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)

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

Sterol regulatory element-binding proteins 1 and 2 (SREBP-1 and SREBP-2) are important regulators of genes involved in cholesterol and fatty acid metabolism, but have also been implicated in the regulation of the cell cycle and have been associated with the pathogenesis of type 2 diabetes, atherosclerosis and obesity, among others. In this study, we aimed to characterize the binding sites of SREBP-1 and RNA polymerase II through chromatin immunoprecipitation and microarray analysis in 1% of the human genome, as defined by the Encyclopaedia of DNA Elements consortium, in a hepatocellular carcinoma cell line (HepG2). Our data identified novel binding sites for SREBP-1 in genes directly or indirectly involved in cholesterol metabolism, e.g. apolipoprotein C-III (APOC3). The most interesting biological findings were the binding sites for SREBP-1 in genes for host cell factor C1 (HCFC1), involved in cell cycle regulation, and for filamin A (FLNA). For RNA polymerase II, we found binding sites at classical promoters, but also in intergenic and intragenic regions. Furthermore, we found evidence of sterol-regulated binding of SREBP-1 and RNA polymerase II to HCFC1 and FLNA. From the results of this work, we infer that SREBP-1 may be involved in processes other than lipid metabolism.
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PMID:Novel genes in cell cycle control and lipid metabolism with dynamically regulated binding sites for sterol regulatory element-binding protein 1 and RNA polymerase II in HepG2 cells detected by chromatin immunoprecipitation with microarray detection. 1929 68

Hepatitis C virus (HCV) is a major causative agent of blood-borne hepatitis. Most of the HCV-positive individuals have been chronically infected with the virus for decades, leading to development of steatosis, cirrhosis and ultimately hepatocellular carcinoma. In addition, cryoglobulinemia and type 2 diabetes mellitus are associated with a chronic infection with HCV. Hepatocellular carcinoma induced by HCV infection is not caused by only the repeated inflammations but also the biological activity of HCV proteins. HCV core protein has been reported as a component of the viral nucleocapsid as well as the pathogenic factor that could induce the production of oxidative stress and progression of cell growth. In this review, we summarize the current status of our knowledge regarding to the processing and pathogenicity of HCV core protein.
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PMID:[Processing and pathogenicity of HCV core protein]. 1937 96

In chronic hepatitis C, insulin resistance (IR) and type 2 diabetes mellitus (DM) are more prevalent than in healthy controls or in chronic hepatitis B patients. HCV infection promotes IR mainly through increased TNF-a and cytokine suppressor (SOCS-3) production. Both events inhibit insulin receptor and IRS-1 (insulin receptor substrate) tyrosine phosphorylation. Hepatic steatosis is also 2.5 fold more frequent in hepatitis C virus (HCV) infected patients as compared to the general population. Metabolic factors play a crucial role in the etiology of hepatic steatosis genotype non-3 related, which are also the genotypes with a greater association to IR. However, genotype 3, and particularly 3a, has a greater direct steatogenic capacity, and consequently, in those patients, the association with metabolic factors is weaker. Instead, in genotype 3, steatosis associates with viral factors like viral load. Those metabolic factors influence not only the natural history of HCV infection, as well as associate to an accelerated hepatic fibrosis progression, to a worse prognosis when hepatic cirrhosis is present, namely an increased risk of hepatocellular carcinoma, and to a lower sustained viral response rate. On the other hand, in patients who achieve viral eradication, IR and hepatic steatosis may regress, and return if viral infection recurs, which once again indicates an intrinsic steatosis and IR promoter action by HCV.
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PMID:Insulin resistance and steatosis in chronic hepatitis C. 1938 Nov 27

