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)

The recently identified uncoupling protein-3 (UCP-3) gene, predicted to encode a new member of the family of uncoupling proteins, is preferentially expressed in skeletal muscle and has been related to phenotypes of obesity and type 2 diabetes. We have established that during mouse ontogeny, the expression of the UCP-3 gene is switched on in skeletal muscle just after birth. The induction of UCP-3 gene expression is dependent on the initiation of suckling and particularly on lipid intake. Treatment of newborn mice with activators of peroxisome proliferator-activated receptors (PPARs), such as clofibrate, bezafibrate, or (4-chloro-6-(2,3-xylidine)-pirimidinylthio)acetic acid (WY 14,643), mimics the action of food intake on UCP-3 gene expression. The specific ligand of PPAR-alpha WY 14,643 induces UCP-3 gene expression in a time- and dose-dependent manner, whereas the thiazolidinedione BRL 49653, specific for PPAR-gamma, has no effect. These treatments act without altering circulating free fatty acids. During development, skeletal muscle expresses constitutive levels of PPAR-delta mRNA, whereas expression of the PPAR-gamma gene is undetectable. PPAR-alpha gene expression is developmentally regulated in muscle as it is first expressed at birth, just before UCP-3 gene induction occurs. The induction of UCP-3 gene expression by WY 14,643 is impaired in skeletal muscle of premature neonates, which do not express PPAR-alpha. It is proposed that the UCP-3 gene is predominantly regulated in neonatal muscle by PPAR-alpha activation.
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PMID:Activators of peroxisome proliferator-activated receptor-alpha induce the expression of the uncoupling protein-3 gene in skeletal muscle: a potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene expression at birth. 1034 7

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that play an important role in the regulation of genes involved in lipid utilization and storage, lipoprotein metabolism, adipocyte differentiation, and insulin action. The three isoforms of the PPAR family, i.e. alpha, delta, and gamma, have distinct tissue distribution patterns. PPAR-alpha is predominantly present in the liver, and PPAR-gamma in adipose tissue, whereas PPAR-delta is ubiquitously expressed. A recent study reported increased PPAR-gamma messenger RNA (mRNA) expression in the liver in ob/ob mice; however, it is not known whether increased PPAR-gamma expression in the liver has any functional consequences. The expression of PPAR-alpha and -delta in the liver in obesity has not been determined. We have now examined the mRNA levels of PPAR-alpha, -delta, and -gamma in three murine models of obesity, namely, ob/ob (leptin-deficient), db/db (leptin-receptor deficient), and serotonin 5-HT2c receptor (5-HT2cR) mutant mice. 5-HT2cR mutant mice develop a late-onset obesity that is associated with higher plasma leptin levels. Our results show that PPAR-alpha mRNA levels in the liver are increased by 2- to 3-fold in all three obese models, whereas hepatic PPAR-gamma mRNA levels are increased by 7- to 9-fold in ob/ob and db/db mice and by 2-fold in obese 5-HT2cR mutant mice. PPAR-delta mRNA expression is not altered in ob/ob or db/db mice. To determine whether increased PPAR-gamma expression in the liver has any functional consequences, we examined the effect of troglitazone treatment on the hepatic mRNA levels of several PPAR-gamma-responsive adipose tissue-specific genes that have either no detectable or very low basal expression in the liver. The treatment of lean control mice with troglitazone significantly increased the expression of adipocyte fatty acid-binding protein (aP2) and fatty acid translocase (FAT/CD36) in the liver. This troglitazone-induced increase in the expression of aP2 and FAT/CD36 was markedly enhanced in the liver in ob/ob mice. Troglitazone also induced a pronounced increase in the expression of uncoupling protein-2 in the liver in ob/ob mice. In contrast to the liver, troglitazone did not increase the expression of aP2, FAT/CD36, and uncoupling protein-2 in adipose tissue in lean or ob/ob mice. Taken together, our results suggest that the effects of PPAR-gamma activators on lipid metabolism and energy homeostasis in obesity and type 2 diabetes may be partly mediated through their effects on PPAR-gamma in the liver.
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PMID:Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice. 1108 32

PPARdelta (peroxisome proliferator-activated receptor delta)-specific agonists decrease plasma lipids and insulinaemia in obese animals. As skeletal muscle is one of the major organs for fatty acid catabolism, we have investigated the roles of the nuclear receptor in the control of muscle development and lipid metabolism, by using two approaches. We have used C(2)C(12) myotubes in which the PPARdelta activity was altered by overexpression of either native or dominant-negative (DN) mutant forms of PPARdelta. Treatment of C(2)C(12) cells by specific PPARdelta agonists promotes expression of genes for proteins of fatty acid catabolism and increases fatty acid oxidation. These responses were increased in C(2)C(12)-PPARdelta cells and impaired in C(2)C(12)-PPARdeltaDN cells. We also constructed animal models with muscle-specific expression of PPARdelta (Cre/Lox approach). The effects of muscle-specific alteration of PPARdelta activity were studied on muscle development and metabolism as well as on body fat mass. These experiments indicated that PPARdelta plays a crucial role in myofibre typing determination and regulation of muscle oxidative capabilities, and that muscle-specific overexpression of the nuclear receptor leads to reduction of adipocyte size and body fat mass. These data strongly suggest that PPARdelta controls fatty acid catabolism in muscle and that its activation by synthetic agonists could prevent or correct obesity and type 2 diabetes.
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PMID:Roles of PPARdelta in the control of muscle development and metabolism. 1464 Oct 10

