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Role of Adipose Tissue Insulin Resistance in the Natural History of T2DM: Results From the San... Role of Adipose Tissue Insulin Resistance in the Natural History of T2DM: Results From the San...

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Date added: 03/10/2018
Date modified: 03/10/2018
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"Role of Adipose Tissue Insulin Resistance in the Natural History of T2DM: Results From the San Antonio Metabolism Study"

In the transition from normal glucose tolerance (NGT) to type 2 diabetes mellitus (T2DM), the role of b-cell dysfunction and peripheral insulin resistance (IR) is well established. However, the impact of dysfunctional adipose tissue has not been fully elucidated. The aim of this study was to evaluate the role of resistance to the antilipolytic effect of insulin (adipose tissue IR [Adipo-IR]) in a large group of subjects with NGT, impaired glucose tolerance (IGT), and T2DM.

Predictors of Liver Fat and Stiffness in Non-Alcoholic Fatty Liver Disease (NAFLD) – an 11-Year... Predictors of Liver Fat and Stiffness in Non-Alcoholic Fatty Liver Disease (NAFLD) – an 11-Year...

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Date added: 08/07/2018
Date modified: 08/07/2018
Filesize: 1.38 MB
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"Predictors of Liver Fat and Stiffness in Non-Alcoholic Fatty Liver Disease (NAFLD) – an 11-Year Prospective Study"

Liver fat can be non-invasively measured by proton magnetic resonance spectroscopy (1H-MRS) and fibrosis estimated as stiffness using transient elastography (FibroScan). There are no longitudinal data on changes in liver fat in Europids or on predictors of liver stiffness using these methods. We determined liver fat (1H-MRS) and clinical characteristics including features of insulin resistance at baseline and after a median follow-up period of 11.3 (range 7.3–13.4) years in 97 Finnish subjects. Liver stiffness was measured at 11.3 years. Liver fat content decreased by 5% (p < 0.05) over time. Values at baseline and 11.3 years were closely interrelated (r = 0.81, p < 0.001). Baseline liver fat (OR 1.32; 95%CI: 1.15–1.50) and change in BMI (OR 1.67; 95%CI: 1.24–2.25) were independent predictors of liver fat at 11.3 years (AUROC 0.90; 95%CI: 0.83–0.96). Baseline liver fat (AUROC 0.84; 95%CI: 0.76–0.92) predicted liver fat at 11.3 years more accurately than routinely available parameters (AUROC 0.76; 95%CI: 0.65–0.86, p = 0.02). At 11.3 years, 29% of the subjects had increased liver stiffness. Baseline liver fat (OR 2.17; 95%CI: 1.05–4.46) was an independent predictor of increased liver stiffness. These data show that liver fat is more important than the associated metabolic abnormalities as the predictor of future liver fat and fibrosis.

PNPLA3 and obesity: a synergistic relationship in NAFLD PNPLA3 and obesity: a synergistic relationship in NAFLD

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Date added: 05/27/2018
Date modified: 05/27/2018
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NAFLD, the hepatic manifestation of the metabolic syndrome, is a multifactorial condition — environmental factors influence an inherited genetic risk. Stender et al. now describe the additive effect of obesity and NAFLD-associated genetic polymorphisms on steatosis, elevated serum alanine aminotransferase levels and cirrhosis, remarkably illustrating the principle of gene–environment interactions.

Refers to Stender, S. et al. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat. Genet. 49, 842–847 (2017)

Plasma DNA methylation: A potential biomarker for stratification of liver fibrosis in NAFLD Plasma DNA methylation: A potential biomarker for stratification of liver fibrosis in NAFLD

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Date added: 05/22/2016
Date modified: 09/27/2016
Filesize: 2.77 MB
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Liver biopsy is currently the most reliable way of evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Its inherent risks limit its widespread use. Differential liver DNA methylation of peroxisome proliferator-activated receptor gamma (PPARγ) gene promoter has recently been shown to stratify patients in terms of fibrosis severity but requires access to liver tissue. The aim of this study was to assess whether DNA methylation of circulating DNA could be detected in human plasma and potentially used to stratify liver fibrosis severity in patients with NAFLD.

Phosphorylated IGFBP-1 as a non-invasive predictor of liver fat in NAFLD Phosphorylated IGFBP-1 as a non-invasive predictor of liver fat in NAFLD

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Date added: 01/10/2017
Date modified: 01/10/2017
Filesize: 505.25 kB
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Insulin-like growth factor binding protein 1 (IGFBP-1) is a potentially interesting marker for liver fat in NAFLD as it is exclusively produced by the liver, and insulin is its main regulator. We determined whether measurement of fasting serum phosphorylated IGFBP-1 (fS-pIGFBP-1) helps to predict liver fat compared to routinely available clinical parameters and PNPLA3 genotype at rs738409. Liver fat content (proton magnetic resonance spectroscopy) was measured in 378 subjects (62% women, age 43 [30–54] years, BMI 32.7 [28.1–39.7] kg/m2, 46% with NAFLD). Subjects were randomized to discovery and validation groups, which were matched for clinical and biochemical parameters and PNPLA3 genotype. Multiple linear regression and Random Forest modeling were used to identify predictors of liver fat. The final model, % Liver Fat Equation’, included age, fS-pIGFBP-1, S-ALT, waist-to-hip ratio, fP-Glucose and fS-Insulin (adjusted R2 = 0.44 in the discovery group, 0.49 in the validation group, 0.47 in all subjects). The model was significantly better than a model without fS-pIGFBP-1 or S-ALT or S-AST alone. Random Forest modeling identified fS-p-IGFBP-1 as one of the top five predictors of liver fat (adjusted R2 = 0.39). Therefore, measurement of fS-pIGFBP-1 may help in non-invasive prediction of liver fat content.

Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate... Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate...

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Date added: 08/10/2019
Date modified: 08/10/2019
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"Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate adipose tissue remodeling in obesity"

Lipidomic techniques can improve our understanding of complex lipid interactions that regulate metabolic diseases. Here, a serum phospholipidomics analysis identified associations between phosphatidylglycerols (PGs) and gut microbiota dysbiosis. Compared with the other phospholipids, serum PGs were the most elevated in patients with low microbiota gene richness, which were normalized after a dietary intervention that restored gut microbial diversity. Serum PG levels were positively correlated with metagenomic functional capacities for bacterial LPS synthesis and host markers of low-grade inflammation; transcriptome databases identified PG synthase, the first committed enzyme in PG synthesis, as a potential mediator. Experiments in mice and cultured human-derived macrophages demonstrated that LPS induces PG release. Acute PG treatment in mice altered adipose tissue gene expression toward remodeling and inhibited ex vivo lipolysis in adipose tissue, suggesting that PGs favor lipid storage. Indeed, several PG species were associated with the severity of obesity in mice and humans. Finally, despite enrichment in PGs in bacterial membranes, experiments employing gnotobiotic mice colonized with recombinant PG overproducing Lactococcus lactis showed limited direct contribution of microbial PGs to the host. In summary, PGs are inflammation-responsive lipids indirectly regulated by the gut microbiota via endotoxins and regulate adipose tissue homeostasis in obesity.

Peripheral Insulin Resistance Predicts Liver Damage in Diabetic Subjects with NAFLD Peripheral Insulin Resistance Predicts Liver Damage in Diabetic Subjects with NAFLD

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Date added: 12/07/2015
Date modified: 11/07/2016
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BACKGROUND & AIMS:

Surrogate indexes of insulin resistance/sensitivity (IR/IS) are widely used in Non Alcoholic Fatty Liver Disease (NAFLD) although they have never been validated in this population. We aimed to validate the available indexes in NAFLD subjects and to test their ability to predict liver damage also in comparison with NAFLD Fibrosis Score (NFS).

METHODS:

Surrogate indexes were validated by tracer technique (D2-glucose and U-13C-glucose) in the basal state and during an Oral Glucose Tolerance Test (OGTT). The best performing indexes were used in an independent cohort of 145 non-diabetic NAFLD subjects to identify liver damage (fibrosis and NASH).

RESULTS:

In the validation NAFLD cohort, HOMA-IR, IGR and ISI Stumvoll had the best association with hepatic IR, while peripheral IS was most significantly related to OGIS, ISI Stumvoll and eMCRnodem . In the independent cohort, only OGTT derived indexes were associated with liver damage and OGIS was the best predictor of significant (≥F2) fibrosis (OR=0.76, 95% CI= 0.61-0.96, P=0.0233) and of NASH (OR=0.75, 95% CI=0.63-0.90, P=0.0021). Both OGIS and NFS identified advanced (F3/F4) fibrosis, but OGIS predicted it better than NFS (OR=0.57, 95% CI=0.45-0.72, P<0.001) and was also able to discriminate F2 from F3/F4 (P<0.003).

CONCLUSIONS:

OGIS is associated with peripheral IS in NAFLD and is inversely associated with an increased risk of significant/advanced liver damage in non-diabetic subjects with NAFLD.

Obesity/insulin resistance rather than liver fat increases coagulation factor activities and express Obesity/insulin resistance rather than liver fat increases coagulation factor activities and express

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Date added: 03/08/2017
Date modified: 03/08/2017
Filesize: 256 Bytes
Downloads: 1517

Increased liver fat may be caused by insulin resistance and adipose tissue inflammation or by the common I148M variant in PNPLA3 at rs738409, which lacks both of these features. We hypothesised that obesity/insulin resistance rather than liver fat increases circulating coagulation factor activities. We measured plasma prothrombin time (PT, Owren method), activated partial thromboplastin time (APTT), activities of several coagulation factors, VWF:RCo and fibrinogen, and D-dimer concentration in 92 subjects divided into groups based on insulin sensitivity and PNPLA3 genotype.

We conclude that obesity/insulin resistance rather than an increase in liver fat is associated with a procoagulant plasma profile. This reflects adipose tissue inflammation and increased hepatic production of coagulation factors and their susceptibility for activation.

Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance

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Date added: 01/09/2017
Date modified: 01/10/2017
Filesize: 1.02 MB
Downloads: 888

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.

Non-alcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum Non-alcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum

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Date added: 05/22/2016
Date modified: 05/22/2016
Filesize: 256 Bytes
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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction in the Western world and is increasing owing to its close association with obesity and insulin resistance. NAFLD represents a spectrum of liver disease that, in a minority of patients, can lead to progressive nonalcoholic steatohepatitis (NASH), fibrosis, and ultimately hepatocellular carcinoma and liver failure. NAFLD is a complex trait resulting from the interaction between environmental exposure and a susceptible polygenic background and comprising multiple independent modifiers of risk, such as the microbiome. The molecular mechanisms that combine to define the transition to NASH and progressive disease are complex, and consequently, no pharmacological therapy currently exists to treat NASH. A better understanding of the pathogenesis of NAFLD is critical if new treatments are to be discovered.