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)

In type 2 diabetes, impaired insulin signaling leads to hyperglycemia and other metabolic abnormalities. To study a new class of antidiabetic agents, we compared two small, nonpeptide molecules that activate insulin receptor (IR) beta-subunit tyrosine kinase activity: Merck L7, a direct IR agonist, and Telik's TLK16998, an IR sensitizer. In rat hepatoma cells (HTCs) that overexpress the IR (HTC-IR), IR autophosphorylation was directly activated by L7 in the absence of insulin. TLK16998 did not directly activate IR autophosphorylation, but it enhanced IR autophosphorylation in the presence of insulin. Tyrosine phosphorylation of an endogenous 185-kDa IR substrate was also significantly enhanced by both Merck L7 alone and TLK16998 plus insulin. Adding TLK16998 to L7 produced synergistic effects, further indicating that these two compounds act on the IR through separate mechanisms. We next studied HTC-IR(Delta485-599) cells, which overexpress a mutant IR with a deletion in the alpha-subunit connecting domain that does not undergo autophosphorylation in response to insulin binding. L7 was able to directly activate autophosphorylation of the deletion mutant IR in these cells, whereas TLK16998 had no effect. Compounds were then tested in three other cell models of impaired IR function. Both TLK16998 and Merck L7 improved IR autophosphorylation in cells with diminished IR signaling due to either treatment with tumor necrosis factor-alpha or overexpression of membrane glycoprotein PC-1. However, in TPA (tetradecanoylphorbol acetate)-treated cells, TLK16998 but not Merck L7 was able to significantly reverse the impaired insulin-stimulated IR autophosphorylation. In summary, these two classes of IR activators selectively increased IR function in a variety of insulin-resistant cell lines.
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PMID:Small molecule insulin receptor activators potentiate insulin action in insulin-resistant cells. 1157 15

Type 2 diabetes mellitus, which affects approximately 7% of the population, is a disease of relative insulin insufficiency manifested by insulin resistance in skeletal muscle, liver and adipose tissue. This results in increased hepatic glucose production with compensatory hyperinsulinaemia. The secondary hyperinsulinaemia is associated with an increased incidence of hepatocellular carcinoma and non-alcoholic steatohepatitis (NASH). It is estimated that insulin resistance is present in 50-70% of patients with NASH and that the incidence of NASH in type 2 diabetes is 60-80%. The prevalence of cirrhosis in established type 2 diabetes is as high as 10% and the prevalence of hepatitis C is 3-11%. It was in this setting that the insulin sensitisers were developed. The thiazolidinediones represent a significant and unique pharmacological breakthrough for the management of type 2 diabetes mellitus. The first of the drugs, troglitazone, proved to be hepatotoxic and has been withdrawn from the market. Two cases of hepatotoxicity of rosiglitazone have been reported. It remains unclear whether or not hepatotoxicity is a class effect or is related to the unique tocopherol side chain of troglitazone. However, it appears that the incidence of hepatotoxicity of rosiglitazone is much lower than that of troglitazone. It is not yet known if any hepatotoxicity occurs with pioglitazone.
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PMID:Thiazolidinedione hepatotoxicity: a class effect? 1196 28

Mutations in the HNF4alpha gene have been correlated with maturity-onset diabetes of the young, which is characterized mainly by pancreatic beta-cell dysfunction and is also associated with mild liver abnormalities. HNF4alpha D126Y and D126H mutations were found in a patient with early-onset type 2 diabetes, and the R324H mutation was found in a common type 2 diabetic nephropathic patient. We investigated whether these mutations, which have not yet been functionally characterized, impair HNF4alpha function in three cell models: HEK 293 embryonal kidney cells, HepG2 hepatoma cells, and betaTC3 pancreatic beta-cells. The R324H mutation had no effect on HNF4alpha function with either the HNF1alpha and L-type pyruvate kinase (LPK) promoters, but the D126Y and D126H mutations impaired HNF4alpha transcriptional activities in all tested cell lines. These impairments by D126Y and D126H mutations, which are located in the T box, are not due to a loss of dimerization but to a loss of DNA binding. Interestingly, the strongest functional consequences of these mutations were observed on the HNF1alpha promoter in betaTC3 cells. Given the key role of the transcription factor HNF1alpha in pancreatic beta-cell function, it can be inferred that impairment of HNF4alpha function by these mutations affects metabolic pathways in pancreatic beta-cells and contributes to development of diabetes. Moreover, the HNF4alpha-mediated activation of the apolipoprotein CIII promoter in HepG2 cells was significantly impaired by D126Y and D126H mutations. These results support clinical findings that liver function can also be impaired in diabetic patients having HNF4alpha mutations.
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PMID:Mutations in hepatocyte nuclear factor 4alpha (HNF4alpha) gene associated with diabetes result in greater loss of HNF4alpha function in pancreatic beta-cells than in nonpancreatic beta-cells and in reduced activation of the apolipoprotein CIII promoter in hepatic cells. 1211 Sep 48

