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)

Rosiglitazone is one of the members in the thiazolidinedione (TZD) class of anti-diabetic agents that have proven efficacy in the treatment of patients with type 2 diabetes. We studied serum from a patient who developed acute, severe thrombocytopenia after exposure to rosiglitazone maleate (Avandia) and proposed the mechanisms for rosiglitazone-induced thrombocytopenia. Tested by flow cytometry, the patient's serum was positive for rosiglitazone-induced antibody with the binding ratio of 5.93 (mean fluorescence intensity, MFI) in the presence of the patient's serum and rosiglitazone in a final concentration of 0.53 mmol/l. The antibody was found to bind both glycoprotein (GP) IIb-IIIa complex and GP Ib/IX complex by MAIPA assay using five different monoclonal antibodies (mAbs) against GP complexes Ib/IX, GPIIb/IIIa or GPIa/IIa. Immunoprecipitation studies showed that both GPIIb/IIIa and GP Ib/IX complex were precipitated by antibody in the presence, but not in the absence of rosiglitazone. These findings provide evidence that immune thrombocytopenia can be caused by sensitivity to the antidiabetic agent rosiglitazone maleate. This report documents the first case of rosiglitazone-induced immune thrombocytopenia.
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PMID:Rosiglitazone-induced immune thrombocytopenia. 1712 88

Subjects (N = 22,808) with inadequately controlled type 2 diabetes mellitus (T2DM) were included in a large 6-month observational study in Germany. Rosiglitazone (RSG) was added to existing therapy in line with daily practice, with 19,962 subjects evaluated for efficacy by treatment group: RSG monotherapy (n = 1017), RSG plus metformin (MET) (n = 7160), RSG plus sulphonylurea (n = 5033), triple oral therapy (n = 4247), and the remaining subject population (n = 2505). Overall, RSG significantly reduced median HbA(1c) and fasting blood glucose by 1.3% and 50 mg/dl over 6 months (p < 0.001 for both). The proportion of subjects achieving glycaemic goals of <or= 6.5% and <or= 7.0% increased from 5.7% to 33.8%, and from 13.9% to 55.5%, respectively (p < 0.001 for both). Mean systolic and diastolic blood pressures were reduced in the total subject population by 6 mmHg and 2 mmHg, respectively (p < 0.001 for both). RSG had a neutral or reductive effect on mean weight of most (69%) subjects. Consistent with clinical trial data, RSG mono- or combination therapy improved glycaemic control when used in daily clinical practice and is generally well-tolerated.
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PMID:Rosiglitazone is effective and well-tolerated in a range of therapeutic regimens during daily practice in patients with type 2 diabetes. 1693 44

Monocytes and macrophages play a key role in the progression of atheromatous changes. The peroxisome proliferator-activated receptor gamma (PPAR gamma) can limit macroangiopathy through the control of cytokine transcription. The objectives of this study were to examine the influence of PPAR gamma and its agonist (rosiglitazone) on the TNFalpha, IL-6, IL-8 and IL-10 gene expression in monocytes of patients with diabetic macroangiopathy and to analyse obtained results in context of selected atherogenic factors ant direct indicators of endothelial lesion. TNFalpha, IL-6, IL-8, IL-10 and PPAR gamma gene expression was assessed in peripheral blood monocytes in 45 patients with type 2 diabetes before and following 22 weeks of rosiglitazone therapy (real-time PCR [Applied Biosystems]). As indicators of endothelial lesion, concentration of thrombomodulin (immunoassay [Diagnostica Stago]) and amount of circulating blood endothelial cells (immunofluorescence method with MoAb CLB-HEC19) were determined. Following rosiglitazone therapy, a statistically significant downward tendency of TNFalpha (p=0.026) and IL-8 (p=0.008) gene expression was noted. Before and following rosiglitazone treatment, PPAR gamma, IL-6 and IL-10 gene expression was undetectable in studied monocytes in vivo. In conclusion, TNFalpha and IL-8 play an important role in monocyte atherogenic activity. Rosiglitazone reduces monocyte proinflammatory readiness by influencing the expression of selected atherogenic cytokines (PPAR gamma-independent pathway).
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PMID:Stimulation of the peroxisome proliferator-activated receptor gamma (PPAR gamma) and the expression of selected blood monocyte cytokine genes in diabetic macroangiopathy. 1714 Dec 46

