children.

Background: To investigate the association of four insulin resistance (IR) indicators with hepatic steatosis and fibrosis in patients with metabolic syndrome (MetS), as well as to compare the diagnostic value of these indicators in identifying hepatic steatosis and fibrosis in individuals with MetS., Methods: This cross-sectional study used the data from the National Health and Nutrition Examination Survey 2017-2018. IR indicators included homeostasis model assessment of IR (HOMA-IR), triglyceride/glucose (TyG) index, triglyceride glucose-waist-to-height ratio (TyG-WHtR), and metabolic score for IR (METS-IR). The main endpoints of this study were hepatic steatosis and hepatic fibrosis. Weighted univariate and multivariate logistic regression models were employed to evaluate the association between four IR indicators and both hepatic steatosis, hepatic fibrosis. The efficacy of various IR indicators in the detection of hepatic steatosis and hepatic fibrosis were assessed using receiver operating characteristics curve (ROC)., Results: A total of 876 participants with MetS were enrolled. Among the participants, hepatic steatosis was observed in 587 MetS individuals, while hepatic fibrosis was identified in 151 MetS individuals. In multivariate logistic regression model, HOMA-IR, TyG, TyG-WHtR, and METS-IR were related to the increased odd of hepatic steatosis. Additionally, HOMA-IR, TyG-WHtR, and METS-IR were associated with increased odd of hepatic fibrosis. According to the ROC analysis, the area under the curve (AUC) of the TyG-WHtR (AUC = 0.705, 95%CI: 0.668-0.743) was higher than HOMA-IR (AUC = 0.693, 95%CI: 0.656-0.730), TyG (AUC = 0.627, 95%CI: 0.587-0.666), and METS-IR (AUC = 0.685, 95%CI: 0.648-0.722) for identifying hepatic steatosis of MetS patients. Likewise, TyG-WHtR was also higher than HOMA-IR, TyG, and METS-IR for identifying hepatic fibrosis of MetS patients., Conclusion: HOMA-IR, TyG-WHtR, and METS-IR may be associated with the risk of hepatic steatosis and fibrosis among the U.S. adult population with MetS. In addition, TyG-WHtR may have a good predictive value for hepatic steatosis and hepatic fibrosis., (© 2024. The Author(s).)

While the association of metabolic dysfunction-associated steatotic liver disease (MASLD) with obesity and insulin resistance is widely appreciated, there are a host of complex interactions between the liver and other endocrine axes. While it can be difficult to definitively distinguish direct causal relationships and those attributable to increased adipocyte mass, there is substantial evidence of the direct and indirect effects of endocrine dysregulation on the severity of MASLD, with strong evidence that low levels of growth hormone, sex hormones, and thyroid hormone promote the development and progression of disease. The impact of steroid hormones, e.g. cortisol and dehydroepiandrosterone, and adipokines is much more divergent. Thoughtful assessment, based on individual risk factors and findings, and management of non-insulin endocrine axes is essential in the evaluation and management of MASLD. Multiple therapeutic options have emerged that leverage various endocrine axes to reduce the fibroinflammatory cascade in MASH., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The aim of this study was to evaluate insulin resistance and hepatic steatosis and their association with diabetes duration, control and chronic complications in patients with type 1 diabetes., Methods: We studied medical records of 181 consecutive hospitalized adult patients with type 1 diabetes. Estimated glucose disposal rate (eGDR), Insulin Sensitivity Score (ISS), Fatty Liver Index (FLI) and Hepatic Steatosis Index (HSI) were calculated., Results: Patients in the 1 st tertile of eGDR (<4.1 mg/kg -1 -min -1 ) and ISS (<4.8) had higher prevalence of ischemic cardiovascular disease (ICVD) (P<0.001), hepatic steatosis, higher gamma glutamyl transpeptidase, HSI, FLI compared with participants from the 2 nd and 3 rd tertile of eGDR and ISS. Compared with those without steatosis, patients with ultrasound-diagnosed steatosis (30.5%) had a lower ISS (4.4±1.9 vs. 6.3±2.4, P<0.001), eGDR (4.5±3.0 vs. 5.8±2.7, P=0.01), higher FLI (72.5±25.1 vs. 51.0±27.2, P<0.001), HSI (37.5±6.1 vs. 35.2±4.7, P=0.03) and prevalence of ICVD (71.7 vs. 45.7%, P=0.004) and retinopathy (69.6 vs. 52.4%, P=0.03). Factors independently associated with hepatic steatosis were only ICVD (OR=2.584, P=0.029), ISS (OR 0.148, P<0.001), aspartate aminotransferase (OR=1.025, P=0.038) and male gender (OR=2.726, P=0.016)., Conclusions: Insulin resistance and hepatic steatosis are common in type 1 diabetes and have a significant association with ICVD, independently of diabetes duration, control and insulin doses.

Dysregulation of glucose metabolism in response to diet-induced obesity contributes toward numerous complications, such as insulin resistance and hepatic steatosis. Therefore, there is a need to develop effective strategies to improve glucose homeostasis. In this review, we first discuss emerging evidence from epidemiological studies and rodent experiments that increased consumption of EPA (either as oily fish, or dietary/pharmacological supplements) may have a role in preventing impairments in insulin and glucose homeostasis. We then review the current evidence on how EPA-derived metabolites known as hydroxyeicosapentaenoic acids (HEPEs) may be a major mode of action by which EPA exerts its beneficial effects on glucose and lipid metabolism. Notably, cell culture and rodent studies show that HEPEs prevent fat accumulation in metabolic tissues through peroxisome proliferator activated receptor (PPAR)-mediated mechanisms. In addition, activation of the resolvin E1 pathway, either by administration of EPA in the diet or via intraperitoneal administration of resolvin E1, improves hyperglycemia, hyperinsulinemia, and liver steatosis through multiple mechanisms. These mechanisms include shifting immune cell phenotypes toward resolution of inflammation and preventing dysbiosis of the gut microbiome. Finally, we present the next steps for this line of research that will drive future precision randomized clinical trials with EPA and its downstream metabolites. These include dissecting the variables that drive heterogeneity in the response to EPA, such as the baseline microbiome profile and fatty acid status, circadian rhythm, genetic variation, sex, and age. In addition, there is a critical need to further investigate mechanisms of action for HEPEs and to establish the concentration of HEPEs in differing tissues, particularly in response to consumption of oily fish and EPA-enriched supplements., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Obesity is an expanding global public health problem and a leading cause of metabolic disorders. The hepatokine Fetuin B participates in regulating insulin resistance, glucose metabolism and liver steatosis. However, the mechanism underlying Fetuin B activation remains unclear. Our previous population-based study demonstrated a significant association between serum Fetuin B and body fat mass in an obese population, which indicates its potential in mediating obesity-related metabolic disorders. In the present study, we further revealed a significant correlation between Fetuin B and leptin, the classic adipokine released by expanding adipose tissue, in this obese population. Consistently, elevated Fetuin B and leptin levels were confirmed in diet-induced obese mice. Furthermore, an in vitro study demonstrated that the leptin signalling pathway directly activated the transcription and expression of Fetuin B in primary hepatocytes and AML12 cells in a STAT3-dependent manner. STAT3 binds to the response elements on FetuB promoter to directly activate FetuB transcription. Finally, the mediating effect of Fetuin B in insulin resistance induced by leptin was confirmed according to mediation analysis in this obese population. Therefore, our study identifies leptin-STAT3 as an upstream signalling pathway that activates Fetuin B and provides new insights into the pathogenic mechanisms of obesity-related metabolic disorders., (© 2022. The Author(s).)