Interleukin (IL)-6 is one of several proinflammatory cytokines that have been associated with insulin resistance and type 2 diabetes. A two- to threefold elevation of circulating IL-6 has been observed in these conditions. Nonetheless, little evidence supports a direct role for IL-6 in mediating insulin resistance. Here, we present data that IL-6 can inhibit insulin receptor (IR) signal transduction and insulin action in both primary mouse hepatocytes and the human hepatocarcinoma cell line, HepG2. This inhibition depends on duration of IL-6 exposure, with a maximum effect at 1-1.5 h of pretreatment with IL-6 in both HepG2 cells and primary hepatocytes. The IL-6 effect is characterized by a decreased tyrosine phosphorylation of IR substrate (IRS)-1 and decreased association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 in response to physiologic insulin levels. In addition, insulin-dependent activation of Akt, important in mediating insulin's downstream metabolic actions, is markedly inhibited by IL-6 treatment. Finally, a 1.5-h preincubation of primary hepatocytes with IL-6 inhibits insulin-induced glycogen synthesis by 75%. These data suggest that IL-6 plays a direct role in insulin resistance at the cellular level in both primary hepatocytes and HepG2 cell lines and may contribute to insulin resistance and type 2 diabetes.
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PMID:Interleukin-6 induces cellular insulin resistance in hepatocytes. 1245 91

Increased hepatic glucose output and decreased glucose utilization are implicated in the development of type 2 diabetes. We previously reported that the expression of a novel gene, Tanis, was upregulated in the liver during fasting in the obese/diabetic animal model Psammomys obesus. Here, we have further studied the protein and its function. Cell fractionation indicated that Tanis was localized in the plasma membrane and microsomes but not in the nucleus, mitochondria, or soluble protein fraction. Consistent with previous gene expression data, hepatic Tanis protein levels increased more significantly in diabetic P. obesus than in nondiabetic controls after fasting. We used a recombinant adenovirus to increase Tanis expression in hepatoma H4IIE cells and investigated its role in metabolism. Tanis overexpression reduced glucose uptake, basal and insulin-stimulated glycogen synthesis, and glycogen content and attenuated the suppression of PEPCK gene expression by insulin, but it did not affect insulin-stimulated insulin receptor phosphorylation or triglyceride synthesis. These results suggest that Tanis may be involved in the regulation of glucose metabolism, and increased expression of Tanis could contribute to insulin resistance in the liver.
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PMID:Elevation in Tanis expression alters glucose metabolism and insulin sensitivity in H4IIE cells. 1266 63

Phospho enolpyruvate carboxykinase (PEPCK) plays an important role in gluconeogenesis and hepatic glucose production. To test the hypothesis that mutations of the PEPCK gene promoter contribute to the increased hepatic glucose production that leads to diabetes, we screened for polymorphisms of the PEPCK promoter region in 252 Japanese type 2 diabetic patients and 188 non-diabetic control subjects. A novel variant at position - 232 (C to G) was found at a similar frequency in type 2 diabetes patients (32 %) and control subjects (35 %) (p = 0.26). However, patients with the - 232 G/G genotype had an earlier age of onset than those with the - 232 C/C or - 232 C/G genotypes (p = 0.028). As the variant might well otherwise influence hormonal action, we transfected PEPCK-luciferase fusion gene constructs with the variant into human hepatoma cells and examined the response to dexamethasone, insulin, and cAMP. The reporter assay showed no significant difference in hormonal responses with the fusion gene containing the variant. Accordingly, the single-base variant at position - 232 of the PEPCK gene promoter is most probably not a major contributor to the pathogenesis of type 2 diabetes. However, this variation may be useful as a genetic marker for other metabolic disorders, especially in Japanese.
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PMID:Identification of a novel variant in the phosphoenolpyruvate carboxykinase gene promoter in Japanese patients with type 2 diabetes. 1291 1

