Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated the glucose and lipid metabolism in 65 patients (aged 1.1-55 years) with mulibrey (muscle-liver-brain-eye) nanism (MUL), which is a monogenic disorder with prenatal-onset growth failure and typical clinical characteristics. MUL is caused by mutations in the TRIM37 gene, encoding a peroxisomal protein (TRIM37) with E3 ubiquitin-ligase activity. The subjects underwent clinical evaluation, abdominal ultrasonography, and laboratory measurements, including a 3-h oral glucose tolerance test. The results showed a dramatic change in glucose and lipid metabolism with age in MUL subjects. While the children had low fasting glucose and insulin levels, 90% of the adults had high fasting and postload insulin values (up to 1,450 mU/l). A 10-fold decrease in the fasting glucose-to-insulin ratio and a 4-fold decrease in whole-body insulin sensitivity index were observed. Insulin resistance, fatty liver, high serum leptin, hypertension, and acantosis nigricans were already evident in many slim prepubertal children. Half of the adults had type 2 diabetes, and an additional 42% showed impaired glucose tolerance. Seventy percent fulfilled the National Cholesterol Education Program criteria for metabolic syndrome. The peroxisomal targeting and the functional link of TRIM37 to the ubiquitin-proteosome pathway may provide novel clues to the development of metabolic syndrome.
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PMID:Insulin resistance syndrome in subjects with mutated RING finger protein TRIM37. 1630 79

Glycated hemoglobin (GHb) measured as HbA1c in diabetic patients, is used to evaluate long-term control of diabetes mellitus, and most accurately reflects the previous 2-3 months of glycemic control. Liver disease is one of the leading causes of death in persons with type 2 diabetes mellitus. Diabetic patients can present with abnormal liver chemistries, from benign nonalcoholic fatty liver disease to severe cirrhosis of the liver. Because liver disease is associated with impaired glucose tolerance and diabetes mellitus, tools are needed to measure long-term glycemic control. In this review we discuss current information on glycated hemoglobin, HbA1c assay methods, attempts to standardize HbA1c assay methods, fructosamine and interferences caused by liver disease. We aim to alert the reader to current problems in determining long-term glycemic control parameters, HbA1c and fructosamine, and describe the measures necessary for proper interpretation of HbA1c.
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PMID:Glycated hemoglobin and liver disease in diabetes mellitus. 1639 39

Changes in human behavior and lifestyle over the last century have resulted in a dramatic increase in the incidence of obesity, type 2 diabetes, and the metabolic syndrome. Differences in the reported overall prevalence of the metabolic syndrome, which is generally in the range of 10-30% depend on the diagnostic criteria and subjects of the study. Recently, Japanese criteria for diagnosis of the metabolic syndrome were defined. With these criteria, presence of visceral obesity is essential for the diagnosis and is simply determined by measurement of waist circumference. Reflecting a dramatic increase in the incidence of obesity and type 2 diabetes, the incidence of the metabolic syndrome is increasing in Japan as well as in Western countries, regardless of the criteria applied. Recently, the number of workers with elevated liver enzymes, in whom virus hepatitis, alcoholic liver disease, drug induced hepatitis, autoimmune hepatitis, and iron overload were ruled out as causal agents, has also be found to be increasing at workplace health checkups. Most of such workers have components of the metabolic syndrome and the presence of steatosis in the liver, this pathologic condition now being termed nonalcoholic fatty liver disease (NAFLD). In this review, we describe the relationship between NAFLD and the metabolic syndrome.
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PMID:Metabolic syndrome from the view point of public health: with special reference to nonalcoholic fatty liver disease. 1640 78

