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)

Retinoid X receptor (RXR) is a nuclear receptor that functions as an obligate heterodimeric partner of peroxisome proliferator-activator receptor (PPAR). Studies have shown that the alpha isoform of RXR and PPARgamma act synergistically to regulate gene expression and insulin action. The aim of the current study was to compare the expression and regulation of RXR in the primary insulin-sensitive tissue, skeletal muscle, of various degrees of insulin-resistant states including obese type 2 diabetic (T2D), obese nondiabetic (OND), and lean nondiabetic (LND) subjects. Insulin action/resistance was determined by a 3-hour hyperinsulinemic, euglycemic (5.0 to 5.5 mmol/L) clamp. Percutaneous biopsy of the vastus lateralis muscle was performed before and after the clamp. RXRalpha mRNA was measured using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay, while protein was determined by Western blotting. All 3 isoforms of RXR, alpha, beta, and gamma, were present in skeletal muscle. Protein expression of RXR isoforms did not differ between groups; RXR alpha mRNA was also similar between groups. Neither RXR alpha mRNA, RXR -beta nor -gamma protein displayed significant relationships with any of the clinical or laboratory parameters measured, including insulin sensitivity. RXR alpha exhibited a negative correlation with free fatty acids levels (r, -.42, P <.05). There was also no relationship between RXR alpha and PPARgamma protein levels. RXR alpha mRNA was unaltered following insulin infusion. We conclude that RXR isoform (alpha, beta, gamma) expression is not tightly controlled by insulin, insulin resistance or type 2 diabetes. Instead, RXR isoforms are likely constitutive proteins or controlled by other factors.
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PMID:Retinoid X receptor expression in skeletal muscle of nondiabetic, obese and type 2 diabetic individuals. 1143 90

The recent discovery and marketing of a new class of antidiabetic drug improving insulin sensitivity, the thiazolidinediones (TZD), has opened interesting therapeutic perspectives. Those molecules correct hyperglycemia and hyperinsulinemia in several animal models of NIDDM. Clinical studies in human have confirmed that TZD lowered postprandial and postabsorptive glycemia and insulinemia. Glucose clamp studies have clearly shown an improvement of insulin-induced glucose utilization (in skeletal muscle). In contrast, the inhibition of glucose production in response to insulin was much less reproducible. TZD have also been used with success to treat insulin resistance in non-diabetic obeses, in glucose-intolerant prediabetic subjects and in patients with polycystic ovary syndrome (pcos). Nevertheless, TZD appears less efficient in human than in animal models. TZD bind to an isoform of a nuclear receptor, the PPARgamma (Peroxisome Proliferator Activated Receptor). PPAR gamma is a transcription factor which, after heterodimerization with the retinoid receptor (RXR), bind to specific response elements of a number of target genes and control their transcription. There is an excellent correlation between the hypoglycemic effects of TZD in vivo and their affinity for PPARgamma in vitro, but the site of action and the molecular mechanism of TZD still remain poorly known. In human, skeletal muscles are responsible for more than 80% of glucose uptake in response to insulin. Unfortunately, skeletal muscles contain limited amounts of PPAR gamma. How TZD with the principal site of action being adipose tissue, can improve glucose metabolism in skeletal muscle? One possibility is the following Another possibility is that chronic treatment with TZD induces PPAR gamma expression in skeletal muscles. Finally, TZD could have a direct effect on skeletal muscles, independently of PPARgamma.
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PMID:[Mechanisms of action of thiazolidinediones]. 1145 21

The thiazolidine-dione derivatives are a new class of oral blood-glucose lowering drugs in type 2 diabetes. They increase the sensitivity of target tissues to insulin, thereby reducing insulin resistance. They act by activation of a specific nuclear receptor--the peroxisome proliferator-activated receptor gamma (PPAR-gamma)--which increases transcription of certain genes involved in adipocyte differentiation and lipid and glucose metabolism. They increase glucose disposal, reduce hepatic glucose output and reduce both plasma glucose and circulating insulin. By reducing insulin requirements the hypersecretion of the beta cell can be diminished, thereby sparing beta cell function. Thiazolidine-dione derivatives reduce plasma glycosylated haemoglobin (HbA1c) by about 1 to 2%. Combination therapy with sulphonylurea derivatives or metformin seems to be more effective, i.e. lower dosages of either agent or both are sufficient to achieve the same reduction in plasma glucose and HbA1c as monotherapy. The thiazolidine-dione derivatives are generally well tolerated and the new drugs such as rosiglitazone and pioglitazone do not seem to be associated with idiosyncratic hepatotoxicity.
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PMID:[The thiazolidinedione derivates: a new class of oral blood glucose lowering agents]. 1160 21

