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)

It is now widely recognized that chronic hepatitis C (CHC) is associated with insulin resistance (IR) and type 2 diabetes, so can be considered a metabolic disease. IR is most strongly associated with hepatitis C virus (HCV) genotype 1, in contrast to hepatic steatosis, which is associated with genotype 3 infection. Apart from the well-described complications of diabetes, IR in CHC predicts faster progression to fibrosis and cirrhosis that may culminate in liver failure and hepatocellular carcinoma. More recently, it has been recognized that IR in CHC predicts a poor response to antiviral therapy. The molecular mechanisms for the association between IR and HCV infection are not well defined. This review will elaborate on the clinical associations between CHC and IR and summarize current knowledge regarding the molecular mechanisms that potentially mediate HCV-associated IR.
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PMID:Molecular mechanisms of insulin resistance in chronic hepatitis C. 1976 85

Sex hormone-binding globulin (SHBG) is the main transport binding protein for sex steroid hormones in plasma and regulates their accessibility to target cells. Plasma SHBG is secreted by the liver under the control of hormones and nutritional factors. In the human hepatoma cell line (HepG2), thyroid and estrogenic hormones, and a variety of drugs including the antioestrogen tamoxifen, the phytoestrogen, genistein and mitotane (Op'DDD) increase SHBG production and SHBG gene promoter activity. In contrast, monosaccharides (glucose or fructose) effectively decrease SHBG expression by inducing lipogenesis, which reduces hepatic HNF-4alpha levels, a transcription factor that play a critical role in controlling the SHBG promoter. Interestingly, diminishing hepatic lipogenesis and free fatty acid liver biosynthesis also appear to be associated with the positive effects of thyroid hormones and PPARgamma antagonists on SHBG expression. This mechanism provides a biological explanation for why SHBG is a sensitive biomarker of insulin resistance and the metabolic syndrome, and why low plasma SHBG levels are a risk factor for developing hyperglycemia and type 2 diabetes, especially in women. These important advances in our knowledge of the regulation of SHBG expression in the liver open new approaches for identifying and preventing metabolic disorder-associated diseases early in life.
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PMID:Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome. 1978 70

Insulin resistance and dyslipidemia are both considered to be risk factors for metabolic syndrome. Low levels of IGF1 are associated with insulin resistance. Elevation of low-density lipoprotein cholesterol (LDL-C) concomitant with depression of high-density lipoprotein cholesterol (HDL-C) increase the risk of obesity and type 2 diabetes mellitus (T2DM). Liver secretes IGF1 and catabolizes cholesterol regulated by the rate-limiting enzyme of bile acid synthesis from cholesterol 7alpha-hydroxylase (CYP7A1). NO-1886, a chemically synthesized lipoprotein lipase activator, suppresses diet-induced insulin resistance with the improvement of HDL-C. The goal of the present study is to evaluate whether NO-1886 upregulates IGF1 and CYP7A1 to benefit glucose and cholesterol metabolism. By using human hepatoma cell lines (HepG2 cells) as an in vitro model, we found that NO-1886 promoted IGF1 secretion and CYP7A1 expression through the activation of signal transducer and activator of transcription 5 (STAT5). Pretreatment of cells with AG 490, the inhibitor of STAT pathway, completely abolished NO-1886-induced IGF1 secretion and CYP7A1 expression. Studies performed in Chinese Bama minipigs pointed out an augmentation of plasma IGF1 elicited by a single dose administration of NO-1886. Long-term supplementation with NO-1886 recovered hyperinsulinemia and low plasma levels of IGF1 suppressed LDL-C and facilitated reverse cholesterol transport by decreasing hepatic cholesterol accumulation through increasing CYP7A1 expression in high-fat/high-sucrose/high-cholesterol diet minipigs. These findings indicate that NO-1886 upregulates IGF1 secretion and CYP7A1 expression to improve insulin resistance and hepatic cholesterol accumulation, which may represent an alternative therapeutic avenue of NO-1886 for T2DM and metabolic syndrome.
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PMID:NO-1886 suppresses diet-induced insulin resistance and cholesterol accumulation through STAT5-dependent upregulation of IGF1 and CYP7A1. 1981 88

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

Hepatocellular carcinoma (HCC) is a common form of cancer that arises from hepatocytes and whose risk may be affected by several known environmental factors, including hepatitis viruses, alcohol, cigarette smoking, and others. Rare monogenic syndromes, such as alpha1-antitrypsin deficiency, glycogen storage disease type I, hemochromatosis, acute intermittent and cutanea tarda porphyria, as well as hereditary tyrosinemia type I are associated with a high risk of HCC. Several common conditions or diseases inherited as polygenic traits e.g. autoimmune hepatitis, type 2 diabetes, a family history of HCC, hypothyroidism, and non-alcoholic steatohepatitis also show an increased risk of HCC compared to the general population. Overall, the genetic susceptibility to HCC is characterized by a genetic heterogeneity; a high individual risk of HCC may thus be caused by several unlinked single gene defects, whose carriers are rare in the general population, or by more common conditions inherited by complex genetics.
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PMID:Risk of HCC: genetic heterogeneity and complex genetics. 2002 54