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the superfamily of nuclear receptors. Three isoforms (alpha, delta, and gamma) have been described. They act on DNA response elements as heterodimers with the nuclear retinoic acid receptor. Their natural activating ligands are fatty acids and lipid-derived substrates. PPAR-alpha is present in liver, heart, and, to a lesser extent, skeletal muscle. When activated, it promotes fatty acid oxidation, ketone body synthesis, and glucose sparing. Fibrates, which are used as hypolipidemic drugs, are ligands of PPAR-alpha. PPAR-delta is ubiquitous and could also favor fatty acid oxidation in tissues in which PPAR-alpha is absent or less expressed. PPAR-gamma is expressed in adipose tissue, lower intestine, and cells involved in immunity. Activation of PPAR-gamma induces the differentiation of preadipocytes into adipocytes and stimulates triglyceride storage. Thiazolidinediones are compounds used as hypoglycemic, muscle insulin-sensitizing agents in type 2 diabetes. Unexpectedly, they are activators of PPAR-gamma. Their action on muscle insulin sensitivity may be secondary to the lowering of circulating lipids on PPAR-gamma activation and to the secretion by adipocytes of insulin-sensitizing hormones such as adiponectin, all promoting glucose utilization. The PPARs are thus major regulators of lipid and glucose metabolism, allowing adaptation to the prevailing nutritional environment.
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PMID:The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. 1474 65

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. Three different PPARs, PPAR-alpha, -gamma, and -delta, have been characterized, and they are distinguished from each other by tissue distribution and cell activation. All PPARs are, to different extents, activated by fatty acids and derivatives. Recently, it has been shown that PPAR-delta serves as a widespread regulator of fat burning, suggesting that it might be a potential target in the treatment of obesity and type 2 diabetes. In an effort to identify polymorphic markers in potential candidate genes for type 2 diabetes, we have sequenced PPAR-delta, including -1,500 bp of the 5' flanking region. Nine polymorphisms were identified in PPAR-delta: four in the intron, one in the 5' untranslated region (UTR), and four in the 3' UTR. Among identified polymorphisms, five common sites, including c.-13454G>T, c.-87T>C, c.2022+12G>A, c.2629T>C, and c.2806C>G, were genotyped in subjects with type 2 diabetes and normal control subjects (n = 702). The genetic associations with the risk of type 2 diabetes and metabolic phenotype were analyzed. No significant associations with the risk of type 2 diabetes were detected. However, several positive associations of PPAR-delta polymorphisms with fasting plasma glucose and BMI were detected in nondiabetic control subjects. The genetic information about PPAR-delta from this study would be useful for further genetic study of obesity, diabetes, and other metabolic diseases.
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PMID:Genetic polymorphisms in peroxisome proliferator-activated receptor delta associated with obesity. 1498 73

In this review, the effect of peroxisome proliferator-activated receptor (PPAR) ligands on atherosclerosis is examined. The PPAR-gamma agonist thiazolidinediones are currently indicated for the management of Type 2 diabetes mellitus, and the PPAR-alpha agonist fibrates are used in dyslipidaemia. Here their mechanism of action and the pre-clinical and clinical evidence for the use of these medications for the prevention and treatment of atherosclerotic disease is explored. In addition, the role of PPAR-delta and the possibilities for the role of dual-binding agonists are examined.
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PMID:Peroxisome proliferator-activated receptor ligands in atherosclerosis. 1550 Mar 88

The three peroxisome-proliferator-activated receptor (PPAR) subtypes, PPAR-gamma, PPAR-alpha and PPAR-delta, are nuclear receptors that have been the focus of extensive research during the past decade. These receptors function as lipid sensors that coordinately regulate the expression of large gene arrays and, thereby, modulate important metabolic events. They are also the targets of drugs that are effective in the treatment of metabolic disorders (type 2 diabetes mellitus and atherosclerosis) that afflict industrialized societies at epidemic levels. Ongoing research indicates that modulation of PPAR activity might be an effective therapy for additional maladies associated with the metabolic syndrome, including obesity. Novel PPAR ligands are now being developed that possess broader efficacies and improved tolerability compared with currently available therapeutic agents.
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PMID:PPARs: therapeutic targets for metabolic disease. 1586 Mar 71

