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)

Troglitazone is a new thiazolidinedione oral antidiabetic agent approved for use to improve glycaemic control in patients with type 2 diabetes. It is rapidly absorbed with an absolute bioavailability of between 40 and 50%. Food increases the absorption by 30 to 80%. The pharmacokinetics of troglitazone are linear over the clinical dosage range of 200 to 600 mg once daily. The mean elimination half-life ranges from 7.6 to 24 hours, which facilitates a once daily administration regimen. The pharmacokinetics of troglitazone are similar between patients with type 2 diabetes and healthy individuals. In humans, troglitazone undergoes metabolism by sulfation, glucuronidation and oxidation to form a sulfate conjugate (M1), glucuronide conjugate (M2) and quinone metabolite (M3), respectively. M1 and M3 are the major metabolites in plasma, and M2 is a minor metabolite. Age, gender, type 2 diabetes, renal impairment, smoking and race do not appear to influence the pharmacokinetics of troglitazone and its 2 major metabolites. In patients with hepatic impairment the plasma concentrations of troglitazone, M1 and M3 increase by 30%, 4-fold, and 2-fold, respectively. Cholestyramine decreases the absorption of troglitazone by 70%. Troglitazone may enhance the activities of cytochrome P450 (CYP) 3A and/or transporter(s) thereby reducing the plasma concentrations of terfenadine, cyclosporin, atorvastatin and fexofenadine. It also reduces the plasma concentrations of the oral contraceptive hormones ethinylestradiol, norethindrone and levonorgestrel. Troglitazone does not alter the pharmacokinetics of digoxin, glibenclamide (glyburide) or paracetamol (acetaminophen). There is no pharmacodynamic interaction between troglitazone and warfarin or alcohol (ethanol). Pharmacodynamic modelling showed that improvement in fasting glucose and triglyceride levels increased with dose from 200 to 600 mg. Knowledge of systemic troglitazone exposure within a dose group does not improve the prediction of glucose lowering response or adverse effects beyond those based on the administered dose.
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PMID:Clinical pharmacokinetics of troglitazone. 1049 99

NIDDM is characterized by a decrease in insulin sensitivity of the liver, the muscles and adipocytes. Diet, exercise and control of excess body weight are the first step of the treatment; they are even able to prevent NIDDM. In this paper the drugs that may improve insulin sensitivity are described with their different specific action on liver, muscles, or adipocytes. Drugs from the thiazolidinedione class act by enhancing the sensitivity to insulin of adipose tissue; they are high-affinity ligands for peroxisome proliferator-activated receptor gamma 2 (PPAR gamma 2 being the predominant form expressed in adipocytes) Hepatotoxicity and weight gain are sides effects of thiazolidinedione. Acipimox (a nicotinic acid analogue) is a NEFA lowering drug that suppress lipolysis, but after a few days of utilisation there is a compensatory free fatty acid rise. Recent data on Metformin action on hepatic insulin sensitivity are discussed and combination with Troglitazone is presented. Vanadyl sulfate may also improve insulin sensitivity but there is no long term human studies.
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PMID:[Insulin resistance: therapeutic approaches]. 1052 Apr 9

About 28% of patients with the Crow-Fukase syndrome exhibit glucose intolerance which may be induced by low serum levels of dehydroepiandrosterone (DHEA). We report a patient with the Crow-Fukase syndrome who exhibited non-insulin dependent diabetes mellitus (NIDDM) worsened prior to admission. He received the DHEA sulfate (DHEA-S) infusion test to evaluate aromatase activity. This patient exhibited an increase in aromatase activity measured by the conversion of the intravenously loaded DHEA-S to estrogen, and low serum levels of DHEA and DHEA-S. These abnormalities returned to nearly normal during the administration of prednisolone, 60 mg per day. No adverse effect on his diabetes was observed during the corticosteroid treatment. Five control patients with diabetes but without the Crow-Fukase syndrome showed no increase in the conversion of DHEA-S to estrogen, which suggests that aromatase activity is normal in diabetes. The increase in aromatase activity in our patient may have led to a low serum concentration of DHEA that in turn caused glucose intolerance and a deterioration of the diabetes prior to admission. Glucocorticoid therapy may be beneficial in Crow-Fukase syndrome to improve the distorted metabolism of DHEA with no adverse effect on the diabetes.
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PMID:Accelerated conversion of dehydroepiandrosterone sulfate to estrogen in a patient with Crow-Fukase syndrome and diabetes mellitus. 1059 29