Plasma inflammatory cytokines are elevated in obese subjects as well as in those with type 2 diabetes. This presumably results in systemic insulin resistance, characterized by a pro-atherogenic plasma lipid profile and reduced apolipoprotein AI (apoAI) protein levels. To determine how cytokine-mediated insulin resistance suppresses apoAI gene expression, we investigated the effect of tumor necrosis factor alpha (TNF alpha) and interleukin-1beta (IL-1beta) on apoAI protein, mRNA, and transcriptional activity in the human hepatoma cell line HepG2. ApoAI secretion was suppressed in a dose-dependent manner in HepG2 cells treated with both cytokines. ApoAI protein levels were 2892+/-22.0, 2263+/-117, 2458+/-25.0, 3401+/-152, 2333+/-248, 1520+/-41.5 and 956.0+/-11.0 arbitrary units (AU) in cells treated with 0, 0.3, 1.0, 3.0, 10, 30, and 100 ng/ml TNF alpha, achieving statistical significance in the 30 and 100 ng/ml range (P<0.0009). ApoAI protein levels were 4055+/-360, 3697+/-101, 3347+/-327, 1561+/-33.0, 1581+/-182, 810.0+/-59.5, and 1766+/-717 AU in cells treated with similar doses of IL-1beta, achieving statistical significance within the range of 3-100 ng/ml (P<0.02). ApoAI mRNA levels were suppressed 50.8% in HepG2 cells treated with 30 ng/ml TNF alpha for 24 h (P<0.05), and remained suppressed for up to 96 h. Similarly, treatment of cells with 30 ng/ml IL-1beta for 24 h, resulted in 42.9% reduction in apoAI mRNA levels (P<0.05) and remained suppressed for up to 96 h. In order to determine if the effect of TNF alpha and IL-1beta occurs at the transcriptional level, HepG2 cells were transfected with a chloramphenicol acetyltransferase (CAT) reporter gene plasmid containing the full-length apoAI promoter, and after 24 h, treated with TNF alpha (30 ng/ml), IL-1beta (30 ng/ml), or both cytokines. CAT activity was suppressed by both cytokines (24.0+/-1.9% acetylation in control cells vs. 5.6+/-1.2% (P<0.0004), 10.2+/-1.5% (P<0.0006), and 3.9+/-0.9% acetylation (P<0.0002) in cells treated with TNF alpha, IL-1beta, and the combination of both cytokines, respectively) suggesting that cytokine-mediated suppression occurs at the transcriptional level. Using a series of apoAI deletion constructs, the cytokine response element was mapped between nucleotides -325 and -186 (relative to the transcriptional start site). This region contains a previously identified and characterized cis-element, site A, which binds several different transcription factors. Finally, electrophoretic mobility shift assays (EMSA) showed that TNF alpha treatment of HepG2 cells is associated with reduced nuclear factor binding to site A. These studies suggest that inflammatory cytokines down-regulate apoAI expression at least partly through inhibition of binding of the nuclear factors to site A of the apoAI promoter.
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PMID:Suppression of apolipoprotein AI gene expression in HepG2 cells by TNF alpha and IL-1beta. 1457 9