Peroxisome proliferator-activated receptor (PPAR)-delta regulates fatty acid oxidation and improves insulin sensitivity. We screened six single nucleotide polymorphisms (SNPs) of the PPAR-delta gene (PPARD) for an association with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in 769 subjects participating in the STOP-NIDDM trial. A 2.7-fold increase in the risk of diabetes was observed in female carriers of the C allele of rs6902123 (95% CI 1.44-5.30; adjusted P = 0.002). In the placebo group, subjects possessing both the 482Ser allele of the PPAR-gamma coactivator-1alpha gene (PGC-1A) and the rare allele of two SNPs of PPARD (rs6902123 and rs3734254) had up to 2.5-fold increased risk for diabetes. Furthermore, women carrying the C allele of rs6902123 of PPARD and the Pro12Pro genotype of the PPAR-gamma2 gene (PPARG2) had a 3.9-fold (95% CI 1.79-8.63; P = 0.001)-higher risk for diabetes than women with protective genotypes. Expression levels of PPAR-delta in subcutaneous adipose tissue of 87 offspring of Finnish patients with type 2 diabetes did not differ among the genotype groups of SNPs of PPARD. We conclude that SNPs in PPARD modify the conversion from IGT to type 2 diabetes, particularly in combination with the SNPs of PGC-1A and PPARG2.
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PMID:Single nucleotide polymorphisms of PPARD in combination with the Gly482Ser substitution of PGC-1A and the Pro12Ala substitution of PPARG2 predict the conversion from impaired glucose tolerance to type 2 diabetes: the STOP-NIDDM trial. 1680 87

The three peroxisome-proliferator-activated receptor (PPAR) subtypes PPAR-alpha, PPAR-gamma, and PPAR-delta are ligand-activated transcription factors of the nuclear receptor family. PPARs form obligate heterodimers with the retinoid X receptor, which bind to peroxisome-proliferator-response elements (PPREs). PPAR-alpha is expressed mainly in liver, brown fat, kidney, heart, and skeletal muscle; PPAR-gamma in intestine and adipose tissue; PPAR-alpha and PPAR-gamma are both expressed in vascular endothelium, smooth muscle cells, macrophages, and foam cells; PPAR-delta in skeletal muscle, human embryonic kidney, intestine, heart, adipose tissue, developing brain, and keratinocytes. Intense interest in the development of drugs with new mechanisms of action for the metabolic syndrome has focused attention on nuclear receptors, such as PPARs that function as regulators of energy homeostasis. Agonists of PPAR-alpha and PPAR-gamma are currently used to treat diabetic dyslipidemia and type 2 diabetes. Dual PPAR-alpha/gamma agonists and PPAR-alpha/gamma/delta pan-agonists are under investigation for treatment of cardiovascular disease and the metabolic syndrome. Selective PPAR modulators (SPPARMs) are PPAR ligands that possess desirable efficacy and improved tolerance. Efforts are being made to identify novel partial agonists or antagonists for PPAR-gamma in order to combine their antidiabetic and antiobesity effects. Glucocorticoids are major mediators of the stress response and could be the link between stress and PPAR activator signaling and thus may affect the downstream metabolic pathways involved in fuel homeostasis.
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PMID:Targeting components of the stress system as potential therapies for the metabolic syndrome: the peroxisome-proliferator-activated receptors. 1714 46

It has been recently reported that activation of PPAR-delta, by specific agonists or genetic manipulation, alleviates dyslipidemia, hyperglycemia, and insulin resistance in animal models of obesity and type 2 diabetes. The purpose of the present study was to determine whether the PPAR-delta agonist has a direct effect on adipokines in visceral adipose tissue of rats and in cultured adipocytes. We examined the expression of visfatin, adiponectin, and resistin mRNA in visceral adipose tissue of Wistar rats fed a high-fat diet and 3T3-L1 adipocytes treated with PPAR-delta agonist (L-165041). Body weight and biochemical measurements were performed. Rats fed a high-fat diet showed a greater increase in body weight than those fed a standard diet (P<0.05), and treatment with L-165041 (10 mg/kg/day) significantly decreased weight gain (P<0.05). The concentration of total cholesterol was lower, and HDL cholesterol was higher in L-165041-treated rats (P<0.05). In the visceral adipose tissue of L-165041-treated rats, visfatin and adiponectin mRNA levels significantly increased compared to those of the untreated rats (P<0.05). However, the expression of resistin decreased in the L-165041-treated rats. Furthermore, in cultured 3T3-L1 adipocytes, the level of visfatin and adiponectin mRNA was up-regulated in response to L-165041 treatment for nine days. By contrast, resistin mRNA levels were down-regulated by L-165041 treatment. The present study provides a novel evidence to suggest that the PPAR-delta agonist has regulatory effects on a variety of adipokines, and these effects might explain some of their metabolic function.
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PMID:Effect of PPAR-delta agonist on the expression of visfatin, adiponectin, and resistin in rat adipose tissue and 3T3-L1 adipocytes. 1741 7


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