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)

We evaluated the effects of phenobarbital, an inducer, on plasma glucose and serum immunoreactive insulin levels and on hepatic glucose and drug metabolism using an animal model of non-insulin dependent diabetes mellitus. Genetically obese (ob/ob) mice, characterized by hyperglycaemia, hyperinsulinaemia, fatty liver and obesity were selected. The impairment of diabetic state with age was associated with increased activities of NADPH producing enzymes, whereas mixed function oxidase system remained unaltered. Phenobarbital reduced serum immunoreactive insulin and plasma glucose levels and decreased gluconeogenesis. Hepatic glucose phosphorylating enzyme activity increased and glucose releasing enzyme activity decreased. The demand for NADPH in drug oxidation reactions, caused by the induction phenomenon, was reflected in the elevated activities of the NADPH producing enzymes in pentose phosphate pathway and in the activities of isocitrate dehydrogenase and malic enzyme from mitochondrial oxidation reactions. Glucose metabolism of lean littermates indicated that phenobarbital induction normalizes impaired intracellular glucose handling but leaves normal glucose metabolism unaltered. Hepatic glucose production rate was related to plasma glucose, NADPH producing enzyme activities and cytochrome P450 content in the obese and lean mice.
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PMID:Effects of enzyme induction therapy on glucose and drug metabolism in obese mice model of non-insulin dependent diabetes mellitus. 250 Oct 61

Troglitazone, a new antihyperglycemic agent, is approved for use alone, with oral sulfonylureas, or with insulin in the treatment of type II diabetes mellitus. Rather than stimulating insulin secretion, it enhances insulin sensitivity. Potential advantages of troglitazone over oral sulfonylureas include decreased endogenous insulin concentrations, decreased exogenous insulin requirements, reduced hypoglycemic risk, and convenient once/day administration. The effect on morbidity and mortality from lowering endogenous and exogenous insulin concentrations remains to be determined. Troglitazone also has potential disadvantages. It induces cytochrome P450 isoenzyme 3A4, although few drug interactions have been identified to date. Serum transaminases must be monitored routinely because of rarely reported cases of idiosyncratic hepatocellular injury. In addition, the cost of troglitazone is much higher than that of other oral antihyperglycemic agents or insulin. Given the available information, troglitazone has limited benefit over oral sulfonylureas or metformin as monotherapy or in combination with oral sulfonylureas. Until additional combination and comparative studies have been done, the agent should be reserved for patients with poor glycemic control receiving high daily doses of insulin.
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PMID:Troglitazone in type II diabetes mellitus. 962 Jan 5

HIV-1 protease-inhibitor treatments are associated with a syndrome of peripheral lipodystrophy, central adiposity, breast hypertrophy in women, hyperlipidaemia, and insulin resistance. The catalytic region of HIV-1 protease, to which protease inhibitors bind, has approximately 60% homology to regions within two proteins that regulate lipid metabolism: cytoplasmic retinoic-acid binding protein type 1 (CRABP-1) and low density lipoprotein-receptor-related protein (LRP). We hypothesise that protease inhibitors inhibit CRABP-1-modified, and cytochrome P450 3A-mediated synthesis of cis-9-retinoic acid, a key activator of the retinoid X receptor; and peroxisome proliferator activated receptor type gamma (PPAR-gamma) heterodimer, an adipocyte receptor that regulates peripheral adipocyte differentiation and apoptosis. Protease-inhibitor binding to LRP would impair hepatic chylomicron uptake and triglyceride clearance by the endothelial LRP-lipoprotein lipase complex. The resulting hyperlipidaemia contributes to central fat deposition (and in the breasts in the presence of oestrogen), insulin resistance, and, in susceptible individuals, type 2 diabetes. Understanding the syndrome's pathogenesis should lead to treatment strategies and to the design of protease inhibitors that do not cause this syndrome.
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PMID:Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. 965 87

