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)

Members of the peroxisome proliferator-activated receptor (PPAR) family might be involved in pathologies with altered lipid metabolism. They participate in the control of the expression of genes involved in lipid metabolism and adipocyte differentiation. In addition, thiazolidinediones improve insulin resistance in vivo by activating PPAR gamma. However, little is known regarding their tissue distribution and relative expression in humans. Using a quantitative and sensitive reverse transcription (RT)-competitive polymerase chain reaction (PCR) assay, we determined the distribution and relative mRNA expression of the four PPARs (alpha,beta, gamma1, and gamma2) and liver X receptor-alpha (LXR alpha) in the main tissues implicated in lipid metabolism. PPAR alpha and LXR alpha were mainly expressed in liver, while PPAR gamma1 predominated in adipose tissue and large intestine. We found that PPAR gamma2 mRNA was a minor isoform, even in adipose tissue, thus causing question of its role in humans. PPAR beta mRNA was present in all the tissues tested at low levels. In addition, PPAR gamma mRNA was barely detectable in skeletal muscle, suggesting that improvement of insulin resistance with thiazolidinediones may not result from a direct effect of these agents on PPAR gamma in muscle. Obesity and NIDDM were not associated with change in PPARs and LXR alpha expression in adipose tissue. The mRNA levels of PPAR gamma1, the predominant form in adipocytes, did not correlate with BMI, leptin mRNA levels, or fasting insulinemia in 29 subjects with various degrees of obesity. These results indicated that obesity is not associated with alteration in PPAR gene expression in abdominal subcutaneous adipose tissue in humans.
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PMID:Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. 923 57

The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. The PPARgamma1 and gamma2 isoforms result from alternative splicing and have ligand-dependent and -independent activation domains. PPARgamma2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5-10-fold more effective than that of PPARgamma1. Insulin stimulates the ligand-independent activation of PPARgamma1 and gamma2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARgamma2 in human adipocytes. Here, we report that a relatively common Pro12Ala substitution in PPARgamma2 is associated with lower body mass index (BMI; P=0.027; 0.015) and improved insulin sensitivity among middle-aged and elderly Finns. A significant odds ratio (4.35, P=0.028) for the association of the Pro/Pro genotype with type 2 diabetes was observed among Japanese Americans. The PPARgamma2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARgamma2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.
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PMID:A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. 980 49

In diabetes-associated microangiopathies and atherosclerosis, there are alterations of the extracellular matrix (ECM) in the intima of small and large arteries. High levels of circulating nonesterified fatty acids (NEFAs) are present in insulin resistance and type 2 diabetes. High concentrations of NEFAs might alter the basement membrane composition of endothelial cells. In arteries, smooth muscle cells (SMCs) are the major producers of proteoglycans and glycoproteins in the intima, and this is the site of lipoprotein deposition and modification, key events in atherogenesis. We found that exposure of human arterial SMCs to 100-300 micromol/albumin-bound linoleic acid lowered their proliferation rate and altered cell morphology. SMCs expressed 2-10 times more mRNA for the core proteins of the proteoglycans versican, decorin, and syndecan 4 compared with control cells. There was no change in expression of fibronectin and perlecan. The decorin glycosaminoglycan chains increased in size after exposure to linoleic acid. The ECM produced by cells grown in the presence of linoleic acid bound 125I-labeled LDL more tightly than that of control cells. Darglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma ligand, neutralized the NEFA-mediated induction of the decorin gene. This suggests that some of the NEFA effects are mediated by PPAR-gamma. These actions of NEFAs, if present in vivo, could contribute to changes of the matrix of the arterial intima associated with micro- and macroangiopathies.
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PMID:Fatty acids modulate the composition of extracellular matrix in cultured human arterial smooth muscle cells by altering the expression of genes for proteoglycan core proteins. 1007 65

