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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many patients with type 2 diabetes require treatment with more than one antihyperglycemic drug to achieve optimal glycemic control. The thiazolidinediones are a novel class of oral antihyperglycemic drugs that improve glycemic control primarily by increasing peripheral insulin resistance and sensitizing the skeletal muscle, liver and adipose tissue to the actions of insulin, in addition to improving beta-cell function. One of the many features of the thiazolidinedione class of drugs is their synergism with other antihyperglycemic drugs that have a different mechanism of action. The combination of metformin hydrochloride, a biguanide that enhances glucose uptake in peripheral tissues and reduces hepatic gluconeogenesis, with rosiglitazone maleate, one of the newly available members of the thiazolidinedione family, offers a rational therapeutic approach to the treatment of type 2 diabetes. In patients whose type 2 diabetes is inadequately controlled with metformin monotherapy, the addition of rosiglitazone significantly improves glycemic control, insulin sensitivity and beta-cell function, compared with either drug alone. In addition, this combination therapy has beneficial effects on other cardiovascular risk factors. Rosiglitazone maleate/metformin hydrochloride combination therapy is well tolerated in patients with type 2 diabetes and has a favorable safety profile. This review summarizes the available evidence on the clinical efficacy and safety of rosiglitazone maleate and metformin hydrochloride combination therapy in patients with type 2 diabetes.
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PMID:Rosiglitazone maleate/metformin hydrochloride: a new formulation therapy for type 2 diabetes. 1551 Feb 36

Thiazolidinediones (TZDs) increase peripheral tissue insulin sensitivity in patients with type 2 diabetes mellitus by activating the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). In bone marrow stromal cell cultures and in vivo, activation of PPARgamma by high doses (20 mg/kg/day) of TZDs has been reported to alter stem cell differentiation by promoting commitment of progenitor cells to the adipocytic lineage while inhibiting osteoblastogenesis. Here, we have examined the in vivo effects of low-dose rosiglitazone (3 mg/kg/day) on bone, administered to mice by gavage for 90 days. Rosiglitazone-treated mice had increased weight when compared with controls, with no significant alterations in serum levels of glucose, calcium or parathyroid hormone (PTH). Bone mineral density (BMD) at the lumbar vertebrae (L1-L4), ilium/sacrum, and total body was diminished by rosiglitazone treatment. Histologically, bone was characterized by decreased trabecular bone volume and increased marrow space with no significant change in bone marrow adipocity. Decreased osteoblast number and activity due to increased apoptotic death of osteoblasts and osteocytes was apparent while osteoclast parameters and serum levels of osteocalcin, alkaline phosphatase activity, and leptin were unaltered by rosiglitazone treatment. Therefore, the imbalance in bone remodeling that follows rosiglitazone administration arises from increased apoptotic death of osteogenic cells and diminished bone formation leading to the observed decrease in trabecular bone volume and BMD. These novel in vivo effects of TZDs on bone are of clinical relevance as patients with type 2 diabetes mellitus and other insulin resistant states treated with these agents may potentially be at increased risk of osteoporosis.
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PMID:Rosiglitazone impacts negatively on bone by promoting osteoblast/osteocyte apoptosis. 1552 88

Insulin resistance is a major endocrinopathy underlying the development of hyperglycaemia and cardiovascular disease in type 2 diabetes. Metformin (a biguanide) and rosiglitazone (a thiazolidinedione) counter insulin resistance, acting by different cellular mechanisms. The two agents can be used in combination to achieve additive glucose-lowering efficacy in the treatment of type 2 diabetes, without stimulating insulin secretion and without causing hypoglycaemia. Both agents also reduce a range of atherothrombotic factors and markers, indicating a lower cardiovascular risk. Early intervention with metformin is already known to reduce myocardial infarction and increase survival in overweight type 2 patients. Recently, a single-tablet combination of metformin and rosiglitazone, Avandamet, has become available. Avandamet is suitable for type 2 diabetic patients who are inadequately controlled by monotherapy with metformin or rosiglitazone. Patients already receiving separate tablets of metformin and rosiglitazone may switch to the single-tablet combination for convenience. Also, early introduction of the combination before maximal titration of one agent can reduce side effects. Use of Avandamet requires attention to the precautions for both metformin and rosiglitazone, especially renal, cardiac and hepatic competence. In summary, Avandamet is a single-tablet metformin-rosiglitazone combination that doubly targets insulin resistance as therapy for hyperglycaemia and vascular risk in type 2 diabetes.
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PMID:Avandamet: combined metformin-rosiglitazone treatment for insulin resistance in type 2 diabetes. 1552 21