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

Insulin resistance in liver and muscle tissue, together with beta-cell secretory defects, leads to overt type 2 diabetes mellitus. In the early stages of this progressive disorder, glycaemic control can be established through diet and exercise alone. Indeed, in some patients, marked weight reduction can lead to normalized fasting blood glucose. As a consequence, pharmacological approaches to weight loss have been investigated as a new option for the management of type 2 diabetes in obese patients. The serotonin- and noradrenaline-reuptake inhibitor sibutramine has emerged as the most promising agent in the treatment of obesity, although it appears to be less effective in diabetic patients than in non-diabetic patients. Other weight-reducing agents of potential benefit include noradrenergic anorexiants, orlistat, leptin, and beta3-agonists. Insulin and insulin secretagogues, the oldest available antidiabetic drugs, have been used to compensate for beta-cell secretory defects in patients with type 2 diabetes. Repaglinide, a new, fast-acting insulin secretagogue with a short duration of action, reduces postprandial hyperglycaemia when taken shortly before meals. Other novel antidiabetic agents are currently under development, including pramlintide (an amylin analogue) and glucagon-like peptide. Pramlintide slows gastric emptying and delays glucose absorption, and glucagon-like peptide is the most potent endogenous stimulator of glucose-induced insulin release. Recent advances in type 2 diabetes therapy have seen the development of the thiazolidinediones (troglitazone, rosiglitazone, and pioglitazone), which improve insulin resistance in patients whose diabetes is poorly controlled by diet and exercise therapy. Thiazolidinediones bind to peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and act through a process involving gene regulation at a transcriptional level. Troglitazone, the first approved drug in the class, has been shown to decrease plasma glucose levels as monotherapy but is more effective in combination with sulphonylureas, metformin, or insulin. However, despite its generally good safety profile, troglitazone has been associated with severe idiosyncratic hepatocellular injury. There have been more than 150 spontaneous reports of serious hepatic events, including at least 25 instances in which patients died or required a liver transplant. Rosiglitazone, the most potent thiazolidinedione, is still in clinical development, as is pioglitazone. To date, rosiglitazone has been shown to have no reported cases of idiosyncratic drug reactions leading to jaundice or liver failure and no clinically significant drug interactions with cytochrome P450 3A4-metabolized drugs such as nifedipine. Although the available data for pioglitazone are limited to the results of short-term studies, it is reported to be safe and well tolerated. Combination therapy is increasingly important in type 2 diabetes management following failure of monotherapy because complementary mechanisms of action of the different classes of oral agents demonstrate synergistic effects when used in combination. Oral agents may also be used as adjuncts to insulin for achieving glycaemic control.
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PMID:Promising new approaches. 1122 Feb 87

Decreased insulin sensitivity plays a major role in various human diseases. particularly type 2 diabetes mellitus, and is associated with a higher risk of atherosclerosis and cardiovascular complications. Thiazolidinediones, more commonly termed glitazones, are the first drugs to specifically target muscular insulin resistance. They have proven efficacy for reducing plasma glucose levels in patients with type 2 diabetes mellitus treated with diet alone, sulphonylureas, metformin or insulin. In addition, they are associated with some improvement of the cardiovascular risk profile. However, troglitazone, the first compound approved by the Food and Drug Administration in the US, proved to be hepatotoxic and was withdrawn from the market after the report of several dozen deaths or cases of severe hepatic failure requiring liver transplantation. It remains unclear whether or not hepatotoxicity is a class effect or is related to unique properties of troglitazone. Rosiglitazone and pioglitazone, two other glitazones, appear to have similar efficacy with regard to blood glucose control in patients with type 2 diabetes mellitus as compared with troglitazone. In controlled clinical trials, the incidence of significant (> or =3 x upper limit of normal) increases in liver enzyme levels (ALT in particular) was similar with rosiglitazone or pioglitazone as compared with placebo, whereas troglitazone was associated with a 3-fold greater incidence. In contrast to the numerous case reports of acute liver failure in patients receiving troglitzone, only a few case reports of hepatotoxicity have been reported in patients treated with rosiglitazone until now, with a causal relationship remaining uncertain. Furthermore, no single case of severe hepatotoxicity has been reported yet with pioglitazone. It should be mentioned that troglitazone, unlike pioglitazone and rosiglitazone, induces the cytochrome P450 isoform 3A4, which is partly responsible for its metabolism, and may be prone to drug interactions. Importantly enough, obesity, insulin resistance and type 2 diabetes mellitus are associated with liver abnormalities, especially non-alcoholic steatohepatitis, independent of any pharmacological treatment. This association obviously complicates the selection of patients who are good candidates for a treatment with glitazones as well as the monitoring of liver tests after initiation of therapy with any thiazolidinedione compound. While regular monitoring of liver enzymes is still recommended and more long term data are desirable, current evidence from clinical trials and postmarketing experience in the US supports the conclusion that rosiglitazone and pioglitazone do not share the hepatotoxic profile of troglitazone.
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PMID:Hepatotoxicity with thiazolidinediones: is it a class effect? 1173 45