Rosiglitazone(RSG) is an oral antidiabetic agent of the thiazolidinedion(TDZ) class that exerts its antihyperglycemic effect by reducing insulin resistance. Actions of TDZs is thought to be mediated primarily through activating the nuclear receptor peroxisome proliferator activated receptor-gamma (PPAR-gamma). RSG has a higher affinity for PPAR-gamma than troglitazone or pioglitazone and the in vivo antidiabetic potency of RSG is correlated with its high biding affinity. In animal models of insulin resistance, RSG decreased plasma glucose, triglyceride and insulin levels and also prevented diabetic nephropathy and pancreatic islet cell degeneration. In clinical study, RSG, alone or in combination with other diabetic agents(metformin or sulphonylurea), produces significant improvements in HbA1c levels with type 2 diabetes mellitus. Attention should be paid on liver function in patients taking RSG.
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PMID:[Rosiglitazone(BRL-49653)]. 1171 7

Two members of the group, thiazolidinediones, have been approved for the treatment of type 2 diabetes mellitus. These novel oral antihyperglycaemic agents reduce insulin resistance through binding to and activation of the nuclear receptor, PPAR gamma, with subsequent effects on the glucose and lipid homoeostasis. The compounds will probably exhibit beneficial effects on other facets of the metabolic syndrome. Their effectiveness on glycaemic control appears comparable, as assessed by the literature available. HbA1c is lowered by 1.0 to 1.5%. Both drugs are approved for combination therapy with either metformin or sulphonylureas, not as monotherapy or in combination with insulin. Disturbed heart function (NYHA I-IV) is a contra-indication. In contrast to troglitazone, there is so far no evidence of liver toxicity. In spite of the limited literature, it is anticipated that the present class of oral hypoglycaemic agents will turn out to be an important contribution to improving the metabolic control of patients with type 2 diabetes, if the safety profile remains unchanged in long-term studies.
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PMID:[Thiazolidinediones--a new class of oral antidiabetics]. 1171 52

The thiazolidinediones (TZDs) or 'glitazones' are a new class of oral antidiabetic drugs that improve metabolic control in patients with type 2 diabetes through the improvement of insulin sensitivity. TZDs exert their antidiabetic effects through a mechanism that involves activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR gamma), a nuclear receptor. TZD-induced activation of PPAR gamma alters the transcription of several genes involved in glucose and lipid metabolism and energy balance, including those that code for lipoprotein lipase, fatty acid transporter protein, adipocyte fatty acid binding protein, fatty acyl-CoA synthase, malic enzyme, glucokinase and the GLUT4 glucose transporter. TZDs reduce insulin resistance in adipose tissue, muscle and the liver. However, PPAR gamma is predominantly expressed in adipose tissue. It is possible that the effect of TZDs on insulin resistance in muscle and liver is promoted via endocrine signalling from adipocytes. Potential signalling factors include free fatty acids (FFA) (well-known mediators of insulin resistance linked to obesity) or adipocyte-derived tumour necrosis factor-alpha (TNF-alpha), which is overexpressed in obesity and insulin resistance. Although there are still many unknowns about the mechanism of action of TZDs in type 2 diabetes, it is clear that these agents have the potential to benefit the full 'insulin resistance syndrome' associated with the disease. Therefore, TZDs may also have potential benefits on the secondary complications of type 2 diabetes, such as cardiovascular disease.
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PMID:The mode of action of thiazolidinediones. 1192 33

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor transcription factor that regulates adipocyte differentiation and glucose homeostasis. PPARgamma agonists are potent therapeutic agents for the treatment of type 2 diabetes and obesity. PPARgamma agonists also prevent inflammation in animal models, suggesting their use for the treatment of human inflammatory diseases. Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating disease model of multiple sclerosis (MS) and IL-12 plays a crucial role in the pathogenesis of EAE and MS. In this study we have examined the effect of PPARgamma agonists on the pathogenesis of EAE. In vivo treatment of SJL/J mice with PPARgamma agonists, 15-deoxydelta(12,14) prostaglandin J2 or Ciglitazone, decreased the duration and clinical severity of active immunization and adoptive transfer models of EAE. PPARgamma agonists inhibited EAE in association with a decrease in IL-12 production and differentiation of neural antigen-specific Th1 cells. In vitro treatment of activated T cells with PPARgamma agonists inhibited IL-12-induced activation of JAK-STAT signaling pathway and Th1 differentiation. These findings highlight the fact that PPARgamma agonists regulate central nervous system inflammation and demyelination by inhibiting IL-12 production, IL-12 signaling and Th1 differentiation in EAE.
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PMID:Peroxisome proliferator-activated receptor-gamma agonists inhibit experimental allergic encephalomyelitis by blocking IL-12 production, IL-12 signaling and Th1 differentiation. 1196 Mar 3

