Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-alcoholic fatty liver disease (NAFLD) represents a wide spectrum of diseases, ranging from simple fatty liver (hepatic steatosis) through steatosis with inflammation and necrosis to cirrhosis. NAFLD, which is strongly associated with obesity, insulin resistance and type 2 diabetes, is now well recognized as being part of the metabolic syndrome. The metabolic pathways leading to the development of hepatic steatosis are multiple, including enhanced non-esterified fatty acid release from adipose tissue (lipolysis), increased de novo fatty acids (lipogenesis) and decreased beta-oxidation. Recently, several mouse models have helped to clarify the molecular mechanisms leading to the development of hepatic steatosis in the pathogenesis of NAFLD. This review describes the models that have provided evidence implicating lipogenesis in the development and/or prevention of hepatic steatosis.
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PMID:The role of the lipogenic pathway in the development of hepatic steatosis. 1919 25

The prognosis and management of liver disease greatly depends on the amount of liver fibrosis. Non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), is emerging as a major cause of liver disease in Western countries because of the increasing prevalence of obesity and type 2 diabetes. A key issue in patients with NAFLD is the differentiation of NASH from simple steatosis. It is particularly important to identify NASH patients as they are at greatest risk of developing complications such as cirrhosis, liver failure and hepatocellular carcinoma. The limitations of liver biopsy (invasive procedure, sampling errors, interobserver variability and non-dynamic fibrosis evaluation) have stimulated the search for non-invasive approaches for the assessment of steatosis and liver fibrosis in patients with NAFLD. A variety of methods, including serum markers, imaging techniques such as ultrasound, CT, MRI and measurement of liver stiffness by transient elastography, have been proposed for the non-invasive assessment of steatosis and hepatic fibrosis. This review discusses the advantages and limitations of these different methods in clinical practice.
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PMID:Non-invasive diagnosis of steatosis and fibrosis. 1919 29

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and insulin resistance. It is also a predisposing factor for type 2 diabetes. Dietary factors are believed to contribute to all three diseases. NAFLD is characterized by increased intrahepatic fat and mitochondrial dysfunction, and its etiology may be attributed to excessive fructose intake. Consumption of high fructose corn syrup-55 (HFCS-55) stands at up to 15% of the average total daily energy intake in the United States, and is linked to weight gain and obesity. The aim of this study was to establish whether HFCS-55 could contribute to the pathogenesis of NAFLD, by examining the effects of HFCS-55 on hepatocyte lipogenesis, insulin signaling, and cellular function, in vitro and in vivo. Exposure of hepatocytes to HFCS-55 caused a significant increase in hepatocellular triglyceride (TG) and lipogenic proteins. Basal production of reactive oxygen metabolite (ROM) was increased, together with a decreased capacity to respond to an oxidative challenge. HFCS-55 induced a downregulation of the insulin signaling pathway, as indicated by attenuated (ser473)phosphorylation of AKT1. The c-Jun amino-terminal kinase (JNK), which is intimately linked to insulin resistance, was also activated; and this was accompanied by an increase in endoplasmic reticulum (ER) stress and intracellular free calcium perturbation. Hepatocytes exposed to HFCS-55 exhibited mitochondrial dysfunction and released cytochrome C (CytC) into the cytosol. Hepatic steatosis and mitochondrial disruption was induced in vivo by a diet enriched with 20% HFCS 55; accompanied by hypoadiponectinemia and elevated fasting serum insulin and retinol-binding protein-4 (RBP4) levels. Taken together our findings indicate a potential mechanism by which HFCS-55 may contribute to the pathogenesis of NAFLD.
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PMID:Diabetes of the liver: the link between nonalcoholic fatty liver disease and HFCS-55. 1928 20

Nonalcoholic fatty liver disease is the most common chronic liver disease in industrialized countries and is considered the hepatic manifestation of metabolic syndrome. Apart from correction of underlying metabolic abnormalities, restriction of caloric intake, and physical exercise, no drugs have been licensed for the treatment of nonalcoholic fatty liver disease. Of note, reduced caloric intake and exercise with resultant weight loss may lead to a reduction in liver fat content, but no studies have shown long-term benefits of this. Dipeptidyl peptidase IV inhibitors are promising new oral drugs for the treatment of type 2 diabetes. Here, we hypothesize that dipeptidyl peptidase IV inhibitors can reduce fat infiltration in the liver and thus be a potential treatment for nonalcoholic fatty liver disease. There are 3 lines of evidence supporting this hypothesis. First, dipeptidyl peptidase IV inhibitors are known to improve insulin resistance, a key metabolic abnormality encountered by patients with nonalcoholic fatty liver disease. Second, patients with nonalcoholic steatohepatitis have increased dipeptidyl peptidase IV activity, which has been found to correlate positively with the histopathologic grade and degree of liver steatosis. Finally, data from experimental studies suggest that dipeptidyl peptidase IV inhibitors can reduce liver inflammation and steatosis. In light of these findings, we propose that pharmacologic inhibition of dipeptidyl peptidase IV may provide a new therapeutic option for slowing the progression of nonalcoholic fatty liver disease. Future research is expected to support the efficacy and tolerability of dipeptidyl peptidase IV modulation in early liver steatosis.<br />
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PMID:Dipeptidyl peptidase IV inhibitors: therapeutic potential in nonalcoholic fatty liver disease. 1933 9