Context: There is little information about fatty liver in prediabetes as it transitions to early diabetes., Objective: This study is aimed at evaluating the prevalence and determinants of fatty liver in the Diabetes Prevention Program (DPP)., Methods: We measured liver fat as liver attenuation (LA) in Hounsfield units (HU) in 1876 participants at ~14 years following randomization into the DPP, which tested the effects of lifestyle or metformin interventions versus standard care to prevent diabetes. LA was compared among intervention groups and in those with versus without diabetes, and associations with baseline and follow-up measurements of anthropometric and metabolic covariates were assessed., Results: There were no differences in liver fat between treatment groups at 14 years of follow-up. Participants with diabetes had lower LA (mean ± SD: 46 ± 16 vs 51 ± 14 HU; P < 0.001) and a greater prevalence of fatty liver (LA < 40 HU) (34% vs 17%; P < 0.001). Severity of metabolic abnormalities at the time of LA evaluation was associated with lower LA categories in a graded manner and more strongly in those with diabetes. Averaged annual fasting insulin (an index of insulin resistance [OR, 95% CI 1.76, 1.41-2.20]) waist circumference (1.63, 1.17-2.26), and triglyceride (1.42, 1.13-1.78), but not glucose, were independently associated with LA < 40 HU prevalence., Conclusion: Fatty liver is common in the early phases of diabetes development. The association of LA with insulin resistance, waist circumference, and triglyceride levels emphasizes the importance of these markers for hepatic steatosis in this population and that assessment of hepatic fat in early diabetes development is warranted., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: The etiological mechanism of bile acid (BA) effects on insulin resistance and obesity is unknown., Objective: This work aimed to determine whether plasma BAs are elevated in human obesity and/or insulin resistance., Methods: This observational study was conducted at an academic research center. Seventy-one adult volunteers formed 4 groups: lean insulin-sensitive (body mass index [BMI] ≤ 25 kg/m2, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR] < 2.0, n = 19), overweight/obese nondiabetic who were either insulin sensitive (Obsensitive, BMI > 25 kg/m2, HOMA-IR < 1.5, n = 11) or insulin resistant (Obresistant, BMI > 25 kg/m2, HOMA-IR > 3.0, n = 20), and type 2 diabetes (T2D, n = 21). Main outcome measures included insulin sensitivity by hyperinsulinemic-euglycemic clamp, body composition by dual energy x-ray absorptiometry, abdominal fat distribution, and liver density by computed tomography and plasma BA., Results: In the Obresistant group, glucose infusion rate/fat-free mass (GIR/FFM, an inverse measure of insulin resistance) was significantly lower, and visceral and liver fat higher, compared to lean and Obsensitive individuals, despite similar total adiposity in Obresistant and Obsensitive. Total BA concentrations were higher in Obresistant (2.62 ± 0.333 mmol/L, P = .03) and T2D (3.36 ± 0.582 mmol/L, P < .001) vs Obsensitive (1.16 ± 0.143 mmol/L), but were similar between Obsensitive and lean (2.31 ± 0.329 mmol/L) individuals. Total BAs were positively associated with waist circumference (R = 0.245, P = .041), visceral fat (R = 0.360, P = .002), and fibroblast growth factor 21 (R = 0.341, P = .004) and negatively associated with insulin sensitivity (R = -0.395, P = .001), abdominal subcutaneous fat (R = -0.352, P = .003), adiponectin (R = -0.375, P = .001), and liver fat (Hounsfield units, an inverse marker of liver fat, R = -0.245, P = .04). Conjugated BAs were additionally elevated in T2D individuals (P < .001)., Conclusions: BA concentrations correlated with abdominal, visceral, and liver fat in humans, though an etiological role in insulin resistance remains to be verified., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.

Obesity and cholesterol gallstone disease (GSD) are frequently coexisting diseases; therefore and considering the current worldwide obesity epidemics, a precise understanding of the pathophysiological relationships between GSD and insulin resistance (IR) is important. Classically, obesity has been understood as a risk factor for GSD and the gallbladder (GB) viewed as a simple bile reservoir, with no metabolic roles whatsoever. However, consistent evidence has showed that both GSD and cholecystectomy associates with fatty liver and IR, raising the possibility that the GB is indeed an organ with metabolic regulatory roles. Herein, we review the pathophysiological mechanisms by which GSD, IR, and obesity are interconnected, with emphasis in the actions of the GB as a regulator of bile acids kinetics and a hormone secreting organ, with metabolic actions at the systemic level. We also examine the relationships between increased hepatic lipogenic in IR states and GSD pathogenesis. We propose a model in which GSD and hepatic IR mutually interact to determine a state of dysregulated lipid and energy metabolism that potentiate the metabolic dysregulation of obesity., (© 2019 World Obesity Federation.)

This study focuses on the effect of honokiol (HON) on glucose homeostasis, insulin resistance, dyslipidemia, hepatic steatosis, and inflammation in type 2 diabetic db / db mice. Male C57BL/KsJ- db / db mice were fed a normal diet with or without HON (0.02%, w / w ) or pioglitazone (PIO, anti-diabetic agent, 0.01%, w / w ) for 5 weeks. Blood biomarker, tissue morphology and enzymatic and genetic parameters were determined. PIO significantly decreased food intake, fasting blood glucose, and glycosylated hemoglobin (HbA1c) levels, but markedly increased body weight, adipose tissue weight, and plasma leptin levels. HON did not significantly affect food intake, body weight, or levels of plasma leptin and blood glucose. However, HON led to significant decreases in adipose tissue weight, plasma insulin, blood HbA1c and HOMA-IR levels and improved glucose tolerance. The anti-diabetic and anti-adiposity effects of HON were partially related to the inhibition of gluconeogenic enzymes and their mRNA expression in the liver; and the inhibition of lipogenic enzymes in adipose tissue, respectively. Unlike PIO, HON did not affect dyslipidemia, but ameliorated hepatic steatosis by inhibiting hepatic lipogenic enzymes activity. Moreover, HON exhibited anti-inflammatory effects similar to PIO. These results suggest that HON can protect against type 2 diabetes by improving insulin resistance, glucose and lipid metabolism, and inflammation.

Hepatic insulin resistance in the setting of steatosis is attributable at least in part to the accumulation of bioactive lipids that suppress insulin signaling. The mitochondria-associated glycerol-3-phosphate acyltransferase 1 (GPAT1) catalyzes the first committed step in glycerolipid synthesis, and its activity diverts fatty acids from mitochondrial β-oxidation. GPAT1 overexpression in mouse liver leads to hepatic steatosis even in the absence of overnutrition. The mice develop insulin resistance owing to the generation of saturated diacylglycerol and phosphatidic acid molecular species that reduce insulin signaling by activating PKCϵ and by suppressing mTORC2, respectively. Them2, a mitochondria-associated acyl-CoA thioesterase, also participates in the trafficking of fatty acids into oxidative versus glycerolipid biosynthetic pathways. Them2 mice are protected against diet-induced hepatic steatosis and insulin resistance. To determine whether Them2 contributes to hepatic insulin resistance due to hepatic overexpression of GPAT1, recombinant adenovirus was used to overexpress GPAT1 in livers of chow-fed -/- mice are protected against diet-induced hepatic steatosis and insulin resistance. To determine whether Them2 contributes to hepatic insulin resistance due to hepatic overexpression of GPAT1, recombinant adenovirus was used to overexpress GPAT1 in livers of chow-fed Them2 +/+ and Them2 -/- mice. Hepatic GPAT1 overexpression led to steatosis in both genotypes. In the setting of GPAT1 overexpression, glucose tolerance was reduced in Them2 hepatocytes. These findings suggest a pathogenic role of Them2 in the biosynthesis of glycerolipid metabolites that promote hepatic insulin resistance.+/+ but not Them2 -/- mice, without influencing whole-body insulin sensitivity or basal hepatic glucose production. Improved glucose tolerance in Them2 -/- mice was associated with reduced PKCϵ translocation. Preserved insulin receptor activity was supported by Thr-308 phosphorylation of Akt following GPAT1 overexpression in Them2 -/- hepatocytes. These findings suggest a pathogenic role of Them2 in the biosynthesis of glycerolipid metabolites that promote hepatic insulin resistance., (© 2019 Tillander et al.)

Background/objectives: Gamma-glutamyltranspeptidase (GGT) levels are an independent risk marker for the development of type 2 diabetes (T2DM). We investigated the relationship between the newly identified serum GGT fractions and glucose metabolism in obese subjects before and after bariatric surgery., Subjects/methods: Twenty-nine T2DM subjects, wait-listed for Roux-en-Y gastric bypass (RYGB; n = 21) or laparoscopic sleeve gastrectomy (LSG; n = 8), received a 5-h mixed meal test before (T0), 15 days (T15), and 1 year after surgery (T365). Insulin sensitivity was assessed by the OGIS index and β-cell function by C-peptide analysis; fractional GGT (b-, s-, m-, and f-GGT) analysis was performed by gel-filtration chromatography., Results: At T15, total GGT activity decreased by 40% after LSG (p = 0.007) but remained unchanged after RYGB. At T365, all patients showed a reduction in total GGT, in particular b-GGT (≥ 60%) and m-GGT (≥ 50%). In patients with biopsy-proven steatohepatitis (n = 10), total, b-, s-, and m-GGT fractions at T0 were significantly higher than in patients with low-grade steatosis (p = 0.016, 0.0003, and 0.005, respectively); at T365, there was a significant fall in total GGT as well as in each fraction in both groups. In a multiple regression model, b-GGT was the only fraction related to insulin sensitivity (p = 0.016; β coeff. = - 14.0) independently of BMI, fasting glucose, and triglycerides., Conclusions: While GGT activity is generally associated with impaired glucose metabolism, fractional GGT analysis showed that the b-GGT fraction specifically and independently tracks with insulin resistance.