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, with approximately 70% of cases resulting from hepatitis B and C viral infections, aflatoxin exposure, chronic alcohol use or genetic liver diseases. The remaining approximately 30% of cases are associated with obesity, type 2 diabetes and related metabolic diseases, although a direct link between these pathologies and HCCs has not been established. We tested the long-term effects of high-fat and low-fat diets on males of two inbred strains of mice and discovered that C57BL/6J but not A/J males were susceptible to non-alcoholic steatohepatitis (NASH) and HCC on a high-fat but not low-fat diet. This strain-diet interaction represents an important model for genetically controlled, diet-induced HCC. Susceptible mice showed morphological characteristics of NASH (steatosis, hepatitis, fibrosis and cirrhosis), dysplasia and HCC. mRNA profiles of HCCs versus tumor-free liver showed involvement of two signaling networks, one centered on Myc and the other on NFkappaB, similar to signaling described for the two major classes of HCC in humans. miRNA profiles revealed dramatically increased expression of a cluster of miRNAs on the X chromosome without amplification of the chromosomal segment. A switch from high-fat to low-fat diet reversed these outcomes, with switched C57BL/6J males being lean rather than obese and without evidence for NASH or HCCs at the end of the study. A similar diet modification may have important implications for prevention of HCCs in humans.
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PMID:Diet-induced hepatocellular carcinoma in genetically predisposed mice. 1945 84

Plasma cell membrane glycoprotein-1, or ectonucleotide pyrophosphatase/phosphodieterase (PC-1/ENPP1) has been shown to inhibit insulin signaling in cultured cells in vitro and in transgenic mice in vivo when overexpressed. Furthermore, both genetic polymorphism and increased expression of PC-1 have been reported to be associated with type 2 diabetes in humans. Thus it was proposed that PC-1 inhibition represents a potential strategy for the treatment of type 2 diabetes. However, it has not been proven that suppression of PC-1 expression or inhibition of its function will actually improve insulin sensitivity. We show in the current study that transient overexpression of PC-1 inhibits insulin-stimulated insulin receptor tyrosine phosphorylation in HEK293 cells, while knockdown of PC-1 with siRNA significantly increases insulin-stimulated Akt phosphorylation in HuH7 human hepatoma cells. Adenoviral vector expressing a short hairpin RNA against mouse PC-1 (PC-1shRNA) was utilized to efficiently knockdown PC-1 expression in the livers of db/db mice. In comparison with db/db mice treated with a control virus, db/db mice treated with the PC-1shRNA adenovirus had approximately 80% lower hepatic PC-1 mRNA levels, approximately 30% lower ambient fed plasma glucose, approximately 25% lower fasting plasma glucose, and significantly improved oral glucose tolerance. Taken together, these results demonstrate that suppression of PC-1 expression improves insulin sensitivity in vitro and in an animal model of diabetes, supporting the proposition that PC-1 inhibition is a potential therapeutic approach for the treatment of type 2 diabetes.
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PMID:Suppression of PC-1/ENPP-1 expression improves insulin sensitivity in vitro and in vivo. 1957 57

The biguanide derivative metformin is a potent anti-diabetic drug widely used in the treatment of type 2 diabetes mellitus. Its major effect on glucose metabolism consists in the inhibition of hepatic glucose production. Since the mechanisms of metformin action are only partially understood at the molecular level, we studied the regulation of the gene promoter activity of glucose-6-phosphatase (G6Pase), the central hepatic gluconeogenic enzyme, by this drug. We have found that both metformin and insulin inhibit the basal and dexamethasone/cAMP-stimulated G6Pase promoter activity in hepatoma cells. Since one of the pharmacological targets of metformin is AMP-activated protein kinase (AMPK) and activation of AMPK is known to inhibit hepatic glucose production by the suppression of G6Pase gene transcription, we studied the effect of AMPK in this context. Under nonstimulated conditions, the inhibitory effect of both insulin and metformin was partially counteracted to a similar extent by treatment with compound C, a specific inhibitor of AMPK. In contrast, under conditions of stimulation with dexamethasone and cAMP, treatment with compound C reversed the inhibitory effect of metformin on G6Pase promoter activity to a similar extent as compared to nonstimulated conditions, whereas the effect of insulin was almost resistant to treatment with the AMPK-antagonist. These data indicate a differential AMPK-dependent regulation of G6Pase gene expression by insulin and metformin under basal and dexamethasone/cAMP-stimulated conditions.
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PMID:Regulation of glucose-6-phosphatase gene expression by insulin and metformin. 1957 80

