Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Orexins (hypocretins) are lateral hypothalamic neuropeptides implicated in regulating feeding and the sleep-wake cycle. To study their possible relevance to obesity and diabetes, we measured hypothalamic prepro-orexin mRNA levels in obese, normoglycemic Zucker fatty (fa/fa) and in hyperglycemic, non-obese Zucker diabetic fatty (ZDF) rats. Hypothalamic prepro-orexin mRNA concentrations in Zucker fatty rats were 31% lower than those in lean controls (0. 69+/-0.06 vs. 1.00+/-0.10 arbitrary units, P<0.05), but did not differ between ZDF diabetic rats and non-diabetic controls. Treatment of ZDF diabetic rats with rosiglitazone (1 or 3 mg/kg body weight daily for 13 weeks) normalized plasma glucose and significantly reduced plasma insulin, while leptin levels were 67% higher than in untreated ZDF rats (20.2+/-0.5 vs. 12.1+/-2.5, P<0. 001). Rosiglitazone treatment markedly enhanced weight gain compared with untreated ZDF rats (final weight 732+/-13 g vs. 409+/-13 g, P<0. 001) even though they were restricted to the same food intake. Rosiglitazone-treated ZDF rats had significantly lower hypothalamic prepro-orexin mRNA levels (0.68+/-0.07 arbitrary units) than both non-diabetic lean controls (1.00+/-0.10, P=0.02) and untreated diabetics (1.03+/-0.14, P=0.03). Our data suggest that prepro-orexin gene expression may be suppressed by substantial weight gain. Obesity-related signals that might mediate this effect have not been identified, but plasma leptin, insulin and glucose are not obviously involved.
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PMID:Down-regulation of orexin gene expression by severe obesity in the rats: studies in Zucker fatty and zucker diabetic fatty rats and effects of rosiglitazone. 1081 39

Rosiglitazone (Avandiatrade mark) is a new generation thiazolidinedione used in the treatment of Type 2 diabetes. As with other thiazolidinediones, it binds to the gamma-isoform of the peroxisome proliferator-activated receptor (PPAR), a nuclear hormone receptor. Subsequent to PPAR-gamma activation, rosiglitazone increases insulin suppression of hepatic glucose output and increases peripheral glucose uptake in the muscles, thereby improving the glycaemic state of the individual. In rodent models of obesity and Type 2 diabetes, rosiglitazone has been shown to have positive effects in the main target organs responsible for the condition, namely the liver, pancreas, skeletal muscle and adipose tissue. These studies also suggest that rosiglitazone may help in preserving renal and pancreatic function that deteriorates in chronic hyperinsulinaemia. In clinical studies, rosiglitazone has been shown to be effective, safe and well-tolerated, not only when used as monotherapy, but also when used in combination with sulphonylureas, metformin or insulin. Unlike troglitazone, rosiglitazone is not metabolised via CYP3A4 and is thus unlikely to be subject to clinically important drug interactions. In addition, no evidence of hepatotoxicity has been associated with rosiglitazone to date. Rosiglitazone should therefore be strongly considered as part of the overall management of Type 2 diabetes.
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PMID:Rosiglitazone: a new therapy for Type 2 diabetes. 1113 21

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

Obesity is associated with risk factors for cardiovascular disease, including insulin resistance, and can lead to cardiac hypertrophy and congestive heart failure. Here, we used the insulin-sensitizing agent rosiglitazone to investigate the cellular mechanisms linking insulin resistance in the obese Zucker rat heart with increased susceptibility to ischemic injury. Rats were treated for 7 or 14 days with 3 mg/kg per os rosiglitazone. Hearts were isolated and perfused before and during insulin stimulation or during 32 min low-flow ischemia at 0.3 ml small middle dot min(-1) small middle dot grams wet wt(-1) and reperfusion. D[2-(3)H]glucose was used as a tracer of glucose uptake, and phosphorus-31 nuclear magnetic resonance spectroscopy was used to follow energetics during ischemia. At 12 months of age, obese rat hearts were insulin resistant with decreased GLUT4 protein expression. During ischemia, glucose uptake was lower and depletion of ATP was greater in obese rat hearts, thereby significantly impairing recovery of contractile function during reperfusion. Rosiglitazone treatment normalized the insulin resistance and restored GLUT4 protein levels in obese rat hearts. Glucose uptake during ischemia was also normalized by rosiglitazone treatment, thereby preventing the greater loss of ATP and restoring recovery of contractile function to that of lean rat hearts. We conclude that rosiglitazone treatment, by normalizing glucose uptake, protected obese rat hearts from ischemic injury.
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PMID:Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker Fatty rat heart. 1191 33

The insulin sensitizer drug, rosiglitazone, has been shown to have a protective effect on pancreatic islet cell structure and function in animal models of type 2 diabetes. The identification of new molecular targets associated both with islet cell dysfunction and protection is a crucial research goal. In the present study, a proteomics approach has been used to identify such targets. Obese C57Bl/6J lep/lep mice and lean littermates were given the insulin sensitizer drug BRL49653, rosiglitazone. It normalized the impaired glucose tolerance in lep/lep mice but had no significant effect on glucose tolerance in the lean mice. Pancreatic islet polypeptides were arrayed by a two-dimensional gel electrophoresis system that separated more than 2500 individual spots. Three overexpressed and six underexpressed proteins were significant (p < 0.05) between lep/lep and lean mice, and four were modulated significantly (p < 0.05) by the rosiglitazone treatment of the obese mice. The identity of these differentially expressed proteins was made using mass spectrometric analysis and provided evidence that differential expression of actin-binding proteins may be an important aspect of defective islet function. Rosiglitazone increased carboxypeptidase B expression in both lep/lep and normal mice suggesting that this might be an independent effect of rosiglitazone that contributes to improved insulin processing.
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PMID:Effect of rosiglitazone on the differential expression of diabetes-associated proteins in pancreatic islets of C57Bl/6 lep/lep mice. 1223 79

