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

ArticleinDiabetic Medicine 29(9):1098-107 · June 2012with61 Reads
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.
    • "Specifically, in the presence of insulin resistance, increased FFA fluxes to the liver increase the availability of long-chain fatty acyl-CoAs for hepatic lipid metabolism. Such an effect occurs in sedentary obese individuals, who do not benefit from the ameliorating effect of increased muscle activity and increased mitochondrial fatty acid oxidation, which would normally buffer the liver from the burden of high FFA levels [33]. With the increased fluxes of long-chain fatty acyl CoAs through the liver, evidence is accumulating that hepatic lipid accumulation is capable of promoting hepatic insulin resistance and hepatic inflammation through accumulation of di-acyl glycerols (DAGs) and protein kinase C (PKC-) activity, inhibiting the insulin signalling pathway and promoting insulin resistance (reviewed in detail in [28]). "
    [Show abstract] [Hide abstract] ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide, causing considerable liver-related mortality and morbidity. Over the last 10years, it has also become increasingly evident that NAFLD is a multisystem disease, affecting many extra-hepatic organ systems and interacting with the regulation of multiple metabolic pathways. NAFLD is potentially involved in the aetiology and pathogenesis of type 2 diabetes via its direct contribution to hepatic/peripheral insulin resistance and the systemic release of multiple hepatokines that may adversely affect glucose metabolism and insulin action. In this updated review, we discuss the rapidly expanding body of clinical and epidemiological evidence that supports a strong link between NAFLD and the risk of developing type 2 diabetes. We also briefly examine the conventional and the more innovative pharmacological approaches for the treatment of NAFLD that may influence the risk of developing type 2 diabetes.
    Article · Apr 2016
    • "Indeed, NAFLD is strongly associated with MetS which, in its turn, carries a higher risk of progressive NASH [2,45610111213141587,88]. Moreover, as discussed below, visceral overweight/obesity, glucose intoler- ance/T2DM and hypertriglyceridaemia are the individual MetS features that are more strongly associated with NAFLD development and progression [2,45610111213141587,88]. Although a strong and bidirectional association links NAFLD and T2DM as a key component feature of the MetS, to date there is less evidence of an association between NAFLD and hypertension. "
    [Show abstract] [Hide abstract] ABSTRACT: An improved understanding of non-alcoholic fatty liver disease epidemiology would lead to identification of individuals at high risk of developing chronic liver disease and extra-hepatic complications, thus contributing to more effective case finding of non-alcoholic fatty liver disease among selected groups. We aimed to illustrate the epidemiology of non-alcoholic fatty liver disease in high-risk groups, which were identified based on existing literature. To this end, PubMed was searched to retrieve original articles published until May 2015 using relevant and pertinent keywords “nonalcoholic fatty liver disease” and “diabetes”, “obesity”, “hyperlipidemia”, “familial heterozygous hypobetalipoproteinemia”, “hypertension”, “metabolic syndrome”, “ethnicity”, “family history” or “genetic polymorphisms”. We found that age, sex and ethnicity are major physiological modifiers of the risk of non-alcoholic fatty liver disease, along with belonging to “non-alcoholic fatty liver disease families” and carrying risk alleles for selected genetic polymorphisms. Metabolic syndrome, diabetes, obesity, mixed hyperlipidaemia and hypocholesterolaemia due to familial hypobetalipoproteinaemia are the major metabolic modifiers of non-alcoholic fatty liver disease risk. Compared with these metabolic conditions, however, arterial hypertension appears to carry a relatively more modest risk of non-alcoholic fatty liver disease. A better understanding of the epidemiology of non-alcoholic fatty liver disease may result in a more liberal policy of case finding among high-risk groups
    Article · Aug 2015
    • "Nonalcoholic fatty liver disease (NAFLD) is considered to be a manifestation of metabolic syndrome VASCULAR DIABETOLOGY and is strongly related to excessive cardiovascular risk as well as renal disease121314. On the other hand, NAFLD may independently contribute to insulin resistance [15] and vascular stiffness [16] . Furthermore, NAFLD is considered to be among the leading causes of liver cirrhosis and hepatocellular carcinoma [17]. "
    [Show abstract] [Hide abstract] ABSTRACT: Obstructive sleep apnea is a common disorder acting as a risk factor for the development and progression of cardiometabolic derangements including non-alcoholic fatty liver disease. Recent research data suggest that non-alcoholic fatty pancreatic disease may be a more sensitive marker than non-alcoholic fatty liver disease for early subclinical metabolic risk and may contribute to the progression of subclinical disease to overt type 2 diabetes mellitus. We postulate that obstructive sleep apnea may be a risk factor for non-alcoholic fatty pancreatic disease. It is well known that intermittent hypoxia related to obstructive sleep apnea leads to hormonal derangements. Excessive lipolysis, enhanced lipid synthesis and systemic and local inflammation may favor ectopic fat deposition similarly to non-alcoholic fatty liver disease. Furthermore, it is possible that obstructive sleep apnea can lead to pancreatic beta cell damage via intermittent hypoxia.Testing of the hypothesis: Future research should focus on the following: first, whether non-alcoholic fatty pancreatic disease is an independent risk factor for the development of metabolic disease including diabetes mellitus or is a simple consequence of obesity; second, the prevalence of non-alcoholic fatty pancreatic disease among people with obstructive sleep apnea and vice versa, which should be compared to the prevalence of these diseases in general population; third, whether coexistence of these conditions is related to greater cardiometabolic risk than either disease alone; and fourth, whether the treatment of obstructive sleep apnea will translate into the resolution of non-alcoholic fatty pancreatic disease. If proven, this hypothesis will provide new knowledge on the complex interplay between various metabolic insults. Second, screening for NAFPD may identify individuals at risk for developing type 2 diabetes mellitus for targeted prevention. Third, screening for the presence of non-alcoholic fatty pancreatic disease in patients with obstructive sleep apnea may help to decrease the incidence of diabetes mellitus through a targeted prevention.
    Full-text · Article · Jan 2014
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