Non-alcoholic fatty liver disease or NAFLD is a chronic liver condition characterized by hepatic steatosis and associated with insulin resistance and type 2 diabetes mellitus (T2DM). In many patients fat accumulation leads to steatohepatitis (NASH) with chronic necrosis, inflammation, and fibrosis, and eventually to the development of cirrhosis. Obese and T2DM patients are at the greatest risk for NASH and progressive disease. New diagnostic techniques, such as magnetic resonance imaging and spectroscopy (MRS), have enhanced our way to non-invasively quantify liver fat and suggest that the epidemic of NAFLD is much larger than previously believed. However, the diagnosis of NAFLD for clinicians remains difficult due to a number of factors: limited awareness, non-specific symptoms, few laboratory findings, and the need for a liver biopsy to confirm the diagnosis. Traditional treatment approaches have centered on weight loss, but data are limited on its long-term efficacy, and the overall compliance is poor. Recently, pioglitazone has been shown to be safe and effective in patients with NASH and may radically change our approach to the disease. Still, many aspects remain poorly understood. Taken together, wider use of new diagnostic methods and treatment approaches appears to signal the dawn of a new era in the management of NAFLD.
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PMID:New diagnostic and treatment approaches in non-alcoholic fatty liver disease (NAFLD). 1935 60

Non-alcoholic fatty liver disease (NAFLD), defined as excessive fat accumulation into the hepatocytes, has a prevalence of approximately 15 to 25%. Frequently associated risk factors for NAFLD are obesity, type 2 diabetes and dyslipidemia. It has been proponed that a mitochondrial dysfunction would play a crucial role in the disease development.On the other hand, focus is on insulin resistance syndrome, the only metabolic alteration strongly associated with this malady. The disease is suspected in individuals with insulina resistance characteristics such as metabolic syndrome and also in those with augmented serum aminotransferases levels. Different tests with biochemical markers have been proposed to predict the development of fibrosis or steatohepatitis. Therapeutic options in NAFLD patients are limited and weight lost remains as the most recommended one.
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PMID:[Non alcoholic fatty liver. A frequent entity with an unknown outcome]. 1942 8

Non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C virus (HCV) infection are major causes of liver disease frequently described in outpatient patients with glucose abnormalities. Hyperferritinemia, which suggests that iron overload plays a decisive role in the pathophysiology of insulin resistance and hyperglycemia, is a common finding in both disorders. However, the role of the hepatic iron deposition differs from one to the other. In NAFLD, a moderate liver iron accumulation has been observed and molecular mechanisms, including the downregulation of the liver iron exporter ferroportin-1, have been described. Iron overload will enhance intrahepatic oxidative stress that promotes hepatic fibrosis, interfere with insulin signalling at various levels and may hamper hepatic insulin extraction. Therefore, liver fibrosis, hyperglycemia and hyperinsulinemia will lead to increased levels of insulin resistance and the development of glucose abnormalities. Furthermore, iron depletion by phlebotomy removes liver iron content and reduces serum glucose and insulin resistance in NAFLD patients. Therefore, it seems that iron overload participates in those glucose abnormalities associated with NAFLD. Concerning chronic HCV infection, it has been classically assumed that iron overload contributes to insulin resistance associated with virus infection. However, recent evidence argues against the presence of iron overload in these patients and points to inflammation associated with diabetes as the main contributor to the elevated ferritin levels. Therefore, glucose abnormalities, and specially type 2 diabetes, should be taken into account when evaluating serum ferritin levels in patients with HCV infection.
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PMID:Glucose abnormalities in non-alcoholic fatty liver disease and chronic hepatitis C virus infection: the role of iron overload. 1944 65