The insulin resistance syndrome (IRS) is considered to be a new target of risk-reduction therapy. The IRS is a cluster of closely associated and interdependent abnormalities and clinical outcomes that occur more commonly in insulin-resistant/hyperinsulinemic individuals. This syndrome predisposes individuals to type 2 diabetes, cardiovascular diseases, essential hypertension, certain forms of cancer, polycystic ovary syndrome, nonalcoholic fatty liver disease, and sleep apnea. In patients at high risk for cardiovascular diseases, endothelial dysfunction is observed in morphologically intact vessels even before the onset of clinically manifest vascular disease. Indeed, there are several lines of evidence that indicate that endothelial function is compromised in situations where there is reduced sensitivity to endogenous insulin. It is well established that a decreased bioavailability of nitric oxide (NO) contributes to endothelial dysfunction. Furthermore, NO may modulate insulin sensitivity. Activation of NO synthase (NOS) augments blood flow to insulin-sensitive tissues (i.e. skeletal muscle, liver, adipose tissue), and its activity is impaired in insulin resistance. Inhibition of NOS reduces the microvascular delivery of nutrients and blunts insulin-stimulated glucose uptake in skeletal muscle. Furthermore, induction of hypertension by administration of the NOS inhibitor NG-monomethyl-L-arginine is also associated with insulin resistance in rats. Increased levels of asymmetric dimethylarginine (ADMA) are associated with endothelial vasodilator dysfunction and increased risk of cardiovascular diseases. An intriguing relationship exists between insulin resistance and ADMA. Plasma levels of ADMA are positively correlated with insulin resistance in nondiabetic, normotensive people. New basic research insights that provide possible mechanisms underlying the development of insulin resistance in the setting of impaired NO bioavailability will be discussed.
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PMID:Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA. 1644 67

Nonalcoholic steatohepatitis (NASH), the lynchpin between steatosis and cirrhosis in the spectrum of nonalcoholic fatty liver disorders (NAFLD), was barely recognized in 1981. NAFLD is now present in 17% to 33% of Americans, has a worldwide distribution, and parallels the frequency of central adiposity, obesity, insulin resistance, metabolic syndrome and type 2 diabetes. NASH could be present in one third of NAFLD cases. Age, activity of steatohepatitis, and established fibrosis predispose to cirrhosis, which has a 7- to 10-year liver-related mortality of 12% to 25%. Many cases of cryptogenic cirrhosis are likely endstage NASH. While endstage NAFLD currently accounts for 4% to 10% of liver transplants, this may soon rise. Pathogenic concepts for NAFLD/NASH must account for the strong links with overnutrition and underactivity, insulin resistance, and genetic factors. Lipotoxicity, oxidative stress, cytokines, and other proinflammatory mediators may each play a role in transition of steatosis to NASH. The present "gold standard" management of NASH is modest weight reduction, particularly correction of central obesity achieved by combining dietary measures with increased physical activity. Whether achieved by "lifestyle adjustment" or anti-obesity surgery, this improves insulin resistance and reverses steatosis, hepatocellular injury, inflammation, and fibrosis. The same potential for "unwinding" fibrotic NASH is indicated by studies of the peroxisome proliferation activator receptor (PPAR)-gamma agonist "glitazones," but these agents may improve liver disease at the expense of worsening obesity. Future challenges are to approach NAFLD as a preventive public health initiative and to motivate affected persons to adopt a healthier lifestyle.
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PMID:Nonalcoholic fatty liver disease: from steatosis to cirrhosis. 1644 87

Hepatic steatosis is a core feature of the metabolic syndrome and type 2 diabetes and leads to hepatic insulin resistance. Malonyl-CoA, generated by acetyl-CoA carboxylases 1 and 2 (Acc1 and Acc2), is a key regulator of both mitochondrial fatty acid oxidation and fat synthesis. We used a diet-induced rat model of nonalcoholic fatty liver disease (NAFLD) and hepatic insulin resistance to explore the impact of suppressing Acc1, Acc2, or both Acc1 and Acc2 on hepatic lipid levels and insulin sensitivity. While suppression of Acc1 or Acc2 expression with antisense oligonucleotides (ASOs) increased fat oxidation in rat hepatocytes, suppression of both enzymes with a single ASO was significantly more effective in promoting fat oxidation. Suppression of Acc1 also inhibited lipogenesis whereas Acc2 reduction had no effect on lipogenesis. In rats with NAFLD, suppression of both enzymes with a single ASO was required to significantly reduce hepatic malonyl-CoA levels in vivo, lower hepatic lipids (long-chain acyl-CoAs, diacylglycerol, and triglycerides), and improve hepatic insulin sensitivity. Plasma ketones were significantly elevated compared with controls in the fed state but not in the fasting state, indicating that lowering Acc1 and -2 expression increases hepatic fat oxidation specifically in the fed state. These studies suggest that pharmacological inhibition of Acc1 and -2 may be a novel approach in the treatment of NAFLD and hepatic insulin resistance.
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PMID:Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. 1648 39