Aim: Hepatic insulin clearance (HIC) is important in regulating plasma insulin levels. Diminished HIC causes inappropriate hyperinsulinaemia, and both obesity and fatty liver (FL), which are known to decrease HIC, can be found either together in the same patient or on their own. The mechanism by which obesity reduces HIC is presumed to be mediated by FL. However, few reports have examined the role of FL in the relationship between obesity and HIC in type 2 diabetes (T2D) patients. Therefore, our study investigated the association of HIC with clinical factors, including insulin sensitivity indices, focusing on the presence or absence of FL and obesity in T2D patients., Method: Baseline data from 419 patients with T2D (279 men, 140 women; mean age: 57.6 years; body mass index: 25.5kg/m 2 ) controlled by diet and exercise were analyzed. HIC was calculated from the ratio of fasting c-peptide to fasting insulin levels (HIC CIR ). Correlation analyses between HIC CIR and clinical variables were performed using Pearson's product-moment correlation coefficients and single regression analysis in all participants and in those with obesity and FL either alone or in combination., Results: HIC CIR was significantly correlated with whole-body insulin sensitivity indices and influenced by FL, but only in the FL group was obesity independently influenced HIC level. HIC CIR decreased in those with both FL and obesity compared with those with only one such complication., Conclusion: HIC CIR may be used to evaluate whole-body insulin sensitivity in T2D. Also, compared with obesity, the influence of FL strongly contributed to a reduced HIC., Trial Registration Number: These trials were registered by the Japan Pharmaceutical Information Centre clinical trials information (JapicCTI) as 101349 and 101351., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The prevalence of Non-alcoholic fatty liver diseases (NAFLD) increased rapidly in the world. However, the pathogenesis of is still unclear. Hepatic steatosis and insulin resistance are considered to be central to the pathophysiology of NAFLD. MicroRNAs are short non-coding RNAs and has been reported to be involved in pathogenesis of NAFLD and related metabolic diseases. Here, we investigated the mechanisms by which miR-150 regulate hepatic steatosis and insulin resistance in high fat diet (HFD) induced NAFLD model. The expression of miR-150 was up-regulated dramatically in both human NAFLD patients and HFD mice model, as well as in hepatocytes treated with oleic acid. miR-150 deficiency ameliorated the hepatic steatosis and insulin resistance significantly in NAFLD mice. miR-150 deficiency decreased the expression of genes related to fatty acid uptake, synthesis and gluconeogenesis, while increased the expression of genes related to fatty acid β-oxidation. Further, we identified that CFLAR is a direct downstream target of miR-150. Overexpression of miR-150 reduced both the mRNA and protein levels of CFLAR in vitro. And overexpression of miR-150 significantly inhibited the luciferase activity of CFLAR 3'-UTR, while the effect of miR-150 was blocked when the binding site of miR-150 within the CFLAR 3'-UTR was mutated. We also found that miR-150 deficiency decreased the expression of p-Jnk1 and p-Ask1, while the effect of miR-150 on steatosis and insulin signaling was blocked by CFLAR overexpression. In conclusion, our data indicated that miR-150 potentially contributes to the hepatic steatosis and insulin resistance in NAFLD. miR-150/CFLAR pathway may be a new therapeutic strategy against NAFLD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background & Objectives: One of the multiple factors contributing to virological response in chronic hepatitis C (CHC) is interferon-gamma-inducible protein-10 (IP-10). Its level reflects the status of interferon-stimulated genes, which in turn is associated with virological response to antiviral therapy. The aim of this study was to evaluate the role of serum IP-10 levels on sustained virological response (SVR) and the association of this parameter with insulin resistance (IR) and liver histology., Methods: Two hundred and three consecutive biopsy proven CHC patients were included in the study. Serum levels of IP-10 were determined using ELISA method. IR was evaluated by homeostasis model assessment-IR (HOMA-IR). Histological features were assessed invasively by liver biopsy and noninvasively using FibroTest, ActiTest and SteatoTest. Predictive factors for SVR and their interrelations were assessed., Results: A cut-off value for IP-10 of 392 pg/ml was obtained to discriminate between responders and non-responders. SVR was obtained in 107 patients (52.70%). Area under the receiver operating characteristic curve for SVR was 0.875 with a sensitivity of 91.6 per cent, specificity 74.7 per cent, positive predictive value 80.3 per cent and negative predictive value 88.7 per cent. Higher values of IP-10 were associated with increasing stages of fibrosis (P<0.01) and higher grades of inflammation (P=0.02, P=0.07) assessed morphologically and noninvasively through FibroTest and ActiTest. Significant steatosis and IR were also associated with increased levels of IP-10 (P=0.01 and P=0.02). In multivariate analysis, IP-10 levels and fibrosis stages were independently associated with SVR., Interpretation & Conclusions: Our findings showed that the assessment of serum IP-10 level could be a predictive factor for SVR and it was associated with fibrosis, necroinflammatory activity, significant steatosis and IR in patients with chronic HCV infection.

Lipodystrophies are heterogeneous disorders characterized by varying degrees of body fat loss and predisposition to insulin resistance and its metabolic complications. They are subclassified depending on degree of fat loss and whether the disorder is genetic or acquired. The two most common genetic varieties include congenital generalized lipodystrophy and familial partial lipodystrophy; the two most common acquired varieties include acquired generalized lipodystrophy and acquired partial lipodystrophy. Highly active antiretroviral therapy-induced lipodystrophy in patients infected with human immunodeficiency virus and drug-induced localized lipodystrophy are common subtypes. The metabolic abnormalities associated with lipodystrophy include insulin resistance, hypertriglyceridemia, and hepatic steatosis. Management focuses on preventing and treating metabolic complications., (Published by Elsevier Inc.)

We investigated the effects of metformin and celecoxib on obesity-induced adipose tissue inflammation, insulin resistance (IR), fatty liver, and high blood pressure in high-fat (HF) fed rats. Male Sprague-Dawley rats were fed with either regular or HF diet for 8 weeks. Rats fed with regular diet were treated with vehicle for further 4 weeks. HF fed rats were divided into 6 groups, namely, vehicle, celecoxib (30mg/kg/day), metformin (300mg/kg/day), metformin (150mg/kg/day), metformin (300mg/kg/day) with celecoxib (30mg/kg/day), and metformin (150mg/kg/day) with celecoxib (15mg/kg/day) for additional 4 weeks. Increased body weight in HF fed rats was significantly reduced by metformin alone and metformin combined with celecoxib. The increases in the HOMA-IR value and the area under the curve of glucose following an oral glucose tolerance test, systolic blood pressure, and adipocyte size were significantly diminished in treated rats, especially rats undergoing combined treatment. Treatments with either celecoxib or in combination with metformin resulted in a reduction in AT macrophage infiltration and decreases in levels of adipose tissue TNF-α, MCP-1, and leptin levels in high-fat (HF) fed rats. Furthermore, the elevated hepatic triglycerides content was significantly decreased in the combined treatment group compared to that of groups of celecoxib or metformin alone. Celecoxib exerts a synergistic beneficial effect with metformin on and obesity-associated metabolic and cardiovascular disorders in high-fat fed rats., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: The aim of the present study was to examine the association between plasminogen activator inhibitor-1 (PAI-1), an acute phase protein strongly associated with cardiovascular disease risk, and adiposity, insulin resistance, and inflammation among overweight and obese children with a wide range of hepatic steatosis., Methods: Plasma PAI-1 levels were measured in a prospectively recruited cohort of 39 overweight or obese children who underwent comprehensive anthropometric assessment and metabolic measurements. Hepatic steatosis was quantified using magnetic resonance spectroscopy and participants were divided into 3 groups based on whether they had normal hepatic steatosis (<5%), low hepatic steatosis (≥5%-10%), and high hepatic steatosis (>10%)., Results: Plasma PAI-1 levels significantly increased across the severity of hepatic steatosis in overweight and obese children, and this association was independent of body mass index z score, visceral fat, insulin resistance, and inflammatory markers (P < 0.05)., Conclusion: Hepatic steatosis in children is positively associated with circulating levels of PAI-1 independent of body mass index, insulin resistance, and inflammatory markers. Further studies are needed to clarify the potential role of PAI-1 as a therapeutic target in pediatric nonalcoholic fatty liver disease., Competing Interests: CONFLICT OF INTEREST/FINANCIAL DISCLOSURE STATEMENT All authors have no personal or financial conflicts of interest to declare.