The aldehyde oxidoreductase (MOD) isolated from the sulfate reducer Desulfovibrio desulfuricans (ATCC 27774) is a member of the xanthine oxidase family of molybdenum-containing enzymes. It has substrate specificity similar to that of the homologous enzyme from Desulfovibrio gigas (MOP) and the primary sequences from both enzymes show 68 % identity. The enzyme was crystallized in space group P6(1)22, with unit cell dimensions of a=b=156.4 A and c=177.1 A, and diffraction data were obtained to beyond 2.8 A. The crystal structure was solved by Patterson search techniques using the coordinates of the D. gigas enzyme. The overall fold of the D. desulfuricans enzyme is very similar to MOP and the few differences are mapped to exposed regions of the molecule. This is reflected in the electrostatic potential surfaces of both homologous enzymes, one exception being the surface potential in a region identifiable as the putative docking site of the physiological electron acceptor. Other essential features of the MOP structure, such as residues of the active-site cavity, are basically conserved in MOD. Two mutations are located in the pocket bearing a chain of catalytically relevant water molecules. As deduced from this work, both these enzymes are very closely related in terms of their sequences as well as 3D structures. The comparison allowed confirmation and establishment of features that are essential for their function; namely, conserved residues in the active-site, catalytically relevant water molecules and recognition of the physiological electron acceptor docking site.
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PMID:Gene sequence and crystal structure of the aldehyde oxidoreductase from Desulfovibrio desulfuricans ATCC 27774. 1070 12

Troglitazone, a PPAR-gamma agonist, is a new drug for type 2 diabetes. The drug decreases blood glucose via enhancing insulin action. Recently Sankyo pharmaceutical company is warning severe hepatotoxicity by troglitazone. It recommends to examine liver function every month in diabetic patients treated with the drug in order early to find drug-induced hepatitis. In Japan 153 diabetic patients treated with the drug developed severe hepatitis and 8 of them died of drug-side effects. Quinone metabolite of troglitazone predominantly in the liver to a sulfate conjugate and activation of PPAR gamma and PXR(pregnane X receptor) by troglitazone are supposed to be factors of hepatotoxic mechanism.
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PMID:[Clinical effect and side effect of troglitazone]. 1070 61

Lipoprotein(a) (Lp(a)) with atherogenic and thrombotic properties has been frequently studied in diabetes, because a high cardiovascular risk has been reported both in type 1 and type 2 diabetes. Few studies have considered genetic factors, especially the isoforms of apolipoprotein(a). The aim of this work is to determine the distribution of apo(a) phenotypes in the serum of 148 diabetic patients (59 type 1, 89 type 2) with or without vascular complications. Apo(a) phenotypes are determined using 4-15% sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by immunoblotting (PhastSystem - Pharmacia). An inverse relationship is observed between Lp(a) serum concentration and the apparent molecular mass of apo(a) isoforms: type 1 r=- 0.61, p<0.01; type 2 r=- 0.55, p<0.01. The frequency of apo(a) isoforms is significantly different between type 1 and type 2 diabetes mellitus. A higher prevalence of isoforms of low molecular weight was observed in the type 2 diabetic population.
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PMID:Determination of lipoprotein(a) concentrations and apolipoprotein(a) molecular weights in diabetic patients. 1080 24

Treatment with moderate levels of albumin-bound, nonesterified fatty acids (NEFA) induce important alterations of the structure and functionality of proteoglycans secreted by endothelial cells and arterial smooth muscle cells. In endothelial cell monolayers, the reduction on relative amount and sulfation of heparan sulfate proteoglycans is associated with an increased permeability to albumin. In smooth muscle cells, NEFA-albumin complex increased the expression of the genes for the core proteins of the proteoglycans syndecan, decorin and perlecan. This effect appears mediated by peroxisome proliferator-activated receptor gamma (PPARg). The matrix produced by the cells treated with NEFA-albumin had a higher affinity with low-density lipoproteins (LDLs). We speculate about the possibility that under dyslipidemias associated with increased exposure of vascular cells to NEFA, like in type 2 diabetes, similar alterations may contribute to associated macrovascular and microvascular complications.
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PMID:Lipid mediators that modulate the extracellular matrix structure and function in vascular cells. 1112 3

Chlorogenic acid derivatives were recently identified as novel, potent, and specific inhibitors of the hepatic glucose 6-phosphate translocase. Inhibition of the glucose 6-phosphate translocase leads to a decrease in hepatic glucose production, rendering chlorogenic acid derivatives as potential novel therapeutics in patients with type 2 diabetes. The present study examines the hepatic uptake mechanism of the radiolabeled chlorogenic acid derivative S 1743 into freshly isolated rat hepatocytes. Initial uptake rates were Na(+)-independent and followed saturation kinetics with no superimposition of facilitated diffusion. Inhibition studies demonstrated that other chlorogenic acid derivatives inhibited uptake of the radiolabeled compound S 1743 into rat hepatocytes in the range of 1.1 to 11 microM, whereas the natural chlorogenic acid (up to 100 microM) had no effect at all. In addition, inhibition of S 1743 uptake into rat hepatocytes was found in the presence of sulfobromophthalein, sulfolithocholyltaurine, estrone-3-sulfate, cholyltaurine, verapamil, bumetanide, probenecide, phenol red, digoxin, and ouabain (in decreasing order) but not with N-methylnicotinamide, alpha-ketoglutarate, p-aminohippurate, geneticin sulfate, and 5-sulfosalicylate. The observed inhibition pattern suggested that members of the family of the organic anion transporting polypeptides (Oatps) could be involved in hepatic uptake of chlorogenic acid derivatives. Indeed, S 1743 uptake could be demonstrated in Oatp1- and Oatp2-expressing Xenopus laevis oocytes as well as in Oatp1-expressing Chinese hamster ovary cells. A comparison of the inhibition pattern obtained in hepatocytes compared with that obtained in Oatp1-expressing Chinese hamster ovary cells suggests that facilitated uptake by Oatp1 is a major contributor in total hepatic uptake of chlorogenic acid derivatives.
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PMID:Hepatic uptake of synthetic chlorogenic acid derivatives by the organic anion transport proteins. 1112 67