This study was conducted to evaluate the efficacy and tolerability of rosiglitazone in the treatment of patients with secondary oral antidiabetic drug (OAD) failure and to directly compare its use with bedtime insulin. A total of 112 Chinese patients with type 2 diabetes and conventional OAD failure were recruited. Patients were randomly assigned to treatment with rosiglitazone or bedtime isophane insulin; they continued to take their original oral antidiabetic drugs. Glycemic index, other clinical profiles, and tolerability were assessed during treatment and 1 y after add-on treatment was provided. Among the 112 patients, mean age (+/-SD) was 58.2+/-11.0 y (median, 58 y; range, 37 to 84 y). Both rosiglitazone (n=56) and insulin (n=56) significantly improved fasting glucose (2.4 and 3.7 mmol/L, respectively) and hemoglobin A1c concentrations (1.1% and 1.3%, respectively). Both therapies increased body mass index after 1 y of treatment (0.9 and 0.8 kg/m2, respectively). Only rosiglitazone increased high-density lipoprotein cholesterol concentrations (0.1 mmol/L). Four patients (7.1%) who were given rosiglitazone developed adverse effects (2, ankle edema, and 2, gastrointestinal disturbance). Six insulin-treated patients (10.7%) described adverse effects (5, early morning hypoglycemia, and 1, anxiety). Investigators concluded that in Chinese patients with type 2 diabetes and secondary conventional OAD failure, 1 y of treatment with rosiglitazone or bedtime insulin added to the regular regimen resulted in similar improvements in glycemic control. Rosiglitazone was also associated with improved high-density lipoprotein cholesterol levels. The addition of rosiglitazone may offer a safe and effective alternative to bedtime insulin treatment.
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PMID:Rosiglitazone versus bedtime insulin in the treatment of patients with conventional oral antidiabetic drug failure: a 1-year randomized clinical trial. 1714 16

Peripheral insulin levels are determined by beta-cell secretion, insulin sensitivity, and hepatic insulin extraction (HIE). We have previously shown that whereas sulfonylureas reduce insulin extraction, metformin enhances HIE. However, the effects of thiazolidinediones (TZDs) on HIE remain uncertain. Thus, we investigated the potential contribution of hepatic insulin clearance to peripheral insulin levels during rosiglitazone therapy in African Americans with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM). The study was composed of 12 first-degree relatives with IGT and 17 patients with newly diagnosed type 2 DM. Nineteen healthy relatives with normal glucose tolerance served as controls. Serum glucose, insulin, and C-peptide, and HIE (C-peptide-insulin molar ratios) were measured at t = 0 and 120 minutes during oral glucose tolerance test (OGTT) in all the subjects. The OGTT was performed before and after 3 months of rosiglitazone therapy (4 mg/d x 4 weeks and >8 mg/d x 8 weeks) in patients with IGT and type 2 DM. Insulin resistance index and beta-cell function were calculated in each subject using homeostasis model assessment (HOMA). Rosiglitazone therapy improved but did not normalize the overall glycemic control in the IGT and type 2 DM groups. After rosiglitazone therapy, the mean serum insulin and C-peptide levels at fasting remained unchanged. However, the 2-hour serum glucose and insulin were lower, whereas serum C-peptide was unchanged during 3 months of rosiglitazone treatment. Mean insulin resistance index of HOMA was reduced by 30% (4.12 +/- 1.95 vs 6.33 +/- 3.54, P < .05) in the type 2 DM group and by 21% (3.78 +/- 2.45 vs 4.81 +/- 3.49, P = NS) in the IGT group. Mean HIE values were significantly lower (70%) in the type 2 DM and IGT groups when compared with the normal glucose tolerance group. At 3 months, basal HIE was not significantly changed by rosiglitazone therapy in IGT and type 2 DM groups when compared with the baseline (0 month). However, rosiglitazone therapy was associated with increased HIE at 2 hours during OGTT by 40% and 30% in the IGT and type 2 DM groups, respectively, from the baseline (0 month) values. Furthermore, HIE inversely correlated with the insulin resistance index of HOMA (r = -.46, P < .05). We conclude that rosiglitazone therapy improved overall glucose tolerance and enhanced insulin sensitivity in patients with IGT and type 2 DM. Although basal HIE remained unchanged, rosiglitazone therapy increased postglucose challenge HIE in African Americans with IGT and type 2 DM. We speculate that TZDs increase insulin clearance or HIE after oral glucose challenge. This study suggests that in addition to insulin sensitization, rosiglitazone may be involved in insulin metabolism. The significance of the increased insulin clearance by TZD therapy remains uncertain and deserves further investigation in patients with insulin resistance and glucose intolerance.
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PMID:Thiazolidinediones increase hepatic insulin extraction in African Americans with impaired glucose tolerance and type 2 diabetes mellitus. A pilot study of rosiglitazone. 1716 Dec 22