We examined the metabolic effects of rosiglitazone therapy on glucose control, insulin sensitivity, insulin secretion, and adiponectin in first-degree relatives of African Americans with type 2 diabetes (DM) with impaired glucose tolerance (IGT) and DM for 3 months. The study was comprised of 12 first-degree relatives with IGT, 17 newly diagnosed DM, and 19 healthy relatives with normal glucose tolerance (NGT). Oral glucose tolerance test (OGTT) was performed before and after 3 months of rosiglitazone therapy (4 to 8 mg/d) in patients with IGT and DM. Serum glucose, insulin, C-peptide, and adiponectin levels were measured before and 2 hours during OGTT in the NGT and patients with IGT and DM. Insulin resistance index (HOMA-IR) and beta-cell function (HOMA-%B) were calculated in each subject using homeostasis model assessment (HOMA). Rosglitazone improved the overall glycemic control in the IGT and DM groups. Following rosiglitazone, the beta-cell secretion remained unchanged, while HOMR-IR was reduced in DM by 30% (4.12 +/- 1.95 v 6.33 +/- 3.54, P < .05) and the IGT group (3.78 +/- 2.45 v 4.81 +/- 3.49, P = not significant [NS]). Mean plasma adiponectin levels were significantly (P < .05) lower in the DM (6.74 +/- 1.95 microg/mL) when compared with the NGT group(9.61 +/- 5.09). Rosiglitazone significantly (P < .001) increased adiponectin levels by 2-fold in patients with IGT (22.2 +/- 10.97 microg/mL) and 2.5-fold greater in DM (15.68 +/- 8.23 microg/mL) at 3 months when compared with the 0 month. We conclude that adiponectin could play a significant role (1) in the pathogenesis of IGT and DM and (2) the beneficial metabolic effects of thiazolidinediones (TZDs) in high-risk African American patients.
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PMID:Effects of rosglitazone on plasma adiponectin, insulin sensitivity, and insulin secretion in high-risk African Americans with impaired glucose tolerance test and type 2 diabetes. 1556 99

Type 2 diabetes mellitus is a complex metabolic disease that occurs when insulin secretion can no longer compensate insulin resistance in peripheral tissues. At the molecular level, insulin resistance correlates with impaired insulin signalling. This review provides new insights into the molecular mechanisms of insulin action and resistance in brown adipose tissue and pinpoints the role of this tissue in the control of glucose homeostasis. Brown adipocytes are target cells for insulin and IGF-I action, especially during late foetal development when insulin supports survival and promotes both adipogenic and thermogenic differentiation. The main pathway involved in insulin induction of adipogenic differentiation, monitored by fatty acid synthase expression, is the cascade insulin receptor substrate (IRS)-1/phosphatidylinositol 3-kinase (PI3K)/Akt. Glucose transport in these cells is maintained mainly by the activity of GLUT4. Acute insulin treatment stimulates glucose transport largely by mediating translocation of GLUT4 to the plasma membrane, involving the activation of IRS-2/PI3K, and the downstream targets Akt and protein kinase C zeta. Tumour necrosis factor (TNF-alpha) caused insulin resistance on glucose uptake by impairing insulin signalling at the level of IRS-2. Activation of stress kinases and phosphatases by this cytokine contribute to insulin resistance. Furthermore, brown adipocytes are also target cells for rosiglitazone action since they show a high expression of peroxisome proliferator activated receptor gamma, and rosiglitazone increased the expression of the thermogenic uncoupling protein 1. Rosiglitazone ameliorates insulin resistance provoked by TNF-alpha, completely restoring insulin-stimulated glucose uptake in parallel to the insulin signalling cascade. Accordingly, foetal brown adipocytes represent a model for investigating insulin action, as well as for the mechanism by which rosiglitazone increase insulin sensitivity under situations that mimic insulin resistance.
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PMID:The brown adipose cell: a model for understanding the molecular mechanisms of insulin resistance. 1565 20