Background: Insulin resistance promotes liver disease progression and may be associated with a lower response rate in treated hepatitis C virus (HCV) infected patients. n-3 polyunsaturated fatty acid (PUFA) supplementation may reduce insulin resistance. The present study aimed to evaluate the effect of n-3 PUFA supplementation on insulin resistance in these patients., Methods: In a randomised, double-blind clinical trial, 154 patients were screened. After applying inclusion criteria, 52 patients [homeostasis model assessment index of insulin resistance (HOMA-IR ≥2.5)] were randomly divided into two groups: n-3 PUFA (n = 25/6000 mg day(-1) of fish oil) or control (n = 27/6000 mg day(-1) of soybean oil). Both groups were supplemented for 12 weeks and underwent monthly nutritional consultation. Biochemical tests were performed at baseline and after intervention. Statistical analysis was performed using the Wilcoxon Mann-Whitney test for comparisons and the Wilcoxon test for paired data. Statistical package r, version 3.02 (The R Project for Statistical Computing) was used and P < 0.05 (two-tailed) was considered statistically significant., Results: Comparisons between groups showed that n-3 PUFA supplementation was more effective than the control for reducing HOMA-IR (P = 0.015) and serum insulin (P = 0.016). The n-3 PUFA group not only showed a significant reduction in HOMA-IR 3.8 (3.2-5.0) versus 2.4 (1.8-3.3) (P = 0.002); serum insulin 17.1 (13.8-20.6) μIU mL(-1) versus 10.9 (8.6-14.6) μIU mL(-1) (P = 0.001); and glycated haemoglobin 5.4% (5.0-5.7%) versus 5.1% (4.8-5.6%) (P = 0.011), but also presented an increase in interleukin-1 97.5 (0.0-199.8) pg mL(-1) versus 192.4 (102.2-266.8) pg mL(-1) (P = 0.003) and tumour necrosis factor 121.2 (0.0-171.3) pg mL(-1) versus 185.7 (98.0-246.9) pg mL(-1) (P = 0.003)., Conclusions: n-3 PUFA supplementation reduces insulin resistance in genotype 1 HCV infected patients., (© 2015 The British Dietetic Association Ltd.)

Context: Patients with nonalcoholic fatty liver disease (NAFLD) are at increased risk of cardiovascular disease, and atherogenic lipoproteins may play an important role., Objective: The objective of the study was to determine the contribution of the severity of steatohepatitis to atherogenic dyslipidemia in patients with NAFLD., Design: This was a cross-sectional study., Setting: The study was conducted at a university hospital., Patients: Patients were recruited from outpatient clinics or from the general population (n = 188)., Interventions: Measurement of hepatic triglyceride content by magnetic resonance spectroscopy, histology (liver biopsy), metabolic profile by means of an oral glucose tolerance test, and lipoprotein analyses were performed., Outcomes: Outcomes measured included standard lipids, lipoprotein subfraction analysis (apolipoprotein B/A1 levels, low-density lipoprotein (LDL) particle size/phenotype, and LDL/high-density lipoprotein subfractions), and insulin resistance., Results: Patients with NAFLD had severe insulin resistance, especially at the level of the adipose tissue, when compared with patients without NAFLD. Despite small differences in triglycerides and high-density lipoprotein-cholesterol, patients with NAFLD had a significantly higher plasma apolipoprotein B to apolipoprotein A1 ratio (0.66 ± 0.02 vs 0.58 ± 0.02, P = .01) and smaller LDL particle size (216.2 ± 0.7 vs 219.4 ± 1.1 Å, P = .01). Of note, these differences between patients with/without NAFLD were independent of the presence of obesity. Severity of steatohepatitis did not significantly influence the lipoprotein profile. Worse atherogenic dyslipidemia was best predicted by the degree of liver fat accumulation and adipose tissue and systemic insulin resistance., Conclusions: NAFLD was associated with a worse atherogenic lipoprotein profile, regardless of similar body mass index and other clinical parameters. We speculate that this lipoprotein profile is driven mostly by liver fat content and insulin resistance and appears not to be worsened by obesity or the severity of liver disease (nonalcoholic steatohepatitis).

Objective: High-protein diets are being promoted to reduce insulin resistance and hepatic steatosis in metabolic syndrome. Therefore, the effect of protein source in high-protein diets on reducing insulin resistance and hepatic steatosis was examined., Methods: Fa/fa Zucker rats were provided normal-protein (15% of energy) casein, high-protein (35% of energy) casein, high-protein soy, or high-protein mixed diets with animal and plant proteins., Results: The high-protein mixed diet reduced area under the curve for insulin during glucose tolerance testing, fasting serum insulin and free fatty acid concentrations, homeostatic model assessment index, insulin to glucose ratio, and pancreatic islet cell area. The high-protein mixed and the high-protein soy diets reduced hepatic lipid concentrations, liver to body weight ratio, and hepatic steatosis rating. These improvements were observed despite no differences in body weight, feed intake, or adiposity among high-protein diet groups. The high-protein casein diet had minimal benefits., Conclusions: A high-protein mixed diet was the most effective for modulating reductions in insulin resistance and hepatic steatosis independent of weight loss, indicating that the source of protein within a high-protein diet is critical for the management of these metabolic syndrome parameters., (© 2015 The Obesity Society.)

Mitogen inducible gene-6 (Mig-6) is a feedback inhibitor of epidermal growth factor receptor (EGFR) signaling pathway. The liver-specific knockout mice of the Mig-6 gene (Mig-6 d/d ) showed hepatomegaly and increased hypercholesterolemia. In this study, the biomarkers of insulin resistance and the effects of high-fat diets in the wild (Mig-6 f/f ) and Mig-6 d/d mice were analyzed. The fasting plasma concentrations of glucose, triglyceride, cholesterols, free fatty acids, and HOMA-IR were measured and the glucose tolerance and insulin resistance tests were performed in the 25-week-old Mig-6 f/f and the Mig-6 d/d mice. The protein levels of active insulin receptor, glucose 6-phosphatase, and phosphoenolpyruvate carboxykinase were analyzed in the liver and fat. The fasting plasma cholesterol and glucose concentration were higher in the Mig-6 d/d mice than the Mig-6 f/f mice with increased fat deposition in the liver. But the Mig-6 d/d mice had the improved glucose intolerance and insulin resistance without increased amount of phosphoinsulin receptor after insulin infusion in the liver. The hepatic concentration of phosphoenolpyruvate carboxykinase was increased in fasting Mig-6 d/d mice. The feeding of high-fat diet accelerated the plasma lipids profiles and HOMA-IR in the Mig-6 d/d mice but had no differential effects in oral glucose tolerance test and insulin tolerance test in both genotypes. These results suggest that the activated EGFR signaling might increase the fasting plasma glucose concentration through inducing the hepatic steatosis and the improved whole-body insulin resistance in the KO mice be caused by decreased adipogenesis in fat tissues., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this article.