Abstract Epidemiological data clearly indicate a link between chronic hepatitis C (CHC) and disturbed glucose homeostasis. The prevalences of both type 2 diabetes mellitus (T2DM) and insulin resistance (IR) are higher among those chronically infected with hepatitis C when compared with the general population and those with other causes of chronic liver disease. Both IR and diabetes are associated with adverse outcomes across all stages of CHC including the liver transplant population. The adverse effects that directly influence patient outcome are reduced responsiveness to antiviral therapy, more rapid progression of fibrosis to cirrhosis and a higher incidence of hepatocellular carcinoma. Although both viral and host factors are known to contribute to IR (and therefore the risk of T2DM), there is a paucity of evidence to support interventions targeting IR with pharmacotherapy or lifestyle intervention. The purpose of this review is to examine the impact of abnormalities of glucose homeostasis in CHC, and in so doing, to raise a number of questions. How do we identify those at risk of diabetes in CHC? Can we reduce the incidence of hepatoma and reduce transplant-related morbidity and mortality by preventing or treating diabetes? Can we improve the response to antiviral therapy by pretreating IR and T2DM in treatment candidates? Ultimately, can we cure two diseases, diabetes and CHC, with one treatment?
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PMID:Hepatitis C and diabetes: one treatment for two diseases? 2004 49

Non-alcoholic fatty liver represents one of the most prevalent conditions affecting about one third of the general population in the Western world, and its prevalence is continuously increasing parallel to the epidemics of obesity. Non-alcoholic fatty liver is a strong predictor of non-alcoholic steatohepatitis, but also of cirrhosis, end-stage liver disease and hepatocellular carcinoma. In recent years, non-alcoholic fatty liver (in addition to overall and visceral obesity) has emerged as a risk factor for insulin resistance, hypertension, dyslipidemia, cardiovascular events and type 2 diabetes. This review summarizes the information currently available about the mechanisms involved in liver fat accumulation (e.g. hepatic lipid supply, de novo lipogenesis, lipid oxidation and the packaging and secretion of triglycerides in the form of very-low-density lipoproteins). New aspects concerning mechanisms potentially leading to a 'dissociation' of fatty liver and insulin resistance are also discussed. Understanding the pathogenesis of fatty liver and its complications, including the identification of new factors secreted from the liver under excess fat accumulation that are involved in the regulation of metabolism ('hepatokines'), is crucial in order to develop and implement efficient prevention and treatment strategies.
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PMID:Environmental and genetic determinants of fatty liver in humans. 2046 Sep 7

Over the last few years, the paradigm in hepatology has changed from focusing on a single liver disease to considering concurrent diseases, in particular obesity and related metabolic factors. Obesity has reached epidemic proportions globally and is associated with insulin resistance, steatosis and a low-grade systemic inflammatory state. These metabolic factors have a synergistic role in the natural history and treatment outcomes related to chronic liver disease. This is characterized best in chronic hepatitis C where steatosis and insulin resistance are caused by viral and metabolic effects. Non-alcoholic fatty liver disease and related metabolic abnormalities also exacerbate other diseases, such as alcoholic liver disease and haemochromatosis. In addition, there is growing evidence linking obesity and type 2 diabetes with hepatocellular carcinoma in subjects with chronic viral hepatitis. The pathogenesis of co-morbid disease may be related to increased oxidative stress, inflammatory injury and cell death, along with altered hepatocyte regeneration and repair. Hyperinsulinaemia and other metabolic factors may also have a direct role in the progression of liver injury. Data indicate that weight reduction improves steatosis and inflammation in patients with chronic hepatitis C. This has important clinical and therapeutic implications and suggests that obesity should be actively addressed in the management of patients with other chronic liver diseases.
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PMID:Metabolic factors and non-alcoholic fatty liver disease as co-factors in other liver diseases. 2046 Sep 9

Insulin resistance is a characteristic of type 2 diabetes and is a major independent risk factor for progression to the disease. In particular, insulin resistance associates with increased body fat and almost certainly contributes to the dramatic increase in risk of type 2 diabetes associated with obesity. Therefore, in order to design truly effective insulin sensitising agents, targeted at the mechanism of disease development, we aimed to generate an obesity-related insulin resistant cell model. Rat hepatoma cells were grown in the presence of serum isolated from obese rodents or obese human volunteers, and the insulin sensitivity of the cells monitored over time by measuring a well-characterised insulin regulated gene promoter. Higher insulin concentrations were required to fully repress the gene in the cells grown in obese rodent serum compared with those grown in serum from lean rodents (almost a 10-fold shift in insulin sensitivity). This was reversed by restoration of normal growth medium, while the insulin resistance was prevented by pioglitazone or metformin. Meanwhile, growth of cells in serum collected from obese human volunteers with diabetes also reduced the insulin sensitivity of the rat cells. No clinical marker predicted the degree of insulin resistance that was generated by the human serum. We have developed a novel insulin resistant cell model for the study of the molecular development of obesity-linked insulin resistance, screen for compounds to overcome obesity-related insulin resistance and potentially search for novel serum biomarkers of insulin resistance.
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PMID:Generation, validation and humanisation of a novel insulin resistant cell model. 2059 91

Type 2 diabetes mellitus (DM2) has been associated with hepatocellular carcinoma (HCC) development. To study this relationship, we enrolled 465 HCC patients compared with 618 Cirrhotic cases and 490 Controls. The prevalence of DM2 is significantly higher in HCC patients with an Odds Ratio of 3.12 versus Controls. In HCC cases with alcohol abuse, the frequency of DM2 is the highest. In our HCC patients, when HCV infection is associated with alcohol abuse, the liver cancer develops earlier. In addition, multivariate analysis shows that alcohol consumption is an independent risk factor for HCC more relevant than HCV infection.
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PMID:Alcohol and HCV chronic infection are risk cofactors of type 2 diabetes mellitus for hepatocellular carcinoma in Italy. 2061 35


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