Peroxisome proliferator-activated receptors (PPARs) participate in the molecular mechanism of pathologies with altered lipid homeostasis such as type 2 diabetes or obesity. The insulin sensitizer drug, rosiglitazone, has been shown to bind and activate PPAR-gamma1 in adipocytes and PPAR-gamma2 in hepatocytes. The identification of new molecular targets associated with fatty acid oxidation and PPAR-gamma nuclear receptor regulation in insulin resistance tissues is a key research goal. In the present study, we have used a proteomic approach to identify such targets. Lean and obese C57 Bl/6J lep/lep mice were given BRL49653, rosiglitazone, 10 mg/kg diet, by dietary admixture for 7 days. Rosiglitazone normalized the impaired glucose tolerance and dyslipidemia in lep/lep mice but had no significant effect in the lean mice. Samples of liver, white and brown adipose tissue, and muscle proteins were obtained and 100 microg of proteins was arrayed by two-dimensional gel electrophoresis. Thirty-four polypeptides were differentially expressed (p < 0.05) between lep/lep and lean mice and eleven were significantly (p < 0.05) modulated by rosiglitazone treatment of the obese mice. None of the proteins was modulated by rosiglitazone treatment of the lean mice. The identity of these differentially expressed proteins was made using tandem mass spectrometric analysis and revealed components of fatty acid and carbohydrate metabolism as well as proteins with unknown function.
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PMID:Effect of rosiglitazone on the differential expression of obesity and insulin resistance associated proteins in lep/lep mice. 1292 76

Burgeoning obesity is increasing the prevalence of type II diabetes mellitus. As a consequence, there will be an even greater burden of cardiovascular disease, end-stage renal disease, blindness, and lower extremity amputations. If diagnosed, impaired glucose tolerance presents an opportunity for intervention that potentially could delay or prevent the development of diabetes. Recent prospective studies document the effectiveness of exercise and weight reduction in preventing diabetes. Metformin is less effective than intense lifestyle interventions. Acarbose, losartan, orlistat, pravastatin, ramipril, and hormone replacement therapy are associated with lower rates of the development of diabetes. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial and the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial were designed to assess not only the prevention of diabetes but also the impact on cardiovascular morbidity and mortality.
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PMID:Preventing type II diabetes mellitus. 1505 49

We hypothesized that improved glucose tolerance with rosiglitazone treatment would coincide with decreased levels of i.m. triacylglycerol (IMTG), diacylglycerol, and ceramide. Obese Zucker rats were randomly divided into two experimental groups: control (n = 9) and rosiglitazone (n = 9), with lean Zucker rats (n = 9) acting as a control group for obese controls. Rats received either vehicle or 3 mg/kg rosiglitazone for 6 wk. Glucose tolerance was impaired (P < 0.01) in obese compared with lean rats, but was normalized after rosiglitazone treatment. IMTG content was higher in obese compared with lean rats (70.5 +/- 5.1 vs. 27.5 +/- 2.0 micromol/g dry mass; P < 0.05) and increased an additional 30% (P < 0.05) with rosiglitazone treatment. Intramuscular fatty acid composition shifted toward a higher proportion of monounsaturates (P < 0.05) in obese rosiglitazone-treated rats due to an increase in palmitoleate (16:1; P < 0.05). Rosiglitazone treatment increased (P < 0.05) skeletal muscle diacylglycerol and ceramide levels by 65% and 100%, respectively, compared with obese rats, but elevated muscle diacylglycerol was not associated with changes in the total or membrane contents of the diacylglycerol-sensitive protein kinase C isoforms theta;, delta, alpha, and beta. In summary, we observed a disassociation among skeletal muscle IMTG, diacylglycerol and ceramide content, and glucose tolerance with rosiglitazone treatment in obese Zucker rats. Our data suggest, therefore, that rosiglitazone enhances glucose tolerance by mechanisms other than reduction of fatty acid accumulation within skeletal muscle.
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PMID:Rosiglitazone enhances glucose tolerance by mechanisms other than reduction of fatty acid accumulation within skeletal muscle. 1537 26

We previously demonstrated that transgenic mice overexpressing mouse apolipoprotein A-II (apoA-II) exhibit several traits associated with the insulin resistance (IR) syndrome, including increased atherosclerosis, hypertriglyceridemia, obesity, and IR. The skeletal muscle appeared to be the insulin-resistant tissue in the apoA-II transgenic mice. We now demonstrate a decrease in FA oxidation in skeletal muscle of apoA-II transgenic mice, consistent with reports that decreased skeletal muscle FA oxidation is associated with increased skeletal muscle triglyceride accumulation, skeletal muscle IR, and obesity. The decrease in FA oxidation is not due to decreased carnitine palmitoyltransferase 1 activity, because oxidation of palmitate and octanoate were similarly decreased. Quantitative RT-PCR analysis of gene expression demonstrated that the decrease in FA oxidation may be explained by a decrease in medium chain acyl-CoA dehydrogenase. We previously demonstrated that HDLs from apoA-II transgenic mice exhibit reduced binding to CD36, a scavenger receptor involved in FA metabolism. However, studies of combined apoA-II transgenic and CD36 knockout mice suggest that the major effects of apoA-II are independent of CD36. Rosiglitazone treatment significantly ameliorated IR in the apoA-II transgenic mice, suggesting that the underlying mechanisms of IR in this animal model may share common features with certain types of human IR.
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PMID:Mechanisms mediating insulin resistance in transgenic mice overexpressing mouse apolipoprotein A-II. 1546 64


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