Dorothy Hodgkin Lecture 2012 Non-alcoholic fatty liver disease, insulin resistance and ectopic fat: A new problem in diabetes management

Nutrition and Metabolism and NIHR Southampton Biomedical Research Centre, University Hospital Southampton and Faculty of Medicine, University of Southampton, Southampton, UK.
Diabetic Medicine (Impact Factor: 3.12). 06/2012; 29(9):1098-107. DOI: 10.1111/j.1464-5491.2012.03732.x
Source: PubMed


Diabet. Med. 29, 1098–1107 (2012)
Non-alcoholic fatty liver disease is now recognized as the hepatic component of the metabolic syndrome. Non-alcoholic fatty liver disease is a spectrum of fat-associated liver conditions that can result in end-stage liver disease and the need for liver transplantation. Simple steatosis, or fatty liver, occurs early in non-alcoholic fatty liver disease and may progress to non-alcoholic steatohepatitis, fibrosis and cirrhosis with increased risk of hepatocellular carcinoma. Prevalence estimates for non-alcoholic fatty liver disease range from 17 to 33% in the general populations and it has been estimated that non-alcoholic fatty liver disease exists in up to 70% of people with Type 2 diabetes. Non-alcoholic fatty liver disease increases risk of Type 2 diabetes and cardiovascular disease. In people with Type 2 diabetes, non-alcoholic fatty liver disease is the most frequent cause (∼80%) of fatty liver diagnosed by ultrasound. As non-alcoholic fatty liver disease is strongly associated with insulin resistance, the presence of non-alcoholic fatty liver disease with diabetes often contributes to poor glycaemic control. Consequently, strategies that decrease liver fat and improve whole-body insulin sensitivity may both contribute to prevention of Type 2 diabetes and to better glycaemic control in people who already have developed diabetes. This review summarizes the Dorothy Hodgkin lecture given by the author at the 2012 Diabetes UK annual scientific conference, proposing that fatty acid fluxes through the liver are crucial for the pathogenesis of non-alcoholic fatty liver disease and for increasing insulin resistance.