Background: The effect of hepatitis B virus (HBV) infection on fatty liver disease is unclear., Objectives: The aim of this study was to investigate the viral and host causes of fatty liver in chronic hepatitis B (CHB) patients. This study included 88 CHB patients of which 17 were not treated. Liver biopsy was performed in each patient. Group 1 included those with hepatic steatosis (n=28) and group 2 those without hepatic steatosis. The groups were compared in terms of age, body mass index (BMI), Homeostasis Model Assessment- Insulin Resistance (HOMA-IR), viral load, biochemical parameters and histological findings. Patients in group 1 were subdivided according to the degree of steatosis as follows: grade 1 (15 patients, 53.6%), grade 2 (6 patients, 21.4%), and grade 3 (7 patients, 25%)., Results: In group 1 (n=28), mean age, BMI, cholesterol, and HOMA-IR were found to be significantly higher than in group 2 (n=60). There were no significant differences in the positivity of viral load, HbeAg, treatment, fibrosis and other laboratory parameters between the two groups. HOMA-IR was the only independent predictive factor of liver steatosis in patients with CHB in logistic regression analysis., Conclusion: Hepatic steatosis in CHB patients was associated with host metabolic factors.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in parallel with the prevalence of obesity. DNA damage-inducible protein 34 (GADD34/Ppp1r15a), originally isolated from UV-inducible transcripts in Chinese hamster ovary (CHO) cells, dephosphorylates several kinases that function in important signaling cascades, including dephosphorylation of eIF2α. We examined the effects of GADD34 on natural life span by using GADD34-deficient mice. Here we observed for the first time that with age GADD34-deficient mice become obese, developing fatty liver followed by liver cirrhosis, hepatocellular carcinoma, and insulin resistance. We found that myofibroblasts and immune cells infiltrated the portal veins of aged GADD34-deficient mouse livers. A high-fat diet (HFD) induced a higher level of steatosis in young GADD34-deficient mice compared with WT mice. Differentiation into fat is dependent on insulin signaling. Insulin signaling in young GADD34-deficient mice was higher than that in WT mice, which explained the higher fat differentiation of mouse embryonic fibroblasts (MEFs) observed in GADD34-deficient mice. Through aging or a HFD, insulin signaling in GADD34-deficient liver converted to be down regulated compared with WT mice. We found that a HFD or palmitate treatment converted insulin signaling by up-regulating TNF-α and JNK.

Background: Overweight subjects easily develop alterations of the glucose and lipid metabolism and are exposed to an increased cardiometabolic risk. This condition is potentially reversible through the improvement of dietary and behavioural habits. However, a well-assembled nutraceutical would be a useful tool to better improve the metabolic parameters associated to overweight and insulin resistance., Methods: To evaluate the effect of a combined nutraceutical containing berberine, chlorogenic acid and tocotrienols, we performed a double blind, cross-over designed trial versus placebo, in 40 overweight subjects with mixed hyperlipidaemia. After the first 8 weeks of treatment (or placebo), patients were asked to observe a 2-week washout period, and they were then assigned to the alternative treatment for a further period of 8 weeks. Clinical and laboratory data associated to hyperlipidaemia and insulin resistance have been obtained at the baseline, at the end of the first treatment period, after the washout, and again after the second treatment period., Results: Both groups experienced a significant improvement of anthropometric and biochemical parameters versus baseline. However, total cholesterol, LDL cholesterol, triglycerides, non-HDL cholesterol, fasting insulin, HOMA-IR, GOT and Lipid Accumulation Product decreased more significantly in the nutraceutical group versus placebo., Conclusions: This combination seems to improve a large number of metabolic and liver parameters on the short-term in overweight subjects. Further studies are needed to confirm these observations on the middle- and long-term.

Rats fed with high-fat-high-sucrose (HFHS) diet are known to manifest metabolic syndrome including hyperinsulinemia, hyperleptinemia, hyperglycemia, diabetic dyslipidemia, and hepatic steatosis. The aim of the current study is to determine the temporal relationships between the development of hepatic steatosis and the onset of insulin and leptin resistance in hypothalamus and liver in male Wistar rats (six weeks of age) fed chow or HFHS diet for up to 8 weeks. Fasting plasma glucose, lipids/lipoproteins, insulin and leptin levels were quantified, histopathologic score of hepatic steatosis and inflammation were assessed, and the responses of common checkpoints of insulin and leptin signalling responsible for lipogenesis and gluconeogenesis were analyzed. In addition, acute insulin or leptin administration was performed at different stages of HFHS dieting to determine the responsiveness of the respective signalling pathways. Hyperinsulinemia, hyperglycemia, dyslipidemia, and increased homeostasis model assessment of basal insulin resistance occurred 1-week after HFHS dieting, coinciding with upregulation of suppressor of cytokine signalling 3 in both hypothalamus and liver. However, hepatosteatosis, accompanied with increased expression of sterol regulatory element binding protein 1c and phosphoenolpyruvate carboxykinase, did not manifest until 4- to 8-week after HFHS dieting. Lowered insulin sensitivity (shown by decreased insulin receptor substrate 1 and protein kinase B phosphorylation) occurred approximately 2 weeks prior to leptin resistance (shown by impaired signal transducer and activator of transcription 3 activation) in both the liver and hypothalamus. Acute insulin/leptin administration also demonstrated the impaired insulin or leptin signalling transduction. These data suggest that lowered insulin sensitivity and leptin resistance occurred at least 2-3 weeks earlier than the manifestation of hepatosteatosis in rats fed HFHS diet.

Background: Hepatosteatosis can develop due to insulin resistance. The effect of thyroid function status on insulin sensitivity and resistance is of great interest but the data is still conflicting., Objectives: The aim of this study was to evaluate the effects of thyroid dysfunctions on insulin resistance in patients with hepatosteatosis., Material and Methods: A total of 407 patients with hepatosteatosis were divided into three groups: 102 subjects with hypothyroidism, 103 with hyperthyroidism and 202 with normal thyroid function (control group). We measured serum thyroid stimulating hormone (TSH), free T4 (FT4) and free T3 (FT3) concentrations, blood glucose and insulin levels, serum lipid levels, hepatic transaminases and the homeostasis model assessment of insulin resistance (HOMA IR)., Results: Neither hypothyroidism patients nor hyperthyroidism patients showed significant differences in HOMA IR, glucose and insulin levels (p>0.05 for each). The frequency of insulin resistance was similar in all groups (p>0.05)., Conclusions: Based on our findings, hypothyroidism and hyperthyroidism are not correlated to insulin resistance in patients with hepatosteatosis. Different causes which are associated with insulin resistance should be investigated in patients with thyroid dysfunction and hepatosteatosis.

Chronic low-grade inflammation is an important contributor to the development of insulin resistance, a hallmark of type 2 diabetes mellitus (T2DM). Obesity and high-fat feeding lead to infiltration of immune cells into metabolic tissues, promoting inflammation and insulin resistance. We hypothesized that macrophages from mice lacking NOX2 (Cybb), an essential component of the NADPH oxidase complex highly expressed in immune cells and associated with their inflammatory response, would be less inflammatory and that these mice would be protected from the development of high-fat-induced insulin resistance. Bone marrow-derived macrophages from NOX2 knockout (NOX2-KO) mice expressed lower levels of inflammatory markers (Nos2, Il6); however, NOX2-KO mice were hyperphagic and gained more weight than wild-type (WT) mice when fed either a chow or a high-fat (HF) diet. Surprisingly, NOX2-KO mice stored less lipid in epididymal white adipose tissue but more lipid in liver and had higher indexes of liver inflammation and macrophage infiltration than WT mice. Contrary to our hypothesis, HF-fed NOX2-KO mice were hyperinsulinemic and more insulin resistant than HF-fed WT mice, likely as a result of their higher hepatic steatosis and inflammation. In summary, NOX2 depletion promoted hyperphagia, hepatic steatosis, and inflammation with either normal or high-fat feeding, exacerbating insulin resistance. We propose that NOX2 participates in food intake control and lipid distribution in mice., (Copyright © 2014 the American Physiological Society.)

Ectopic fat accumulation in the liver causes nonalcoholic fatty liver disease (NAFLD), which is the most common cause of chronic liver disease in Western countries. Ectopic liver lipid, particularly diacylglycerol, exacerbates hepatic insulin resistance, promotes systemic inflammation, and increases risk of developing both type 2 diabetes mellitus and cardiovascular disease. Increasing evidence suggests that NAFLD is an emerging risk factor for cardiovascular disease, and although there are currently no licensed treatments for NAFLD per se, current evidence suggests that statin treatment is safe in NAFLD. Presently, there is insufficient evidence to indicate that statins or other cardioprotective agents, such as angiotensin receptor blockers, are effective in treating NAFLD. In this brief narrative review, we discuss the diagnosis of NAFLD and the role of ectopic liver fat to cause insulin resistance and to increase risk of both type 2 diabetes mellitus and cardiovascular disease. For this review, PubMed was searched for articles using the key words non-alcoholic fatty liver disease or fatty liver combined with diabetes risk, cardiovascular risk, and cardiovascular mortality between 1990 and 2014. Articles published in languages other than English were excluded., (© 2014 American Heart Association, Inc.)