Thiazolidinediones (TZD), or glitazones, represent a new generation of antidiabetic drugs that have recently been introduced in Europe. They improve insulin resistance, one of the key anomalies involved in the pathogenesis of type 2 diabetes mellitus, by activating the nuclear peroxoxisome proliferator activated receptor-gamma (PPAR-gamma), leading to crucial metabolic alterations in adipose tissue. Rosiglitazone and pioglitazone have been shown to be active as monotherapy, in combination therapy with metformin or sulfonylureas, and even in triple therapy. They are generally well tolerated but can induce fluid retention. Cardiac failure is a contraindication for the use of TZDs, as is the concomitant administration of insulin. Aside from their effect on glycemic control, TZDs act on several cardiovascular risk factors and may protect pancreatic beta cells from apoptosis. The cardiovascular protective effect of TZDs has recently been demonstrated with the results of the PROactive study, and long-term preservation of beta-cell function is currently under further investigation.
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PMID:Thiazolidinediones for the treatment of type 2 diabetes. 1722 37

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an incretin enhancer that is approved for the treatment of type 2 diabetes. Sitagliptin is mainly renally eliminated and not a potent inhibitor of CYP450 enzymes in vitro. Rosiglitazone, a thiazolidenedione, is an insulin sensitizer and mainly metabolized by CYP2C8. Since both agents may potentially be coadministered, the purpose of this study was to examine the effects of sitagliptin on rosiglitazone pharmacokinetics. In this open-label, randomized, 2-period, crossover study, 12 healthy normoglycemic subjects, 21 to 44 years, received single 4-mg doses of rosiglitazone alone in one period and coadministered with sitagliptin on day 5 following a multiple-dose regimen for sitagliptin (200 mg once daily x 5 days) in the other period. The geometric mean ratios and 90% confidence intervals ([rosiglitazone + sitagliptin]/rosiglitazone) for rosiglitazone AUC(0-infinity) and Cmax were 0.98 (0.93, 1.02) and 0.99 (0.88, 1.12), respectively. In conclusion, sitagliptin did not alter the pharmacokinetics of rosiglitazone in healthy subjects.
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PMID:Multiple-dose administration of sitagliptin, a dipeptidyl peptidase-4 inhibitor, does not alter the single-dose pharmacokinetics of rosiglitazone in healthy subjects. 1724 66

ADOPT ("A Diabetes Outcome Progression Trial") is a double-blind, controlled clinical trial that aims at assessing the efficacy of rosiglitazone, as compared to metformin or glibenclamide, in maintaining long-term glycaemic control in patients with recently diagnosed type 2 diabetes. It randomized 4,360 patients who were followed for a median of 4.0 years. The cumulative incidence of monotherapy failure (defined as a confirmed level of fasting plasma glucose level of more than 180 mg/dl) averaged at 5 years 15% with rosiglitazone, 21% with metformin, and 34% with glibenclamide. This represents a risk reduction for rosiglitazone of 32% as compared to metformin and 63% as compared to glibenclamide (P < 0.001 for both comparisons). Rosiglitazone was associated with more weight gain and edema, metformin with a higher incidence of gastrointestinal events and glibenclamide with a higher risk of hypoglycaemia (P < 0.001). In conclusion, ADOPT showed better glycaemic durability with rosiglitazone monotherapy, compared to metformin or glibenclamide. The potential risks and benefits, the profile of adverse events, and the costs of the three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes.
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PMID:[ADOPT study: which first-line glucose-lowering oral medication in type 2 diabetes?]. 1734 30