The mechanism responsible for the enhanced myocardial susceptibility to ischemic insult in patients with type 2 diabetes is not clear. The present study examines the effect of rosiglitazone treatment on cardiac insulin sensitization and its association with cardioprotection from ischemia/reperfusion injury in an animal model of diabetes. Male Zucker diabetic fatty (ZDF) rats were treated with rosiglitazone (3 mg . kg(-1) . day(-1) orally) or vehicle for 8 days before undergoing 30 min of coronary artery ligation, followed by reperfusion for 4 h (apoptosis) or 24 h (infarction). Rosiglitazone reduced the blood levels of glucose, triglycerides, and free fatty acids; enhanced cardiac glucose oxidation; and increased Akt phosphorylation (Akt-pS473) 2.1-fold and Akt kinase activity 1.8-fold in the ischemic myocardium. The phosphorylation of two downstream targets of Akt, glycogen synthase kinase-3beta and FKHR (forkhead transcription factor), was also enhanced by 2- and 2.9-fold, respectively. In rosiglitazone-treated rats, the number of apoptotic cardiomyocytes and the myocardial infarct size were decreased by 58 and 46%, respectively, and the myocardial contractile dysfunction was improved. Blockade of the insulin-Akt signaling pathway by wortmannin in the 8-day rosiglitazone-treated ZDF rats resulted in a markedly diminished cardioprotective effect of rosiglitazone. In addition, 8-day rosiglitazone treatment in Zucker lean rats or 2-day rosiglitazone treatment in ZDF rats, both of which showed no change in whole-body insulin sensitivity, resulted in a significant reduction in cardiac infarct size, but to a lesser degree when compared with that observed in 8-day rosiglitazone-treated ZDF rats. These results suggest that chronic treatment with rosiglitazone protects the heart against ischemia/reperfusion injury in ZDF rats, and that the enhanced cardiac protection observed after rosiglitazone treatment might be attributable in part to an improvement in cardiac insulin sensitivity.
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PMID:Rosiglitazone treatment in Zucker diabetic Fatty rats is associated with ameliorated cardiac insulin resistance and protection from ischemia/reperfusion-induced myocardial injury. 1567 15

Rates of type 2 diabetes mellitus are increasing worldwide at an explosive rate. This "epidemic" is largely driven by a concomitant obesity epidemic, which is seen not only in affluent countries, but in industrializing countries as well, concomitant with the rapid change toward Western life-style patterns worldwide. Recent clinical trials such as Heart Outcomes Prevention Evaluation (HOPE), Losartan Intervention for Endpoint reduction (LIFE), and Study of Cognition and Prognosis in the Elderly (SCOPE) have indicated that blocking the renin-angiotensin system (RAS) may reduce the risk of developing type 2 diabetes mellitus. This effect may be explained by a variety of diabetogenic factors, which seem to be moderated by angiotensin II, such as free fatty acids (FFA) and the phenomena of adipocyte differentiation, as well as inflammation and oxidative damage. Insulin resistance, usually present in cases of impaired glucose tolerance, is the major identifiable defect in subjects at risk for type 2 diabetes. Elevated FFA levels result in reduced activation of phosphoinositol-3 kinase, an enzyme that is essential for normal insulin-stimulated glucose uptake. This reduction is potentiated by angiotensin II and consequently insulin-stimulated glucose uptake is improved by RAS inhibition. Furthermore, blockade of the angiotensin II AT(1)-receptor has been shown to stimulate the differentiation of adipocytes that store FFAs, which leads to reduced plasma FFA levels and decreased insulin resistance. There are also data suggesting that AT(1)-receptor blockade reduces inflammatory activation and the production of reactive oxygen species (ROS), a major factor in the pathophysiology of diabetes and a major cardiovascular risk factor. Both proinflammatory molecules and ROS increase the risk of insulin resistance and atherogenesis. It is thought that FFAs and hyperglycemia increase ROS production and oxidative stress, leading to the activation of signaling molecules such as nuclear factor kappa-B and other mediators of stress-sensitive pathways, which increases insulin resistance and will lead to beta-cell dysfunction and diabetic complications during the longer term. Inhibiting the RAS seems to have an effect on several steps in this cascade. There is an obvious need for large-scale clinical trials specifically designed to assess the protective benefits of blocking the RAS in individuals at risk of developing type 2 diabetes. Two such trials on the prevention of type 2 diabetes are ongoing, the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications (DREAM) study and the more ambitious Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, which is also assessing prevention of cardiovascular events.
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PMID:Of the renin-angiotensin system and reactive oxygen species Type 2 diabetes and angiotensin II inhibition. 1569 26