Troglitazone (TRZ) is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is proven to lower plasma glucose levels in patients with type 2 diabetes mellitus. However, the concern has been raised because of several reports, in which severe hepatic dysfunction leading to hepatic failure was demonstrated in a few patients receiving the drug. We studied the effects of TRZ on the hepatotoxicity of carbon tetrachloride (CCl(4)) and acetaminophen (APAP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 3A (CYP3A) and 2E1 (CYP2E1). Male standard (Wistar/ST) and type 2 diabetic model (GK/Jal) rats were kept on a powdered chow diet containing 0, 100, 500 mg/kg/rat of TRZ. Three weeks later, the rats were either sacrificed for an in vitro metabolism study or challenged with 0.50 g/kg CCl(4) p.o. or 0.75 g/kg APAP i.p.TRZ at 100 and 500 mg/kg/rat increased the CYP3A level as well as the testosterone 6beta-hydroxylation activities in liver microsomes, but did not affect CYP2E1. TRZ also enhanced APAP hepatotoxicity, as evidenced by significantly increased levels of alanine aminotransferase, aspartate aminotransferase and alpha-glutathione S-transferase in the plasma of rats, and by significantly low hepatic glutathione concentration. Our study demonstrated that high doses of TRZ can enhance hepatotoxicity of APAP in Wistar/ST and GK/Jal by inducing hepatic CYP3A.
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PMID:Troglitazone enhances the hepatotoxicity of acetaminophen by inducing CYP3A in rats. 1206 33

Nateglinide (NA) is a novel oral mealtime glucose regulator, recently approved for the treatment of type II diabetes mellitus. To facilitate clinical studies investigating the dependence of NA elimination on the genotype of cytochrome P450 isoenzymes, we developed a rapid HPLC method for determination of NA in human plasma samples. The validated limit of quantitation (LOQ) of 0.1 microg/ml is low enough to allow determination of pharmacokinetic parameters of the substance. The intra-assay coefficients of variation (CV) ranged from 1.6 to 12.9% at NA concentrations of 0.5-7.5 microg/ml. The inter-assay variation for the same plasma concentrations ranged from 3.8 to 8.4%. The calibration was linear in the range of 0.1-20 microg/ml. For the quantitation of NA, only 50 microl of plasma were needed. Following protein precipitation in human plasma, the samples were separated by isocratic reversed phase HLPC and analyzed using ultraviolet detection at 210 nm. Sample preparation time and analysis time are both short and allow rapid analysis of large sample sets.
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PMID:Rapid and simple method for the analysis of nateglinide in human plasma using HPLC analysis with UV detection. 1261 43

An anti-diabetic agent, troglitazone, was withdrawn from the market because of its association with liver injury. However, the mechanism of the injury has not been elucidated. We examined, retrospectively, the frequency of the polymorphisms of the cytochrome P450 (CYP) 2C19 and 2D6 genes in eight patients with type 2 diabetes who had troglitazone-induced liver injury and 31 subjects who tolerated troglitazone well. Polymorphisms of CYP 2C19 and 2D6 genes were analyzed by polymerase chain reaction using peripheral white blood cells. The incidence of mutations was compared with known population data for the Japanese. Homozygous or compound heterozygous mutations in CYP 2C19 alleles were found in four of the eight (50.0%) patients with troglitazone-induced liver injury. This rate was significantly higher than that in patients without liver injury (four of 31, 12.9%). The frequency of P450 2D6 mutations was the same in both groups. In conclusion, troglitazone-induced liver injury occurred more frequently in subjects with the CYP 2C19 mutations in Japanese patients.
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PMID:Association of troglitazone-induced liver injury with mutation of the cytochrome P450 2C19 gene. 1296 35

Liver steatosis is a common human disease, most often caused by long-term alcohol consumption. Non-alcoholic steatohepatitis (NASH) is characterized by similar histopathological features to those observed in alcoholic liver disease, but occurs in the absence of significant alcohol consumption. Several aetiological factors contribute to NASH: obesity, type 2 diabetes mellitus, hyperlipidaemia, pregnancy, different chemical intoxications, parenteral nutrition, jejeuno-ileal bypass, chronic inflammatory bowel disease, nutritional protein deficiency and congenital metabolic disorders. Biochemically, oxidative stress and lipid peroxidation and their ensuing damage are implicated in the pathogenesis of NASH and alcoholic steatohepatitis (probably resulting from free fatty acids in the mitochondria, and induction of the cytochrome P450 isoform CYP2E1 in hepatocytes and Kupffer's cells). This paper deals with the pathomechanisms, clinical findings and currently available therapies for NASH. The potential use of metadoxine in the treatment of NASH is also discussed.
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PMID:A new approach to drug therapy in non-alcoholic steatohepatitis (NASH). 1470 19


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