Treatment with rosiglitazone, a potent peroxisome proliferator-activated receptor (PPAR) gamma agonist, results in lipid storage coupled with reduced release of free fatty acids into the circulation. Many studies have reported that PPAR-gamma agonists increase subcutaneous adiposity but have no effect on visceral fat mass. Perilipin, a family of phosphoproteins that coat intracellular lipid droplets in adipocytes, is essential for enlargement of lipid droplets. Recently, a functional PPAR-responsive element was identified within the murine perilipin gene. We hypothesized that the depot-specific regulation of perilipin by rosiglitazone may be associated with the fat-redistribution and insulin-sensitizing effects of rosiglitazone. After 6 weeks of rosiglitazone treatment in Otusuka Long-Evans Tokushima Fatty rats, an animal model of type 2 diabetes mellitus, we measured changes in adiposity, triglyceride content in liver and muscle, morphology of the pancreas, and perilipin messenger RNA and protein expression in adipose tissue. Rosiglitazone increased subcutaneous adiposity, decreased triglyceride content of liver and muscle, decreased plasma free fatty acids (2107 +/- 507 micromol/L in the placebo group vs 824 +/- 148 micromol/L in the rosiglitazone group; P < .05), and improved insulin resistance. The islets of placebo-treated rats showed hypertrophy and destruction, whereas the islets of rosiglitazone-treated rats showed hypertrophy, but the islet architecture remained intact. Perilipin messenger RNA and protein expression increased in subcutaneous fat, but did not change in visceral fat, after rosiglitazone treatment. In 3T3-L1 cells, rosiglitazone pretreatment decreased lipolysis and increased perilipin protein. In conclusion, increased perilipin expression in subcutaneous fat after rosiglitazone treatment is likely to be a mediator of reduced lipolysis, resulting in lipid storage in subcutaneous fat, fat redistribution, and insulin sensitization.
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PMID:Depot-specific regulation of perilipin by rosiglitazone in a diabetic animal model. 1744 44

Patients with type 2 diabetes (T2DM) often present a preponderance of small, dense LDL particles (small-LDL), which are associated with a high risk of myocardial infarction. Some studies suggest that PPARgamma-agonists increase LDL cholesterol but have divergent effects on various LDL subclasses in T2DM patients. We studied the effect of rosiglitazone on the LDL subclass profile in T2DM patients with verified coronary artery disease (CAD). 58 patients with T2DM (HbA1c < 8.5%) and CAD were enrolled in a 16-week, randomized, double-blind and placebo-controlled trial with rosiglitazone 8 mg/day (n = 29) or placebo (n = 29). The LDL subclass profile was measured with gel electrophoresis. Rosiglitazone improved insulin sensitivity and glycemic control. Total cholesterol did not change after rosiglitazone treatment (p = 0.062, ANCOVA adjusted for gender and baseline values), whereas LDL (including IDL) cholesterol increased from 2.33 +/- 0.48 to 2.67 +/- 0.61 mmol/l (p = 0.002 vs. baseline, p = 0.0497 vs. placebo) and large buoyant LDL (large-LDL < 250A) increased from 1.31 +/- 0.36 to 1.46 +/- 0.42 mmol/l (p = 0.010 vs. baseline, p = 0.044 vs. placebo) in the rosiglitazone group. No significant changes occurred to the concentration of small-LDL (< 250A), the average LDL particle size, or HDL or triglyceride concentrations. Whole-body insulin sensitivity was associated with the average LDL particle size after intervention in the whole population (r = 0.40, p = 0.002) and in the rosiglitazone group (r = 0.43, p = 0.020). In conclusion, in T2DM patients with CAD, rosiglitazone treatment significantly increases the concentration of large (buoyant) LDL cholesterol, but not of small dense LDL cholesterol. The long term consequences of this divergent effect of rosiglitazone on LDL subfractions require further exploration.
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PMID:The effect of PPARgamma-agonism on LDL subclass profile in patients with type 2 diabetes and coronary artery disease. 1749 10


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