Rosiglitazone (ROSI), thiazolidione peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activator, reduces insulin resistance in patients with type 2 diabetes (T2DM). It also improves vascular reactivity in T2DM patients and some animal models by unclear mechanisms. In order to investigate the effect of ROSI on aortic systolic and diastolic function of insulin resistant-hypertensive rats (IRHR) and the underlying mechanism, male Sprague-Dawley (SD) rats were fed with high fructose (HF) for 8 weeks to induce IRHR model. To verify IRHR model, systolic blood pressure (SBP), fasting blood sugar (FBS), fasting serum insulin (FSI) were measured respectively in each group, and insulin sensitive index (ISI) was also calculated. Subsequently, the vascular function test was performed. The thoracic aortic ring of SD rats was mounted on a bath system. The effect of rosiglitazone on the contraction elicited by L-phenylephrine (PE) and potassium chloride (KCl) and the relaxation induced by acetylcholine (ACh) and sodium nitroprusside (SNP) were measured. To explore the mechanism, nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) was used and serum nitric oxide (NO) was measured. The results obtained were as follows: (1) Rosiglitazone reduced the level of SBP, serum insulin and improved insulin resistance in IRHRs. (2) The contractive responses of thoracic aortic rings to PE and KCl were enhanced and the relaxation response to ACh was depressed significantly in the HF group, and the effect was reversed by ROSI. (3) After pretreatment with L-NAME, the relaxation response to ACh was further impaired in the HF group, this effect was partly reversed by ROSI. (4) Sodium nitroprusside (SNP)-induced vasodilator responses did not differ significantly among the groups. (5) Aortic systolic and diastolic function of the control group was not affected markedly by ROSI. (6) Compared with the control group, serum nitric oxide was significantly reduced in the HF group, but after rosiglitazone treatment it was remarkably increased. These findings suggest that ROSI can improve aortic diastolic function of insulin resistant-hypertensive rats, the mechanism of this effect might be associated with an increase in nitric oxide mediated partly by NOS pathway, a decrease in the level of blood pressure, serum insulin and the improvement of insulin resistance.
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PMID:[Effects of rosiglitazone on aortic function in rats with insulin resistant-hypertension]. 1583 95

Rosiglitazone, an agonist of peroxisome proliferator-activated receptor-gamma (PPAR gamma ), is an insulin-sensitizing antidiabetic agent and inhibits restenosis in animal blood vessels. However, its benefit for patients with type 2 diabetes and coronary artery disease (CAD) after percutaneous coronary intervention is unknown. Patients with diabetes and CAD who had undergone percutaneous coronary intervention were randomized to either receive or not receive rosiglitazone (4 mg/d) for 6 months. After 6 months of rosiglitazone treatment, the plasma levels of fasting glucose and insulin and those of hemoglobin A1C and homeostasis model assessment of insulin resistance were significantly decreased in the rosiglitazone group as compared with baseline levels and those in the control group. After 2 and 6 months of rosiglitazone treatment, the plasma level of high-density lipoprotein was significantly increased in the rosiglitazone group. In addition, plasma levels of monocyte chemoattractant protein-1 and C-reactive protein and hyperresponsiveness of low-dose lipopolysaccharide-induced monocyte chemoattractant protein-1 secretion from monocytes were reduced. Furthermore, the occurrence of coronary events was significantly decreased in the rosiglitazone group at 6-month follow-up. Our data indicate that rosiglitazone may protect the vascular wall through not only improving the features of metabolic disorders but also reducing proinflammatory responses and the occurrence of coronary events in patients with diabetes and CAD after percutaneous coronary intervention.
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PMID:Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces clinical inflammatory responses in type 2 diabetes with coronary artery disease after coronary angioplasty. 1587 88

In the present study, we show that the expression of type 2 glucose transporter isoform (GLUT2) could be regulated by PPAR-gamma in the liver. Rosiglitazone, PPAR-gamma agonist, activated the GLUT2 mRNA level in the primary cultured hepatocytes and Alexander cells, when these cells were transfected with PPAR-gamma/RXR-alpha. We have localized the peroxisome proliferator response element in the mouse GLUT2 promoter by serial deletion studies and site-directed mutagenesis. Chromatin immunoprecipitation assay using ob/ob mice also showed that PPAR-gamma rather than PPAR-alpha binds to the -197/-184 region of GLUT2 promoter. Taken together, liver GLUT2 may be a direct target of PPAR-gamma ligand contributing to glucose transport into liver in a condition when PAPR-gamma expression is increased as in type 2 diabetes or in severe obesity.
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PMID:Identification and characterization of peroxisome proliferator response element in the mouse GLUT2 promoter. 1588 23


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