Insulin-mediated glucose disposal varies widely in apparently healthy human beings, and the more insulin resistant an individual, the more insulin they must secrete in order to prevent the development of type 2 diabetes. However, the combination of insulin resistance and compensatory hyperinsulinemia increases the likelihood that an individual will be hypertensive, and have a dyslipidemia characterized by a high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentration. These changes increase risk of cardiovascular disease (CVD), and in 1988, this cluster of related abnormalities was designated as comprising a syndrome (X). Several other clinical syndromes are now known to be associated with insulin resistance and compensatory hyperinsulinemia. For example, polycystic ovary syndrome appears to be secondary to insulin resistance and compensatory hyperinsulinemia. More recently, studies have shown that the prevalence of insulin resistance/hyperinsulinemia is increased in patients with nonalcoholic fatty liver disease, and there are reports that certain forms of cancer are more likely to occur in insulin resistant/hyperinsulinemic persons. Finally, there is substantial evidence of an association between insulin resistance/hyperinsulinemia, and sleep disordered breathing. Given the rapid increase in the number of clinical syndromes and abnormalities associated with insulin resistance/hyperinsulinemia, it seems reasonable to suggest that the cluster of these changes related to the defect in insulin action be subsumed under the term of the insulin resistance syndrome. In addition to the identification of additional clinical syndromes related to insulin resistance/hyperinsulinemia, a number of new risk factors have been recognized that would increase CVD risk in these individuals. Thus, in addition to a high TG and a low HDL-C, the atherogenic lipoprotein profile in insulin resistant/hyperinsulinemic individuals also includes the appearance of smaller and denser low density lipoprotein particles, and the enhanced postprandial accumulation of remnant lipoproteins; changes identified as increasing risk of CVD. Elevated plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be associated with increased CVD, and there is evidence of a significant relationship between PAI-1 and fibrinogen levels and both insulin resistance and hyperinsulinemia. Evidence is also accumulating that sympathetic nervous system (SNS) activity is increased in insulin resistant, hyperinsulinemic individuals, and, along with the salt sensitivity associated with insulin resistance/hyperinsulinemia, increases the likelihood that these individuals will develop essential hypertension. The first step in the process of atherogenesis is the binding of mononuclear cells to the endothelium, and mononuclear cells isolated from insulin resistant/hyperinsulinemic individuals adhere with greater avidity. This process is modulated by adhesion molecules produced by endothelial cells, and there is a significant relationship between degree of insulin resistance and the plasma concentration of the several of these adhesion molecules. Further evidence of the relationship between insulin resistance and endothelial dysfunction is the finding that asymmetric dimethylarginine, an endogenous inhibitor of the enzyme nitric oxide synthase, is increased in insulin resistant/hyperinsulinemic individuals. Finally, plasma concentrations of several inflammatory markers are elevated in insulin resistant subjects. It is obvious that the cluster of abnormalities associated with insulin resistance and compensatory hyperinsulinemia contains many well-recognized CVD risk factors, choosing which one, or ones, that are primarily responsible for the accelerated atherogenesis that characterizes this syndrome is not a simple task. Indeed, efforts to try to do so by the use of multiple regression analysis of epidemiological data may be more misleading than helpful.
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PMID:Insulin resistance, the insulin resistance syndrome, and cardiovascular disease. 1648 19