Metformin is widely used as a hypoglycemic agent for the treatment of type 2 diabetes. Both metformin and rotenone, an inhibitor of respiratory chain complex I, suppressed glucose-6-phosphatase (G6pc), a rate limiting enzyme of liver glucose production, mRNA expression in a rat hepatoma cell line accompanied by a reduction of intracellular ATP concentration and an activation of AMP-activated protein kinase (AMPK). When yeast NADH-quinone oxidoreductase 1 (NDI1) gene was introduced into the cells, neither inhibition of ATP synthesis nor activation of AMPK was induced by these agents. Interestingly, in contrast to rotenone treatment, G6pc mRNA down-regulation was observed in the NDI1 expressing cells after metformin treatment. Since NDI1 can functionally complement the complex I under the presence of metformin or rotenone, our results indicate that metformin induces down-regulation of G6pc expression through an inhibition of complex I and an activation of AMPK-independent mechanism.
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PMID:Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism. 1966 96

Patients (85%) with hepatocellular adenoma (HCA) are women taking oral contraceptives. They can be divided into four subgroups according to their genotype/phenotype features. (1) Hepatocyte nuclear factor 1alpha (HNF1alpha) biallelic somatic mutations are observed in 35% of the HCA cases. It occurs in almost all cases in women. HNF1alpha-mutated HCA are most of the time, highly steatotic, with a lack of expression of liver fatty acid binding protein (LFABP) in immunohistochemistry analyses. Adenomatosis is frequently detected in this context. An HNF1alpha germline mutation is observed in less than 5% of HCA cases and can be associated with MODY 3 diabetes. (2) An activating beta-catenin mutation was found in 10% of HCA. These beta-catenin activated HCAs are observed in men and women, and specific risk factors, such as male hormone administration or glycogenosis, are associated with their development. Immunohistochemistry studies show that these HCAs overexpress beta-catenin (nuclear and cytoplasmic) and glutamine synthetase. This group of tumours has a higher risk of malignant transformation into hepatocellular carcinoma. (3) Inflammatory HCAs are observed in 40% of the cases, and they are most frequent in women but are also found in men. Lesions are characterised by inflammatory infiltrates, dystrophic arteries, sinusoidal dilatation and ductular reaction. They express serum amyloid A and C-reactive protein. In this group, GGT is frequently elevated, with a biological inflammatory syndrome present. Also, there are more overweight patients in this group. An additional 10% of inflammatory HCAs express beta-catenin, and are also at risk of malignant transformation. (4) Currently, less than 10% of HCAs are unclassified. It is hoped that in the near future it will be possible with clinical, biological and imaging data to predict in which of the 2 major groups (HNF1alpha-mutated HCA and inflammatory HCA) the patient belongs and to propose better guidelines in terms of surveillance and treatment.
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PMID:Hepatocellular adenoma: what is new in 2008. 1966 72

Metabolic syndrome (MS) is one of the most prevalent disease states in the so-called developed countries and is closely associated with the incidence of cardiovascular as well as other diseases. Predominant sign is the abdominal type of obesity with increased visceral fat mass and the associated insulin resistance. Glucose metabolism disorder, dyslipidemia and arterial hypertension are other important attributes. Metabolic syndrome is also closely associated with the liver steatosis, mostly benign and reversible liver disease. Nevertheless, uncomplicated steatosis may, under certain conditions, progress to inflammation and the disease may, through the stage of NASH (nonalcoholic steatohepatitis) and liver fibrosis, result in liver cirrhosis and hepatocellular carcinoma. Anglo-Saxon literature uses the term NAFLD (non-alcoholic fatty liver disease) to refer to these various stages ofthe liver disease (uncomplicated liver steatosis, steatohepatitis, fibrosis and cirrhosis). While simple steatosis is not dangerous for the patient, NASH is the sign of developing cirrhosis. Etiopathogenesis of NASH features identical characteristics as etiopathogenesis of insulin resistance and metabolic syndrome. Even though liver biopsy remains the gold standard in the diagnosis, new diagnostic approaches are emerging that could be useful in distinguishing simple steatosis from NASH. Therapy includes lifestyle changes, insulin resistance-reducing medication (also useful in the treatment of type 2 diabetes) with a range of other agents under development. In the meantime, randomized double-blind placebo-controlled studies with histological proof of the results are still lacking. A range of unresolved issues remains with regards to etiopathogenesis as well as diagnosis and treatment of NAFLD and NASH.
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PMID:[Metabolic syndrome and the liver (NAFLD/NASH)]. 1973 69


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