Context: The association between nonalcoholic fatty liver disease (NAFLD) and subclinical atherosclerosis in type 2 diabetes is controversial., Objective: The objective of the study was to investigate the participation of insulin resistance in the association of NAFLD and the carotid atherosclerotic burden in a large cohort of patients with type 2 diabetes., Design, Setting, and Patients: This was an observational study performed in 4437 consecutively enrolled patients with type 2 diabetes., Main Outcomes Measures: Hepatic steatosis and mean carotid intima-media thickness (C-IMT) were measured using ultrasonography. Insulin resistance was assessed using the short insulin tolerance test., Results: The prevalence of NAFLD was 72.7% in the whole study population. Among subjects with NAFLD, 23.2% were not insulin resistant. There were significant differences in C-IMT and the frequency of carotid atherosclerosis between groups classified by insulin resistance within the same NAFLD strata. C-IMT was highest in subjects with both NAFLD and insulin resistance [0.844 ± 0.004 (mean ± SE) mm vs 0.786 ± 0.008, 0.821 ± 0.007, and 0.807 ± 0.006 mm, P for trend <.001, respectively, in insulin sensitive subjects without NAFLD, insulin resistant subjects without NAFLD, and insulin sensitive subjects with NAFLD]. These differences remained after adjusting for potential confounders. However, C-IMT in subjects having only NAFLD or insulin resistance was not higher than that in those with neither NAFLD nor insulin resistance., Conclusions: NAFLD is very common in subjects with type 2 diabetes, but NAFLD not accompanied by insulin resistance is not associated with a carotid atherosclerotic burden. However, having both NAFLD and insulin resistance seemed to be an independent predictor of increased C-IMT.

Objectives: Nonalcoholic fatty liver disease is the most common chronic liver disease. Fatty pancreas has also been described but is difficult to assess. It is now possible to measure pancreatic and liver fat accurately with magnetic resonance imaging (MRI). We aimed to define the normal range of pancreatic fat and identify factors associated with fatty pancreas. In addition, the effect of fatty liver and fatty pancreas on insulin resistance (IR) and pancreatic β-cell function was studied., Methods: Fat-water MRI and proton-magnetic resonance spectroscopy were performed on 685 healthy volunteers from the general population to measure pancreatic and liver fat, respectively. On the basis of fasting plasma glucose and insulin levels, the IR and β-cell function were assessed using the homeostasis model assessment (HOMA)., Results: Among subjects without significant alcohol consumption or any component of metabolic syndrome, 90% had pancreatic fat between 1.8 and 10.4%. Using the upper limit of normal of 10.4%, 110 (16.1%; 95% confidence interval 13.3-18.8%) subjects had fatty pancreas. On multivariable analysis, high serum ferritin, central obesity, and hypertriglyceridemia were independent factors associated with fatty pancreas. Subjects with both fatty pancreas and fatty liver had higher HOMA-IR than did those with either condition alone. Fatty pancreas was not associated with HOMA-β after adjusting for liver fat and body mass index., Conclusions: In all, 16.1% of this community cohort of adult Hong Kong Chinese volunteers had a fatty pancreas by our definition. Central obesity, hypertriglyceridemia, and hyperferritinemia are associated with fatty pancreas. Individuals with fatty pancreas have increased IR.

Leptin is essential for energy homeostasis and regulation of food intake. Patients with congenital generalized lipodystrophy (CGL) due to mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and the CGL murine model (Agpat2(-/-) mice) both have severe insulin resistance, diabetes mellitus, hepatic steatosis, and low plasma leptin levels. In this study, we show that continuous leptin treatment of Agpat2(-/-) mice for 28 days reduced plasma insulin and glucose levels and normalized hepatic steatosis and hypertriglyceridemia. Leptin also partially, but significantly, reversed the low plasma thyroxine and high corticosterone levels found in Agpat2(-/-) mice. Levels of carbohydrate response element binding protein (ChREBP) were reduced, whereas lipogenic gene expression were increased in the livers of Agpat2(-/-) mice, suggesting that deregulated ChREBP contributed to the development of fatty livers in these mice and that this transcription factor is a target of leptin's beneficial metabolic action. Leptin administration did not change hepatic fatty acid oxidation enzymes mRNA levels in Agpat2(-/-) mice. The selective deletion of leptin receptors only in hepatocytes did not prevent the positive metabolic actions of leptin in Agpat2(-/-) mice, supporting the notion that the majority of metabolic actions of leptin are dependent on its action in nonhepatocyte cells and/or the central nervous system.

Background: Liver regulates lipid metabolism in health and disease states. Nevertheless, the entity of cardiovascular risk (CVR) resulting from dysregulation of lipid metabolism secondary to liver disease is poorly characterized., Aim and Methods: To review, based on a PubMed literature search, the features and the determinants of serum lipid phenotype and its correlation with hepatic steatosis, insulin resistance (IR) and CVR across the wide spectrum of the most common chronic liver diseases due to different etiologies., Results: Alcoholic liver disease (ALD) is associated with steatosis, IR and a typical lipid profile. The relationship between alcohol intake, incident type 2 diabetes (T2D) and CVR describes a J-shaped curve. Non-alcoholic fatty liver disease (NAFLD), and probably nonalcoholic steatohepatitis (NASH) in particular, is associated with IR, atherogenic dyslipidemia and increased CVR independent of traditional risk factors. Moreover, NASH-cirrhosis and T2D contribute to increasing CVR in liver transplant recipients. HBV infection is generally free from IR, steatosis and CVR. HCV-associated dysmetabolic syndrome, featuring steatosis, hypocholesterolemia and IR, appears to be associated with substantially increased CVR. Hyperlipidemia is an almost universal finding in primary biliary cirrhosis, a condition typically spared from steatosis and associated with neither subclinical atherosclerosis nor excess CVR. Finally, little is known on CVR in patients with hepatocellular carcinoma., Conclusions: CVR is increased in ALD, NAFLD and chronic HCV infection, all conditions featuring IR and steatosis. Therefore, irrespective of serum lipid phenotype, hepatic steatosis and IR may be major shared determinants in amplifying CVR in common liver disease due to varying etiology., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Diabetic ketosis had been identified as a characteristic of type 1 diabetes mellitus (T1DM), but now emerging evidence has identified that they were diagnosed as T2DM after long time follow up. This case control study was aimed at comparing the clinical characteristic, β-cell function, and insulin resistance of ketosis and nonketotic onset T2DM and providing evidence for treatment selection. 140 cases of newly diagnosed T2DM patients were divided into ketosis (62 cases) and nonketotic onset group (78 cases). After correction of hyperglycemia and ketosis with insulin therapy, plasma C-peptide concentrations were measured at 0, 0.5, 1, 2, and 3 hours after 75 g glucose oral administration. Area under the curve (AUC) of C-peptide was calculated. Homoeostasis model assessment was used to estimate basal β-cell function (HOMA-β) and insulin resistance (HOMA-IR). Our results showed that ketosis onset group had higher prevalence of nonalcoholic fatty liver disease (NAFLD) than nonketotic group (P = 0.04). Ketosis onset group had increased plasma C-peptide levels at 0 h, 0.5 h, and 3 h and higher AUC(0-0.5), AUC₀₋₁, AUC₀₋₃ (P < 0.05). Moreover, this group also had higher HOMA-β and HOMA-IR than nonketotic group (P < 0.05). From these data, we concluded that ketosis onset T2DM had better islet β-cell function and more serious insulin resistance than nonketotic onset T2DM.