In the last few years there has been an explosion of research that has improved our understanding of the pathogenesis of Type 2 diabetes mellitus (DM-2) and has led to the development of new oral antidiabetic drugs. Thiazolidinediones (TZDs) are the newest of these antidiabetic agents. TZDs are insulin sensitisers that depend on the presence of insulin for their action. They target insulin resistance, which is thought to play a central role in DM-2 and the associated metabolic syndrome characterised by central obesity, hypertension, dyslipidemia and hypercoagulability, all leading to increased cardiovascular morbidity and mortality. As a result, TZDs have the potential to improve other conditions associated with the metabolic syndrome, in addition to their glycaemic action. TZDs act by activating peroxisome proliferator-activated receptor (PPAR) phi a nuclear receptor implicated not only in lipid and glucose metabolism but other physiological functions as well. TZDs may have wide clinical applications beyond DM-2, as they can potentially be used to treat other conditions associated with insulin resistance and PPAR-phi receptors, such as impaired glucose tolerance, polycystic ovarian syndrome and HIV lipodystrophy.
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PMID:Thiazolidinediones in the treatment of type 2 diabetes. 1199 32

The thiazolidinediones (TZD), a new class of oral antidiabetic agent, act by improving insulin sensitivity. TZD correct hyperglycemia and hyperinsulinism in several animal models of NIDDM. Clinical studies in human have confirmed that TZD lowered postprandial and postabsorbtive glycemia and insulinemia. Glucose clamp studies have clearly shown a 30% improvement of insulin-induced glucose utilisation in skeletal muscle. TZD bind to an isoform of a nuclear receptor, the PPARgamma (Peroxisome Proliferator-Activated Receptor). PPARgamma is a transcription factor which, after heterodimerisation with the retinoid receptor (RXR), binds to specific response elements of a number of target genes, and control their transcription. How TZD, with their principal site of action being adipose tissue, can improve glucose metabolism in skeletal muscle? In human, skeletal muscles are responsible for more than 80% of glucose uptake in response to insulin and skeletal muscles contain only a limited amount of PPARgamma! This is the paradox to which we attempt to answer.
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PMID:[PPARgamma and insulin resistance]. 1203 3

Several cardiovascular risk factors (dyslipidaemia, hypertension, glucose intolerance, hypercoagulability, obesity, hyperinsulinaemia and low-grade inflammation) cluster in the insulin resistance syndrome. Treatment of these individual risk factors reduces cardiovascular complications. However, targeting the underlying pathophysiological mechanisms of the insulin resistance syndrome is a more rational treatment strategy to further improve cardiovascular outcome. Our understanding of the so-called cardiovascular dysmetabolic syndrome has been improved by the discovery of nuclear peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated transcription factors belonging to the nuclear receptor superfamily. As transcription factors, PPARs regulate the expression of numerous genes and affect glycaemic control, lipid metabolism, vascular tone and inflammation. Activation of the subtype PPAR-gamma improves insulin sensitivity. Expression of PPAR-gamma is present in several cell types involved in the process of atherosclerosis. Thus, modulation of PPAR-gamma activity is an interesting therapeutic approach to reduce cardiovascular events. Thiazolidinediones are PPAR-gamma agonists and constitute a new class of pharmacological agents for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Two such compounds are currently available for clinical use: rosiglitazone and pioglitazone. Thiazolidinediones improve insulin sensitivity and glycaemic control in patients with type 2 diabetes. In addition, improvement in endothelial function, a decrease in inflammatory conditions, a decrease in plasma levels of free fatty acids and lower blood pressure have been observed, which may have important beneficial effects on the vasculature. Several questions remain to be answered about PPAR-gamma agonists, particularly with respect to the role of PPAR-gamma in vascular pathophysiology. More needs to be known about the adverse effects of thiazolidinediones, such as hepatotoxicity, increased low-density lipoprotein cholesterol levels and increased oedema. The paradox of adipocyte differentiation with weight gain concurring with the insulin-sensitising effect of thiazolidinediones is not completely understood. The decrease in blood pressure induced by thiazolidinedione treatment seems incompatible with an increase in the plasma volume, and the discrepancy between the stimulation of the expression of CD36 and the antiatherogenic effects of the thiazolidinediones also needs further explanation. Long-term clinical trials of thiazolidinediones with cardiovascular endpoints are currently in progress. In conclusion, studying the effects of thiazolidinediones may shed more light on the mechanisms involved in the insulin resistance syndrome. Furthermore, thiazolidinediones could have specific, direct effects on processes involved in the development of vascular abnormalities.
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PMID:Metabolic and additional vascular effects of thiazolidinediones. 1209 15


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