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Journal ArticleDOI

Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With Obesity.

TL;DR: Short-term isocaloric fructose restriction decreased liver fat, VAT, and DNL, and improved insulin kinetics in children with obesity, and support efforts to reduce sugar consumption.
About: This article is published in Gastroenterology.The article was published on 2017-09-01 and is currently open access. It has received 174 citations till now. The article focuses on the topics: Intra-Abdominal Fat & Nonalcoholic fatty liver disease.
Citations
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Journal ArticleDOI
TL;DR: Understanding of pathogenic mechanisms and clinical features of NAFLD is driving progress in therapeutic strategies now in clinical trials and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression are discussed.
Abstract: There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.

2,004 citations

Journal ArticleDOI
TL;DR: Small, more definitive trials are suggested to determine if lowering sugar/HFCS intake, and/or blocking uric acid generation, may help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease.

537 citations


Cites background from "Effects of Dietary Fructose Restric..."

  • ...Conversely, the restriction of fructose for nine days in children with a high baseline fructose intake resulted in both a reduction in liver fat and de novo lipogenesis compared to controls fed an isocaloric diet.(55) In a subset of the same study, there was also an improvement in other features of metabolic syndrome, including diastolic blood pressure, serum triglycerides and insulin resistance....

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Journal ArticleDOI
TL;DR: The cellular mechanisms underlying hepatic fructose metabolism will likely reveal novel targets for the treatment of NAFLD, dyslipidemia, and hepatic insulin resistance, and fructose-containing sugars are a major source of excess calories, suggesting that a reduction of their intake has potential for the prevention ofNAFLD and other obesity-related diseases.
Abstract: Increased fructose consumption has been suggested to contribute to non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, but a causal role of fructose in these metabolic diseases remains debated. Mechanistically, hepatic fructose metabolism yields precursors that can be used for gluconeogenesis and de novo lipogenesis (DNL). Fructose-derived precursors also act as nutritional regulators of the transcription factors, including ChREBP and SREBP1c, that regulate the expression of hepatic gluconeogenesis and DNL genes. In support of these mechanisms, fructose intake increases hepatic gluconeogenesis and DNL and raises plasma glucose and triglyceride levels in humans. However, epidemiological and fructose-intervention studies have had inconclusive results with respect to liver fat, and there is currently no good human evidence that fructose, when consumed in isocaloric amounts, causes more liver fat accumulation than other energy-dense nutrients. In this review, we aim to provide an overview of the seemingly contradicting literature on fructose and NAFLD. We outline fructose physiology, the mechanisms that link fructose to NAFLD, and the available evidence from human studies. From this framework, we conclude that the cellular mechanisms underlying hepatic fructose metabolism will likely reveal novel targets for the treatment of NAFLD, dyslipidemia, and hepatic insulin resistance. Finally, fructose-containing sugars are a major source of excess calories, suggesting that a reduction of their intake has potential for the prevention of NAFLD and other obesity-related diseases.

206 citations

Journal ArticleDOI
13 Jun 2018-BMJ
TL;DR: David S Ludwig and colleagues examine the links between different types of carbohydrates and health and the importance of fibre, fat, and calories in the diet.
Abstract: David S Ludwig and colleagues examine the links between different types of carbohydrates and health

188 citations

Journal ArticleDOI
Sen Ma1
TL;DR: The European Association for the Study of the Liver (EASL) proposed a framework for the principal actions required to improve liver health in Europe as mentioned in this paper , which can serve as a powerful mechanism for improving liver care in Europe.

151 citations

References
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Journal ArticleDOI
TL;DR: The correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
Abstract: The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.

29,217 citations

Journal ArticleDOI
TL;DR: A novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the oral glucose tolerance test (OGTT).
Abstract: OBJECTIVE: Several methods have been proposed to evaluate insulin sensitivity from the data obtained from the oral glucose tolerance test (OGTT). However, the validity of these indices has not been rigorously evaluated by comparing them with the direct measurement of insulin sensitivity obtained with the euglycemic insulin clamp technique. In this study, we compare various insulin sensitivity indices derived from the OGTT with whole-body insulin sensitivity measured by the euglycemic insulin clamp technique. RESEARCH DESIGN AND METHODS: In this study, 153 subjects (66 men and 87 women, aged 18-71 years, BMI 20-65 kg/m2) with varying degrees of glucose tolerance (62 subjects with normal glucose tolerance, 31 subjects with impaired glucose tolerance, and 60 subjects with type 2 diabetes) were studied. After a 10-h overnight fast, all subjects underwent, in random order, a 75-g OGTT and a euglycemic insulin clamp, which was performed with the infusion of [3-3H]glucose. The indices of insulin sensitivity derived from OGTT data and the euglycemic insulin clamp were compared by correlation analysis. RESULTS: The mean plasma glucose concentration divided by the mean plasma insulin concentration during the OGTT displayed no correlation with the rate of whole-body glucose disposal during the euglycemic insulin clamp (r = -0.02, NS). From the OGTT, we developed an index of whole-body insulin sensitivity (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]), which is highly correlated (r = 0.73, P < 0.0001) with the rate of whole-body glucose disposal during the euglycemic insulin clamp. CONCLUSIONS: Previous methods used to derive an index of insulin sensitivity from the OGTT have relied on the ratio of plasma glucose to insulin concentration during the OGTT. Our results demonstrate the limitations of such an approach. We have derived a novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT.

4,988 citations

Journal ArticleDOI
TL;DR: In this article, the authors quantified the biological sources of hepatic and plasma lipoprotein TAG in NAFLD patients, using stable isotopes for four days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipid TAG.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess liver triacylglycerol (TAG), inflammation, and liver damage The goal of the present study was to directly quantify the biological sources of hepatic and plasma lipoprotein TAG in NAFLD Patients (5 male and 4 female; 44 ± 10 years of age) scheduled for a medically indicated liver biopsy were infused with and orally fed stable isotopes for 4 days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipoprotein TAG Hepatic and lipoprotein TAG fatty acids were analyzed by gas chromatography/mass spectrometry NAFLD patients were obese, with fasting hypertriglyceridemia and hyperinsulinemia Of the TAG accounted for in liver, 590% ± 99% of TAG arose from NEFAs; 261% ± 67%, from DNL; and 149% ± 70%, from the diet The pattern of labeling in VLDL was similar to that in liver, and throughout the 4 days of labeling, the liver demonstrated reciprocal use of adipose and dietary fatty acids DNL was elevated in the fasting state and demonstrated no diurnal variation These quantitative metabolic data document that both elevated peripheral fatty acids and DNL contribute to the accumulation of hepatic and lipoprotein fat in NAFLD

2,870 citations


"Effects of Dietary Fructose Restric..." refers methods in this paper

  • ...Our data suggest that the effect of fructose on liver fat is specific and mediated through reductions in DNL. DNL was originally thought to be a minor metabolic pathway in humans.25 However, increased DNL has been demonstrated in adults with NAFLD.35 Using stable isotopes, Donnelly et al.8 showed that in adults with NAFLD, approximately 59% of triglyceride labeled in the liver comes from circulating fatty acids released by peripheral lipolysis, 15% from dietary fat, and 26% from DNL....

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  • ...Using stable isotopes, Donnelly et al.(8) showed that in adults with NAFLD, approximately 59% of triglyceride labeled in the liver...

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