Recent epidemiological data have reaffirmed that elevated plasma triglyceride and low HDL-cholesterol levels are important risk factors for atherosclerotic vascular disease. The rationale for the clinical use of fibric acid derivatives, which are designed to correct this metabolic nexus, is now on firmer ground. The mechanism of action of fibrates on lipoprotein metabolism has recently been elucidated at the molecular level and involves the activation of peroxisome proliferator-activated receptor-alpha 1 in the liver, with the net effect of improving the plasma transport rates of several lipoproteins. Other potential anti-atherothrombotic effects include the inhibition of coagulation and enhancement of fibrinolysis, as well as the inhibition of inflammatory mediators involved in atherogenesis. These consequences probably underpin the favourable effects of fibrates seen in recent angiographic and clinical trials. Two important clinical trials on the effect of gemfibrozil (Veterans Administration-HDL-Cholesterol Intervention Trial) and bezafibrate (Bezafibrate Infarction Prevention Study) have recently been completed in subjects with elevated triglyceride, low HDL and normal or near-normal LDL-cholesterol levels. The results testify to the efficacy of these agents in decreasing the incidence of cardiovascular events, particularly in patients with multiple risk factors and plasma triglyceride levels of over 2.2 mmol/l. The findings of these trials are compared with the statin-based Air Force/Texas Coronary Atherosclerosis Prevention Study, with a recommendation that future studies in appropriately selected patients should examine the synergistic effect of the fibrate/statin combination. The absolute risk reduction in the incidence of coronary events in the Veterans Administration-HDL-Cholesterol Intervention Trial compares favourably with the statin trials. The therapeutic aspects of the efficacy and safety of fibrates are reviewed. Besides primary mixed hyperlipidaemias, particular indications for the clinical use of fibrates include type 2 diabetes, the metabolic syndrome and renal insufficiency. The St Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention Study has suggested that fibrates may decrease the incidence of coronary events in type 2 diabetes, but this hypothesis will be more extensively tested in the Diabetes Atherosclerosis Intervention Study, Fenofibrate in Event Lowering in Diabetes Study and Lipids in Diabetes Study projects. Although significant new knowledge has accrued over the past few years concerning the fundamental and clinical aspects of fibrates, the success of these agents in clinical practice depends on the availability of methods for assessing cardiovascular risk as well as on treatment guidelines, which as presently designed and recommended may be inaccurate and suboptimal.
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PMID:Fibrates, dyslipoproteinaemia and cardiovascular disease. 1068 50

The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-activated transcription factor that regulates several crucial biological processes such as adipogenesis, glucose homeostasis, and cell growth. It is also the functional receptor for a new class of insulin-sensitizing drugs, the thiazolidinediones, now widely used in the treatment of type 2 diabetes mellitus. Here we report that PPARgamma protein levels are significantly reduced in adipose cells and fibroblasts in response to specific ligands such as thiazolidinediones. Studies with several doses of different ligands illustrate that degradation of PPARgamma correlates well with the ability of ligands to activate this receptor. However, analyses of PPARgamma mutants show that, although degradation does not strictly depend on the transcriptional activity of the receptor, it is dependent upon the ligand-gated activation function 2 (AF2) domain. Proteasome inhibitors inhibited the down-regulation of PPARgamma and ligand activation enhanced the ubiquitination of this receptor. These data indicate that, although ligand binding and activation of the AF2 domain increase the transcriptional function of PPARgamma, these same processes also induce ubiquitination and subsequent degradation of this receptor by the proteasome.
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PMID:Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation. 1074 14

Current agents for the treatment of Type 2 diabetes mellitus improve the metabolic profile but do not reinstate normality. They also reduce chronic diabetic complications, but they do not eliminate them. Thus, new agents with novel actions are required to complement and extend the capabilities of existing treatments. Insulin resistance and beta-cell failure, which are crucial components in the pathogenesis of Type 2 diabetes, remain the underlying targets for new drugs. Recently introduced agents include a short-acting non-sulphonylurea insulin-releaser, repaglinide, which synchronizes insulin secretion with meal digestion in order to reduce post-prandial hyperglycaemia. The thiazolidinedione drugs, troglitazone, rosiglitazone and pioglitazone represent a new class of agonists for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). PPARgamma increases the transcription of certain insulin-sensitive genes, thereby improving insulin sensitivity. The intestinal lipase inhibitor orlistat and the satiety-inducer sibutramine are new weight-reducing agents that may benefit glycaemic control in obese Type 2 diabetes patients. Several further new insulin-releasing agents, and agents to retard carbohydrate digestion and modify lipid metabolism stand poised to enter the market. The extent to which they will benefit glycaemic control remains to be seen. However, the prospect of permanently arresting or reversing the progressive deterioration of Type 2 diabetes continues to evade therapeutic capture.
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PMID:New agents for Type 2 diabetes. 1076 69