Since the discovery of the hepatitis C virus (HCV) in 1989, attention has been paid to the association of chronic HCV infection and the development of diabetes. The risk factors for diabetes include older age, HCV genotype 3, severe liver fibrosis, family history of diabetes, and liver/kidney transplantation. Emerging evidence in animals and humans has shown that HCV infection induces hepatic steatosis and increases tumor necrosis factor-alpha level, both resulting in the development of insulin resistance and subsequent type 2 diabetes. It is suggested that the presence of diabetes and hepatic steatosis may enhance fibrosis progression, hepatocellular carcinoma, and atherosclerosis. Interferon is reportedly associated with improved glucose tolerance. However, interferon might enhance underlying autoimmunity against beta cells, leading to overt type 1 diabetes that is genetically predisposed or give rise to hyperglycemia, resulting in the development of type 2 diabetes. In light of the national epidemic of type 2 diabetes, the link between HCV and diabetes would be a major public health problem. Further clinical researches are awaited in order to effectively detect, prevent, and treat HCV-associated type 2 diabetes, which would also slow the progression of hepatitis C itself.
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PMID:Hepatitis C infection and diabetes. 1650 40

Researchers are only gradually becoming aware of the gravity of the risk that overweight and obesity pose for children's health. In this article Stephen Daniels documents the heavy toll that the obesity epidemic is taking on the health of the nation's children. He discusses both the immediate risks associated with childhood obesity and the longer-term risk that obese children and adolescents will become obese adults and suffer other health problems as a result. Daniels notes that many obesity-related health conditions once thought applicable only to adults are now being seen in children and with increasing frequency. Examples include high blood pressure, early symptoms of hardening of the arteries, type 2 diabetes, nonalcoholic fatty liver disease, polycystic ovary disorder, and disordered breathing during sleep. He systematically surveys the body's systems, showing how obesity in adulthood can damage each and how childhood obesity exacerbates the damage. He explains that obesity can harm the cardiovascular system and that being overweight during childhood can accelerate the development of heart disease. The processes that lead to a heart attack or stroke start in childhood and often take decades to progress to the point of overt disease. Obesity in childhood, adolescence, and young adulthood may accelerate these processes. Daniels shows how much the same generalization applies to other obesity-related disorders-metabolic, digestive, respiratory, skeletal, and psychosocial-that are appearing in children either for the first time or with greater severity or prevalence. Daniels notes that the possibility has even been raised that the increasing prevalence and severity of childhood obesity may reverse the modern era's steady increase in life expectancy, with today's youth on average living less healthy and ultimately shorter lives than their parents-the first such reversal in lifespan in modern history. Such a possibility, he concludes, makes obesity in children an issue of utmost public health concern.
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PMID:The consequences of childhood overweight and obesity. 1653 58

Steatosis is a common histological feature of chronic hepatitis C. Two distinct mechanisms seem to be involved in the pathogenesis of hepatic steatosis in chronic hepatitis C virus (HCV) infection. In HCV genotype 3-infected patients, steatosis is likely viral-induced, and represents a direct cytopathic effect of HCV, whereas in patients infected with other genotypes, host metabolic risk factors for insulin resistance such as obesity, type 2 diabetes and hyperlipidemia play a major role in intracellular lipids accumulation. Interestingly, the outcome of steatosis matches the virological response to treatment in HCV genotype 3-infected patients who have purely virus-induced steatosis but not in patients with metabolic causes of steatosis. Suspected molecular underlying mechanisms include interactions between the HCV core protein and intracellular lipid metabolism pathways as well as induction of insulin resistance. Steatosis is of clinical importance as it appears to be associated with more rapid liver fibrosis progression and impaired response to antiviral therapy. However, whether metabolic and host factors associated with steatosis, steatosis per se or both, may be responsible for this association remains to be clarified. This review is aimed at describing the current knowledge of steatosis, insulin resistance and fibrosis progression in chronic hepatitis C.
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PMID:Steatosis, insulin resistance and fibrosis progression in chronic hepatitis C. 1655 84


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