This study is to evaluate the therapeutic effect of fibroblast growth factor 21 (FGF21) on NAFLD in MSG-IR mice and to provide mechanism insights into its therapeutic effect. The MSG-IR mice with insulin resistance were treated with high dose (0.1 micromol.kg-1d-1) and low dose (0.025 micromol.kg-1d-1) of FGF21 once a day for 5 weeks. Body weight was measured weekly. At the end of the experiment, serum lipids, insulin and aminotransferases were measured. Hepatic steatosis was observed. The expression of key genes regulating energy metabolism were detected by real-time PCR. The results showed that after 5 weeks treatment, both doses of FGF21 reduced body weight (P<0.01), corrected dyslipidemia (P<0.01), reversed steatosis and restored the liver morphology in the MSG model mice and significantly ameliorated insulin resistance. Additionally, real-time PCR showed that FGF21 significantly reduced transcription levels of fat synthetic genes, decreased fat synthesis and promoted lipolysis and energy metabolism by up-regulating key genes of lipolysis, thereby liver fat accumulation was reduced and liver function was restored to normal levels. In conclusion, FGF21 significantly reduces body weight of the MSG-IR mice, ameliorates insulin resistance, reverses hepatic steatosis. These findings provide a theoretical support for clinical application of FGF21 as a novel therapeutics for treatment of NAFLD.

Epidemiological and clinical data have clearly demonstrated that non-alcoholic steatohepatitis (NASH) predisposes risk to the development of hepatocellular carcinoma (HCC). NASH is the liver manifestation of metabolic syndrome, which constellates obesity, insulin resistance and dyslipidemia. Although the percentage of patients diagnosed annually with NASH-associated HCC is still relatively low, this number signifies a large population due to the rapidly increasing incidence of obesity and diabetes globally. Fundamental studies on lipid storage, regulation of adipose factors, inflammatory cytokine recruitments and oxidative stress have provided insights into NASH as well as metabolic syndrome. Recent evidence also indicates the significant role of genetic factors in contributing to the pathogenesis of NASH and induced hepatic malignancy. In this review, we attempt to collate current research on NASH biology that lead to our understandings on how metabolic disorders may intersect with cancer development. We also discuss study models that have supported discoveries of molecular and cellular defects, and offered a perspective on therapeutic developments. These studies have collectively increased our knowledge on the complex signaling pathways involved in NASH and cancer, and provided the foundation for improved clinical management of patients with metabolic diseases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Hepatic Notch signaling is inappropriately activated in obese/insulin-resistant mouse models. Genetic or pharmacologic inhibition of hepatic Notch signaling in obese mice simultaneously improves glucose tolerance and reduces hepatic triglyceride content. As such, we predicted that Notch signaling in human liver would be positively associated with insulin resistance and hepatic steatosis. Here, we systematically survey Notch signaling in liver biopsy specimens, and show active Notch signaling in lean and obese adults, with expression of multiple Notch receptors and ligands. In morbidly obese patients undergoing bariatric surgery, we show that Notch activation positively correlates with glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase (PCK1) expression, key regulators of hepatic glucose output. We used immunofluorescence to identify active Notch signaling in hepatocytes and show highest activity in hyperglycemia, which we confirmed is a direct effect of hyperglycemia and insulin resistance. In a validation cohort of leaner individuals undergoing percutaneous liver biopsy for suspected nonalcoholic fatty liver disease (NAFLD), Notch activity showed independent positive association with insulin resistance and hepatic steatosis. Notably, Notch activity showed stronger correlation with the NAFLD activity score and alanine aminotransferase levels than with steatosis alone, suggesting that Notch activity is associated with nonalcoholic steatohepatitis. In summary, this study establishes that Notch signaling is activated in and may represent a therapeutic target for patients with obesity-related liver disease.

Non-alcoholic fatty liver disease (NAFLD) is now recognised as the hepatic component of metabolic syndrome (MetS). NAFLD is an example of ectopic fat accumulation in a visceral organ that causes organ-specific disease, and affects risk of other related diseases such as type 2 diabetes and CVD. NAFLD is a spectrum of fat-associated liver conditions that can culminate in end stage liver disease, hepatocellular carcinoma and the need for liver transplantation. Simple steatosis, or fatty liver, occurs early in NAFLD and may progress to non-alcoholic steatohepatitis, fibrosis and cirrhosis with increased risk of hepatocellular carcinoma. Prevalence estimates for NAFLD range from 2 to 44% in the general population and it has been estimated that NAFLD exists in up to 70% of people with type 2 diabetes. Although many obese people have NAFLD, there are many obese people who do not develop ectopic liver fat. The aim of this review which is based on a presentation at the Royal Society of Medicine, UK in December 2012 is to discuss development of NAFLD, ectopic fat accumulation and insulin resistance. The review will also describe the relationships between NAFLD, type 2 diabetes and CVD.

Nonalcoholic fatty liver disease (NAFLD) is an emerging global health concern. It is the most common form of chronic liver disease in Western countries, affecting both adults and children. NAFLD encompasses a broad spectrum of fatty liver disease, ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), and is strongly associated with obesity, insulin resistance, and dyslipidemia. First-line therapy for NAFLD includes weight loss achieved through diet and physical activity. However, there is a lack of evidenced-based dietary recommendations. The American Diabetes Association's (ADA) recommendations that aim to reduce the risk of diabetes and cardiovascular disease may also be applicable to the NAFLD population. The objectives of this review are to: (1) provide an overview of NAFLD in the context of insulin resistance, and (2) provide a rationale for applying relevant aspects of the ADA recommendations to the nutritional management of NAFLD.

Objective: Hepatic steatosis is strongly associated with insulin resistance, but causative mechanisms that link these conditions are still largely unknown. Nowadays, it is difficult to establish whether fatty liver is the cause of insulin resistance or instead the complex metabolic derangements of insulin resistance determine hepatic steatosis and its progression to fibrosis. In patients with familial hypobetalipoproteinemia (FHBL), hepatic steatosis is because of the genetically determined defective form of apolipoprotein B, independently of metabolic derangements. Therefore patients with FHBL represent a good in vivo model to evaluate the relationships between fatty liver and insulin sensitivity., Methods: We evaluated insulin resistance through HOMA-IR in 60 children with echografic and histological features of steatosis; 30 of whom had nonalcoholic fatty liver disease (NAFLD) and 30 had FHBL., Results: All patients had histological features of hepatic steatosis. Patients with FHBL were hypolipidemic, as expected. No significant differences between two groups were observed in liver function tests. IRI and HOMA-IR were statistically higher in NAFLD subjects compared to the FHBL group., Conclusion: In our study, we demonstrated that in children with FHBL, hepatic steatosis is dissociated from insulin resistance. This finding suggests that fat accumulation per se may be not a sufficient causal factor leading to insulin resistance, and that other mediators may be involved in the development of alteration in glucose metabolism and metabolic syndrome in patients with NAFLD., (© 2012 John Wiley & Sons Ltd.)

Aim: The aim of this study was to investigate the relationships between 25-hydroxy-vitamin D (25(OH)D) and insulin resistance in obese adolescents with non-alcoholic fatty liver disease (NAFLD)., Patients and Methods: Eighty-seven obese adolescents (45 girls and 42 boys, mean age: 12.7 ± 1.3 years, mean body mass index standard deviation score (BMI-SDS): 2.1 ± 0.3) and 30 lean subjects (15 girls and 15 boys, mean age: 12.3 ± 1.45 years, mean BMI-SDS: 0.5 ± 0.7) were enrolled for the study. The obese subjects were divided into two subgroups based on the presence or absence of fatty liver with high transaminases (NAFLD group and non-NAFLD group). Fasting blood samples were assayed for 25(OH)D, transaminases, glucose, and insulin levels. Insulin resistance was calculated by the homeostasis model assessment (HOMA-IR)., Results: 25(OH)D measurements were decreased in both obese groups (NAFLD and non-NAFLD) in comparison with the lean group (29.5 ± 18.4 vs. 41.0 ± 17.9 vs. 48.1 ± 22.2 ng/mL). However; the NAFLD group had significantly lower measurements of 25(OH)D than the non-NAFLD group (p < 0.001) and lean group (p < 0.001). 25(OH)D was negatively correlated with HOMA-IR (r = 0.158, p = 0.01) and with alanine aminotransferase (r = 0.794, p = 0.03) in the NAFLD obese group. There was no significant associations between fasting insulin, BMI-SDS and 25(OH)D in obese groups., Conclusion: We suggest that low 25(OH)D occurs commonly in obese adolescents with NAFLD and we demonstrated an association between insufficient vitamin D status and low insulin sensitivity in obese adolescents with NAFLD., (© Crown Copyright 2013 Published by Elsevier Ltd on behalf of Asia Oceania Assoc. for the Study of Obesity. All rights reserved.)