Nonalcoholic fatty liver disease (NAFLD), first described in 1980, is now recognized as one of the most common causes of elevated liver enzymes and chronic liver disease in Western countries. The incidence of NAFLD in both adults and children is rising, in conjunction with the burgeoning epidemics of obesity and type 2 diabetes mellitus. NAFLD often coexists with other sequelae of the metabolic syndrome: central obesity, type 2 diabetes, hypertension, and hyperlipidemia. NAFLD encompasses a spectrum of pathologic liver diseases ranging from simple hepatic steatosis to a predominant lobular necro-inflammation, with or without centrilobular fibrosis (called nonalcoholic steatohepatitis or NASH). NASH can progress to cirrhosis, decompensated liver disease, and hepatocellular carcinoma. Though the natural history of NASH is still not clearly defined, it has been observed to progress to cirrhosis in 15%-220% of those affected. Insulin resistance is nearly universal in NASH and is thought to play an important role in its pathogenesis leading to dysregulated lipid metabolism. The prevalence of insulin resistance is reported in the general population to be approaching 45%, suggesting that NAFLD and NASH will contin nue to be an important public health concern. To date, NASH has proven to be a difficult disease to treat. Front-line therapy with lifestyle modifications resulting in weight loss through decreased caloric intake and moderate exercise is generally believed to be beneficial in patients with NASH, but is often difficult to maintain long term. Given that insulin resistance plays a dominant role in the pathogenesis, many studies have examined the use of insulin sensitizers: the biguanides (metformin), thiazolidinediones (pioglitazone, troglitazone, and rosiglitazone), glucagon-like peptide-1-receptor agonists, or incretins (exenatide)in NASH. This review will provide an overview of insulin resistance in NAFLD and provide a detailed summary on the clinical data regarding the use of insulin sensitizers in NASH.
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PMID:Insulin sensitizers in nonalcoholic fatty liver disease and steatohepatitis: Current status. 1992 Nov 18

Mean platelet volume (MPV) is an indicator of platelet activation. Platelet activation and aggregation are central processes in the pathophysiology of coronary heart disease. Non-alcoholic fatty liver disease (NAFLD) is present up to one-third of the general population and the majority of patients with cardio-metabolic risk factors such as abdominal obesity, type 2 diabetes and other components of the metabolic syndrome (MS). The aim of the current study was to investigate the MPV in patients who had NAFLD. MPV values of the patients with NAFLD and of the patients without fatty liver disease were compared. NAFLD patients had significantly higher body mass index compared to the control cases. Among biochemical variables, fasting plasma glucose and triglyceride were significantly higher in the NAFLD group. NAFLD cases also had lower platelet count and higher MPV (10.43 +/- 1.14 vs. 9.09 +/- 1.25; p < 0.001, respectively). MPV was positively correlated with AST (r: 0.186, p < 0.042), ALT level (r: 0.279; p 0.002) and the presence of NAFLD (0.492; p < 0.001) but negatively correlated with platelet number (r: -0.26; p 0.004) and creatinine (r: -0.255; p 0.005). In logistic regression analysis (age, gender, NAFLD, body mass index, high-density lipid (HDL) cholesterol, systolic and diastolic blood pressure, triglyceride and fasting plasma glucose were used as covariates) only NAFLD was found to be the independent predictor of MPV (Odds Ratio (OR) 21.98) [95% confidence interval (CI): 2.404-201.048; p: 0.006]. We have shown for the first time in the literature that, patients with NAFLD have higher MPV. It may have prognostic value in NAFLD patients indicating a possible cardiovascular disease (CVD) risk increase.
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PMID:Mean platelet volume in patients with non-alcoholic fatty liver disease. 2114 6

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease, and is commonly observed in patients with obesity or type 2 diabetes. The pathogenesis of hepatic fibrosis is clinically important to the outcome of NAFLD, however, is not well understood. Since dietary habits are often considered to be responsible for NAFLD, we used a synthetic diet rich in disaccharides (12.1% calorie sucrose and lactose), which can be considered for human consumption. We examined the long-term (24 weeks) effect of this diet on the liver of Zucker (fa/fa) rats. The synthetic diet-fed Zucker (fa/fa) rats showed hepatic fibrosis during the development of NAFLD with no apparent infiltration of inflammatory cells. They showed significantly elevated hepatic mRNA levels of proinflammatory and profibrogenic cytokines. These findings suggest that excess long-term feeding of a diet similar to the synthetic diet used in our study leads to hepatic fibrosis during the development of NAFLD in patients with obesity or type 2 diabetes. Our results were different from NAFLD accompanied by infiltration of inflammatory cells. However, they also suggest that long-term feeding of this synthetic diet to Zucker (fa/fa) rats is useful for studying the hepatic fibrogenesis during the pathogenesis of NAFLD.
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PMID:Long-term feeding of a synthetic diet rich in disaccharides induces hepatic fibrosis in nonalcoholic fatty liver disease in Zucker rats. 2004 26


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