Hepatocyte nuclear factor-4alpha (HNF-4alpha), the gene for the maturity-onset diabetes of the young type 1 (MODY1) form of type 2 diabetes mellitus (T2DM), is within the T2DM-linked region on chromosome 20q12-q13.1 and consequently, is a positional candidate gene for T2DM. Mutations in the coding region of HNF-4alpha are rare in diabetes affected subjects. Altered regulation of HNF-4alpha gene expression, controlled by distant enhancer sequences, may contribute to the development of type 2 diabetes. Comparative sequence analysis was performed between 13 kb of genomic DNA 5' to the P1 promoter sequences of the human, mouse, and rat HNF-4alpha coding sequences. Three regions, located at -10.5 kb (295 bp in length), -6.25 kb (421 bp in length), and -5.36 kb (263 bp in length), have significant sequence identity between the species. These three regions were functionally characterized using the chloramphenicol acetyltransferase (CAT) reporter assay, in which the conserved 5' regions of mouse HNF-4alpha were cloned in front of the herpes simplex virus thymidine kinase promoter driving transcription of the CAT gene. A fragment containing the 421 bp conserved region significantly increased CAT activity in differentiated rat hepatoma cells (13.7-+/-1.9-fold control), while only a modest increase in CAT activity was observed in pancreatic cells (2.5-+/-0.9-fold control; 1.6-+/-0.1-fold control) and dedifferentiated hepatoma cells (1.7-+/-0.4-fold control). The remaining two conserved regions increased CAT activity minimally in pancreatic (1.1-+/-0.1-fold control to 1.9-+/-0.1-fold control) and hepatic (1.6-+/-0.5-fold control to 2.3-+/-0.4-fold control) cell lines. Denaturing high-performance liquid chromatography (DHPLC) was used to search for sequence variants in DNA from 259 T2DM individuals. Two single nucleotide polymorphisms (SNPs) were identified, both of which increased CAT activity in the insulinoma cell lines in the CAT reporter assay (1.4-fold increase over wild-type; 1.7-fold increase over wild-type). These results suggest that comparative sequence analysis can efficiently identify regulatory elements and that sequence variants in regulatory elements of HNF-4alpha can contribute to altered HNF-4alpha gene expression.
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PMID:Comparative genomic analysis of the HNF-4alpha transcription factor gene. 1474 Nov 92

Nonalcoholic steatohepatitis (NASH) was originally believed to be a benign disease. However, it has been recently revealed that NASH could lead to irreversible liver disease in some patients. We report an unusual case of hepatocellular carcinoma (HCC) in a 76-year-old man with NASH. He had no history of alcohol consumption, drug use, or blood transfusion. He was negative for all serological viral markers and autoantibodies. In addition, he was obese (body mass index [BMI], 30.75 kg/m(2)) and had type 2 diabetes mellitus. A liver biopsy specimen showed moderate steatosis with necroinflammatory changes, ballooning degeneration, Mallory bodies, pericellular fibrosis, and evidence of nodular regeneration. He was diagnosed with NASH with cirrhosis. Simultaneously, a liver tumor, measuring 19 mm in diameter, was detected in segment 6. A tumor biopsy specimen revealed well-differentiated HCC, and imaging modalities confirmed the characteristics of HCC. To our knowledge, ten patients who had HCC with NASH were reported. In all patients with NASH and HCC, cirrhosis was present. Patients with NASH and cirrhosis may progress to HCC, and regular screening, based on tumor markers and imaging modalities, is needed to detect HCC in patients with NASH and cirrhosis.
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PMID:Hepatocellular carcinoma with nonalcoholic steatohepatitis. 1516 60

The management of chronic viral hepatitis has changed significantly with the availability of effective antiviral agents. There is now a high probability that timely intervention can arrest development of cirrhosis, thereby preventing mortality from portal hypertension, liver failure and liver cancer. This two-part review discusses the implications of this new era of antiviral therapy for physicians. The present review is about chronic hepatitis C virus (HCV); a similar review that considers the treatment of hepatitis B virus will be published in a later issue of the Internal Medicine Journal. Chronic HCV infection is common, but fibrotic progression of liver disease is slow and variable; many infected persons never develop cirrhosis. Case selection for antiviral therapy is crucial. The most effective therapy is a pegylated (long-acting) interferon with ribavirin. Sustained viral response (SVR) (absent viraemia 6 months after completing treatment) can be obtained in 40-60% of individuals infected with genotype 1 and in approximately 67% with genotype 4 after 12 months of treatment. Response rates are higher (75-85%) with genotypes 2 and 3 after only 6 months of treatment. Late relapse is negligible after SVR. This viral cure reverses hepatic fibrosis, reduces the risk of liver failure and of hepato-cellular carcinoma. Combination therapy requires a supportive setting to minimize the impact of side-effects and maximize therapeutic effectiveness. Overall management of HCV-infected persons must also embrace measures to improve quality of life by preventing or dealing with psychosocial issues and advocating lifestyle changes to counter comorbidity from alcohol, central obesity and insulin resistance. These latter factors favour fibrotic disease progression, complications of cirrhosis (such as hepatocellular carcinoma) and development of type 2 diabetes mellitus, as well as eroding the chances of SVR with antiviral therapy.
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PMID:Management of chronic hepatitis C virus infection: a new era of disease control. 1522 94


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