Non-alcoholic fatty liver disease is marked by hepatic fat accumulation not due to alcohol abuse. Several studies have demonstrated that NAFLD is associated with insulin resistance leading to a resistance in the antilipolytic effect of insulin in the adipose tissue with an increase of free fatty acids (FFAs). The increase of FFAs induces mitochondrial dysfunction and development of lipotoxicity. Moreover, in subjects with NAFLD, ectopic fat also accumulates as cardiac and pancreatic fat. In this review we analyzed the mechanisms that relate NAFLD with metabolic syndrome and dyslipidemia and its association with the development and progression of cardiovascular disease.

An association of non-alcoholic fatty liver disease with insulin resistant metabolic syndrome and hypothyroidism has been suggested. Aim of the present study was to explore the above association and also to establish the correlation between hypothyroidism and insulin resistance in patients with nonalcoholic fatty liver disease. Study group comprised 40 cases of non-alcoholic fatty liver disease and 30 healthy controls. Serum samples were analysed for fasting glucose, insulin, lipid profile and thyroid hormones. Insulin resistance was assessed by homeostatic model of assessment calculation. Nonalcoholic fatty liver disease patients demonstrated significantly higher insulin resistance, TSH values and significantly lower FT4 values as compared to controls, which illustrates the prevalence of insulin resistance and hypothyroidism in patients. A significant positive correlation between TSH and Insulin resistance (r = 0.87, p < 0.001) and a significant negative correlation between FT4 and insulin resistance (r = -0.14, p < 0.001) were established in the cases. Moreover TSH was significantly related to low density lipoprotein cholesterol, independent of insulin resistance. There have been some doubts over the clinical correlation between insulin resistance and hypothyroidism to delineate increased risk of cardiovascular disease. So earlier detection and treatment of risk factors may have a significant impact on progression of non-alcoholic fatty liver disease.

Objective: The liver is an insulin-responsive organ that contributes significantly to both whole body insulin sensitivity and availability of sex steroids through the production of sex hormone binding globulin (SHBG). Our objective was to explore whether lower SHBG was associated with ectopic liver fat and mediated its effect on insulin resistance in The Study of Women's Health Across the Nation (SWAN)., Design and Methods: A subset of midlife African American and Caucasian women from SWAN (n = 208; 50.9 ± 0.18 yrs; 71% Caucasian) had computed tomography scans to quantify visceral, subcutaneous and liver fat. Blood samples were collected and assayed for hormonal and metabolic markers., Results: The cohort, while overweight, was generally healthy, and both liver fat and SHBG were unaffected by menopausal stage or race. Both higher liver fat and lower SHBG levels were significantly associated with higher insulin concentrations after adjustment for adiposity (r = -0.25, P < 0.001 and r = -0.18, P = 0.01). SHBG and liver fat had additive effects on insulin concentrations such that women with the lowest SHBG and the highest fat levels had the highest values (interaction P = 0.09). The association between SHBG and insulin was more apparent among women with fattier livers. SHBG and liver fat appear to have independent effects on insulin levels as adjustment for each other did not diminish the strength of either association (P = 0.023 and 0.001 respectively)., Conclusion: These results confirmed the strong independent associations between increased liver fat and decreased SHBG with increased metabolic risk in midlife women. Further these data underscore the need for additional research into the role of liver fat in modifying SHBG's influence on insulin levels., (Copyright © 2013 The Obesity Society.)

The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2(-/-)) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2(-/-) mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aims: Fatty liver disease, especially non-alcoholic fatty liver disease, is considered to be the hepatic manifestation of the metabolic syndrome, both closely associated with insulin resistance. Furthermore, fatty liver disease assessed by ultrasonography is known to be a predictor of the development of Type 2 diabetes mellitus. However, it remains unclear whether fatty liver disease plays a role in the pathogenesis of Type 2 diabetes independently of insulin resistance. In this study, we investigated whether fatty liver disease assessed by the fatty liver index can predict the development of Type 2 diabetes independently of systemic insulin resistance., Methods: We examined the clinical and laboratory data of 7860 subjects without diabetes who underwent general routine health evaluations at the Asan Medical Center in 2007 and had returned for follow-up examinations in 2011. Fatty liver index was calculated using an equation that considers serum triglyceride levels, γ-glutamyltransferase, waist circumference and BMI., Results: During a 4-year period, 457 incident diabetes cases (5.8%) were identified. The odds ratios for the development of Type 2 diabetes were significantly higher in the group with a fatty liver index ≥ 60 (fatty liver index-positive) than in the group with a fatty liver index < 20 (fatty liver index-negative) after adjusting for various confounding variables including homeostasis model assessment of insulin resistance. Odds ratios were significant regardless of the insulin resistance status at baseline., Conclusions: Our results suggest that fatty liver index as a simple surrogate indicator of hepatic steatosis is valuable in identifying subjects at high risk for Type 2 diabetes. In addition, fatty liver disease itself contributes to the development of Type 2 diabetes independently of systemic insulin resistance., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

Background: Insulin resistance has been recognized as a major factor in the development of non-alcoholic fatty liver disease (NAFLD). The association between insulin resistance and NAFLD, as a risk factor independent of obesity has been less well established. This study aims to determine presence of insulin resistance and components of metabolic syndrome in non-obese patients with NAFLD., Methods: 150 patients (mean age 42.25 &#95; 10.50 y; 115 (76%) male, 35 (24%) female) diagnosed with NAFLD participated in the study. We measured body mass index (BMI), waist circumference (WC), waist hip ratio (WHR), fasting lipid profile, fasting glucose, fasting insulin, and liver function. Insulin resistance was calculated using the homeostasis model of assessment (HOMA) formula. Insulin resistance was arbitrarily considered altered when it was >1.64., Results: 120 (80%) of the 150 patients were pbese (BMI >23) according to the Asia Pacific criteria. 40 (30%) had metabolic syndrome. 97.5% (117/120) had insulin resistance with mean HOMA-insulin resistance (IR) of 10.9+/-5.3. Thirty (20%) were non-obese; of these, 7 had central obesity (WC > 90 cm for men, > 80 cm for women). Twenty-three (15.3%) patients were lean NAFLD with BMI 21.6+/-1.5, WC 82.9+/-4.7 (BMI< 23, WC <90 cm in men and < 80 cm in women) 80% of these 23 (18/23) had insulin resistance with mean HOMA-IR of 3.4+/-1.9. Only 4 (17%) did not have any component of metabolic syndrome., Conclusion: Insulin resistance often associated with metabolic syndrome is common and plays a key role amongst lean Indian patients with non-alcoholic fatty liver disease.

Recent studies have elucidated a lower level of serum insulin-like growth factor-I (IGF-I) or a decrease in the IGF-I/IGF-binding protein-3 (IGFBP-3) ratio in patients with type 2 diabetes mellitus or hepatic steatosis. Persistent hepatitis C virus (HCV) infection often evokes metabolic abnormalities including hepatic steatosis and insulin resistance. We hypothesized that the relationship between the ratio of IGF-I/IGFBP-3 and the severity of hepatic steatosis or insulin resistance would be observed in patients with HCV-related chronic liver disease (CLD). On the basis of the classifications proposed by Brunt and colleagues (Am J Gastroenterol 1999; 94: 2467-2474), among the 42 enrolled patients with HCV-related CLD, 23 of them had no hepatic steatosis (grade 0), 14 had grade 1 steatosis, and 5 had grade 2 steatosis. The levels of serum IGF-I in the enrolled patients declined in proportion to the severity of hepatic steatosis, whereas serum IGFBP-3 levels did not affect its severity. Therefore, the ratio of IGF-I/IGFBP-3, which corresponds to the circulating free IGF-I status, was significantly lower in those patients with hepatic steatosis (grades 1 and 2) than in those without hepatic steatosis. Serum IGF-I levels significantly correlated with serum zinc levels (r = 0.370, P = .0266), but IGFBP-3 levels did not. However, the linear regression analysis revealed an inverse correlation between the IGF/IGFBP-3 ratio and the value of homeostasis model for assessment of insulin resistance (r =-0.411, P = .0094). These findings suggest that the decline of the circulating free IGF-I level, which derives from zinc deficiency, may contribute to hepatic steatosis and insulin resistance in patients with HCV-related CLD., (Copyright © 2013 Elsevier Inc. All rights reserved.)