Troglitazone is a nuclear peroxisome proliferator-activated receptor-gamma agonist with insulin-sensitizing properties that has been introduced for the treatment of type 2 diabetes. To further elucidate its mechanism of action, this study examined direct troglitazone effects on glucose and palmitate utilization in isolated rat soleus muscle. Exposure of muscle specimens for 25 h to 5 micromol/liter troglitazone resulted in the distinct inhibition of insulin-stimulated mitochondrial fuel oxidation as indicated by decreased rates of CO(2) produced from glucose (glucose converted to CO(2), nanomoles per gram per hour: control, 1461 +/- 192 versus troglitazone, 753 +/- 80, P <.0001) and palmitate (palmitate converted to CO(2), nanomoles per gram per hour: control, 75 +/- 5 versus troglitazone, 20 +/- 2, P <.0001). Blunted fuel oxidation was accompanied by increased rates of anaerobic glycolysis (lactate release, micromoles per gram per hour: control, 17.3 +/- 1.0 versus troglitazone, 49.2 +/- 2.7, P <.0001) and glucose transport ([(3)H]2-deoxyglucose transport, cpm per milligram per hour: control, 540 +/- 46 versus troglitazone, 791 +/- 61, P <.0001), as well as by decreased rates of glycogen synthesis (glucose incorporation into glycogen, micromoles per gram per hour: control, 2.00 +/- 0.26 versus troglitazone, 1.02 +/- 0.13, P <.001). Such shift toward anaerobic glucose utilization also was seen in the absence of insulin and with short-term troglitazone exposure for 90 min, indicating an underlying mechanism that is rapid and independent of concomitant insulin stimulation. The results demonstrate direct and acute inhibition of fuel oxidation to CO(2) by troglitazone in rat skeletal muscle in vitro.
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PMID:Troglitazone directly inhibits CO(2) production from glucose and palmitate in isolated rat skeletal muscle. 1077 19

This study has investigated the effects of JTT-501, a peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma agonist, on the pathogenesis of diabetic complications in the Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. Comparison is made with troglitazone, a PPAR-gamma agonist. The ZDF rats exhibited hyperglycaemia and hyperlipidaemia, and developed diabetic complications such as cataract, nephropathy, and neuropathy. Treatment with JTT-501 from the prediabetic stage controlled glycaemia and lipidaemia, and prevented the development of diabetic complications. Troglitazone was less effective in controlling serum cholesterol and neuropathy. ZDF rats developed diabetic osteopenia with reduced bone turnover, and this was prevented by JTT-501 and troglitazone, possibly mediated by increased bone turnover and bone formation. Since JTT-501 controlled glycaemia and lipidaemia in ZDF rats and prevented several diabetic complications, it is suggested that treatment with JTT-501, which activates both PPAR-alpha and PPAR-gamma, could provide a valuable therapeutic approach against diabetic complications in type 2 diabetes.
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PMID:Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonist, JTT-501, on diabetic complications in Zucker diabetic fatty rats. 1082 76

Thiazolidinediones (TZDs) reduce insulin resistance in type 2 diabetes by increasing peripheral uptake of glucose, and they bind to and activate the transcriptional factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Studies have suggested that TZD-induced activation of PPAR-gamma correlates with antidiabetic action, but the mechanism by which the activated PPAR-gamma is involved in reducing insulin resistance is not known. To examine whether activation of PPAR-gamma directly correlates with antidiabetic activities, we compared the effects of 4 TZDs (troglitazone, pioglitazone, BRL-49653, and a new derivative, NC-2100) on the activation of PPAR-gamma in a reporter assay, transcription of the target genes, adipogenesis, plasma glucose and triglyceride levels, and body weight using obese KKAy mice. There were 10- to 30-fold higher concentrations of NC-2100 required for maximal activation of PPAR-gamma in a reporter assay system, and only high concentrations of NC-2100 weakly induced transcription of the PPAR-gamma but not PPAR-alpha target genes in a whole mouse and adipogenesis of cultured 3T3L1 cells, which indicates that NC-2100 is a weak PPAR-gamma activator. However, low concentrations of NC-2100 efficiently lowered plasma glucose levels in KKAy obese mice. These results strongly suggest that TZD-induced activation of PPAR-gamma does not directly correlate with antidiabetic (glucose-lowering) action. Furthermore, NC-2100 caused the smallest body weight increase of the 4 TZDs, which may be partly explained by the finding that NC-2100 efficiently induces uncoupling protein (UCP)-2 mRNA and significantly induces UCP1 mRNA in white adipose tissue (WAT). NC-2100 induced UCP1 efficiently in mesenteric WAT and less efficiently in subcutaneous WAT, although pioglitazone and troglitazone also slightly induced UCP1 only in mesenteric WAT. These characteristics of NC-2100 should be beneficial for humans with limited amounts of brown adipose tissue.
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PMID:A new thiazolidinedione, NC-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice. 1090 84

Genetic association studies are viewed as problematic and plagued by irreproducibility. Many associations have been reported for type 2 diabetes, but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma(PPARgamma) with type 2 diabetes. By analysing over 3,000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (85% frequency). Moreover, our results resolve a controversy about common variation in PPARgamma. An initial study found a threefold effect, but four of five subsequent publications failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPARgamma in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk-influencing as much as 25% of type 2 diabetes in the general population.
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PMID:The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. 1097 53


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