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    • "In addition to hepatic insulin resistance, NAFLD is associated with a defect in insulin‐mediated suppression of lipolysis, in keeping with insulin resistance in adipose tissues24. These findings suggest that insulin resistance might be an intrinsic defect in NAFLD, similar to that in type 2 diabetes, and that blunted insulin responsiveness at the level of the adipocytes might contribute to hepatic steatosis through excess free fatty acid flux to the liver25. Isotope‐tracer studies in obese humans with NAFLD on a low‐fat diet showed that nearly 60% of hepatic triglycerides comes from FFA derived from adipose tissues, 26% from de novo lipogenesis and 15% from diet26. "
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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) describes a spectrum of liver conditions from simple steatosis, steatohepatitis to end-stage liver disease. The prevalence of NAFLD has been on the rise in many parts of the world, including Asia, and NAFLD is now the liver disease associated with the highest mortality, consequent to the increased risk of cardiovascular diseases and hepatocellular carcinoma. Whereas NAFLD is an independent risk factor for type 2 diabetes, increased hepatic and peripheral insulin resistance contribute to the pathogenesis of both NAFLD and diabetes, which are associated with enhanced cardiovascular risk. Studies in humans and animal models have suggested obesity as the common link of these two diseases, likely mediated by adipose tissue inflammation and dysregulated adipokine production in obesity. In the present review, we discuss recent advances in our understanding of the role of several novel adipokines (adiponectin, adipocyte fatty acid binding protein and fibroblast growth factor-21) in the pathophysiology of NAFLD and diabetes, as well as their use as potential biomarkers and therapeutic targets for dysglycemia in NAFLD patients.
    Journal of Diabetes Investigstion 09/2013; 4(5):413-425. DOI:10.1111/jdi.12093 · 1.83 Impact Factor
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    • "Nonalcoholic fatty liver disease (NAFLD), characterized by an abnormal accumulation of fat in hepatocytes, is recognized as the most prevalent chronic liver disease in the general population [1], and is increasing rapidly in both Western countries and Asian countries such as Korea [2]. NAFLD is well known to be share the common pathophysiological mechanism of insulin resistance with obesity, metabolic syndrome, and type 2 diabetes [3]. "
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is closely correlated with abnormal accumulation of visceral fat, but the role of skeletal muscle remains unclear. The aim of this study was to elucidate the role of skeletal muscle in development of NAFLD. Among 11,116 subjects (6,242 males), we examined the effects of skeletal muscle mass and visceral fat area (VFA, by bioelectric impedance analysis) on NAFLD using by the fatty liver index (FLI). Of the total subjects (9,565 total, 5,293 males) included, 1,848 were classified as having NALFD (FLI ≥60). Body mass index, lipid profile, fasting plasma glucose, hemoglobin A1c, prevalence of type 2 diabetes (DM), hypertension (HTN), and metabolic syndrome were higher in males than females, but FLI showed no significant difference. The low FLI group showed the lowest VFA and highest skeletal muscle mass of all the groups. Skeletal muscle to visceral fat ratio (SVR) and skeletal muscle index had inverse correlations with FLI, when adjusted for age and gender. In multivariate regression analysis, SVR was negatively associated with FLI. Among SVR quartiles, the highest quartile showed very low risk of NAFLD when adjusted for age, gender, lipid profile, DM, HTN, and high sensitivity C-reactive protein from the lowest quartiles (odds ratio, 0.037; 95% confidence interval, 0.029 to 0.049). Skeletal muscle mass was inversely associated with visceral fat area, and higher skeletal muscle mass may have a beneficial effect in preventing NAFLD. These results suggest that further studies are needed to ameliorate or slow the progression of sarcopenia.
    Diabetes & metabolism journal 08/2013; 37(4):278-85. DOI:10.4093/dmj.2013.37.4.278
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    • "In this respect, the sources that contribute to fatty liver are (i) delivery of dietary fat to the liver (contribution to liver fat ∼5%); (ii) delivery of extrahepatic nonesterified fatty acids (NEFAs) to the liver (contribution to liver fat ∼60%); (iii) the remainder of liver fat accumulation is related to hepatic de novo lipogenesis, which is increased in obese patients [12]. The retention of FAs and TAGs within the hepatocytes that depends on IR and hyperinsulinemia leads to the production of free radicals at a mitochondrial level, capable of inducing lipid peroxidation, cytokine production, and hepatocyte necrosis [13], which may trigger NAFLD progression to the more severe state of NASH [2] [3]. "
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    ABSTRACT: Nonalcoholic fatty liver disease in human obesity is characterized by the multifactorial nature of the underlying pathogenic mechanisms, which include misregulation of PPARs signaling. Liver PPAR-α downregulation with parallel PPAR-γ and SREBP-1c up-regulation may trigger major metabolic disturbances between de novo lipogenesis and fatty acid oxidation favouring the former, in association with the onset of steatosis in obesity-induced oxidative stress and related long-chain polyunsaturated fatty acid n-3 (LCPUFA n-3) depletion, insulin resistance, hypoadiponectinemia, and endoplasmic reticulum stress. Considering that antisteatotic strategies targeting PPAR-α revealed that fibrates have poor effectiveness, thiazolidinediones have weight gain limitations, and dual PPAR-α/γ agonists have safety concerns, supplementation with LCPUFA n-3 appears as a promising alternative, which achieves both significant reduction in liver steatosis scores and a positive anti-inflammatory outcome. This latter aspect is of importance as PPAR-α downregulation associated with LCPUFA n-3 depletion may play a role in increasing the DNA binding capacity of proinflammatory factors, NF-κB and AP-1, thus constituting one of the major mechanisms for the progression of steatosis to steatohepatitis.
    PPAR Research 12/2012; 2012(4):107434. DOI:10.1155/2012/107434 · 1.64 Impact Factor
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