Islet amyloid deposits are a characteristic pathologic lesion of the pancreas in type 2 diabetes and are composed primarily of the islet beta cell peptide islet amyloid polypeptide (IAPP or amylin) as well as the basement membrane heparan sulfate proteoglycan perlecan. Impaired processing of the IAPP precursor has been implicated in the mechanism of islet amyloid formation. The N- and C-terminal cleavage sites where pro-IAPP is processed by prohormone convertases contain a series of basic amino acid residues that we hypothesized may interact with heparan sulfate proteoglycans. This possibility was tested using affinity chromatography by applying synthetic fragments of pro-IAPP to heparin-agarose and heparan sulfate-Sepharose. An N-terminal human pro-IAPP fragment (residues 1-30) was retained by both heparin-agarose and heparan sulfate-Sepharose, eluting at 0.18 m NaCl at pH 7.5. Substitution of alanine residues for two basic residues in the N-terminal cleavage site abolished heparin and heparan sulfate binding activity. At pH 5.5, the affinity of the wild-type peptide for heparin/heparan sulfate was increased, implying a role for histidine residues at positions 6 and 28 of pro-IAPP. A C-terminal pro-IAPP fragment (residues 41-67) had no specific affinity for either heparin or heparan sulfate, and the N- or C-terminal fragments had only weak affinity for chondroitin sulfate. These data suggest that monomeric N-terminal human pro-IAPP contains a heparin binding domain that is lost during normal processing of pro-IAPP.
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PMID:Identification of a heparin binding domain in the N-terminal cleavage site of pro-islet amyloid polypeptide. Implications for islet amyloid formation. 1114 57

Vanadyl sulfate (VOSO(4)) is an oxidative form of vanadium that in vitro and in animal models of diabetes has been shown to reduce hyperglycemia and insulin resistance. Small clinical studies of 2- to 4-week duration in type 2 diabetes (T2DM) have led to inconsistent results. To define its efficacy and mechanism of action, 11 type 2 diabetic patients were treated with VOSO(4) at a higher dose (150 mg/day) and for a longer period of time (6 weeks) than in previous studies. Before and after treatment we measured insulin secretion during an oral glucose tolerance test, and endogenous glucose production (EGP) and whole body insulin-mediated glucose disposal using the euglycemic insulin clamp technique combined [3-(3)H]glucose infusion. Treatment significantly improved glycemic control: fasting plasma glucose (FPG) decreased from 194 +/- 16 to 155 +/- 15 mg/dL, hemoglobin A(1c) decreased from 8.1 +/- 0.4 to 7.6 +/- 0.4%, and fructosamine decreased from 348 +/- 26 to 293 +/- 12 micromol/L (all P < 0.01) without any change in body weight. Diabetics had an increased rate of EGP compared with nondiabetic controls (4.1 +/- 0.2 vs. 2.7 +/- 0.2 mg/kg lean body mass.min; P< 0.001), which was closely correlated with FPG (r = 0.56; P< 0.006). Vanadyl sulfate reduced EGP by about 20% (P< 0.01), and the decline in EGP was correlated with the reduction in FPG (r = 0.60; P< 0.05). Vanadyl sulfate also caused a modest increase in insulin-mediated glucose disposal (from 4.3 +/- 0.4 to 5.1 +/- 0.6 mg/kg lean body mass x min; P< 0.03), although the improvement in insulin sensitivity did not correlate with the decline in FPG after treatment (r = -0.16; P = NS). Vanadyl sulfate treatment lowered the plasma total cholesterol (223 +/- 14 vs. 202 +/- 16 mg/dL; P < 0.01) and low density lipoprotein cholesterol (141 +/- 14 vs. 129 +/- 14 mg/dL; P < 0.05), whereas 24-h ambulatory blood pressure was unaltered. We conclude that VOSO(4) at maximal tolerated doses for 6 weeks improves hepatic and muscle insulin sensitivity in T2DM. The glucose-lowering effect of VOSO(4) correlated well with the reduction in EGP, but not with insulin-mediated glucose disposal, suggesting that liver, rather than muscle, is the primary target of VOSO(4) action at therapeutic doses in T2DM.
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PMID:Vanadyl sulfate improves hepatic and muscle insulin sensitivity in type 2 diabetes. 1123 40


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