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)

Several lines of evidence support a role for protein tyrosine phosphatase 1B (PTP-1B) in metabolism, and specifically in insulin sensitivity and obesity. We report the development of reagents for the amplification and sequencing of the PTP-1B gene, which has resulted in the identification of a novel single nucleotide polymorphism (SNP), designated 981C-->T. We found a significant association between this SNP and the risk of either impaired glucose tolerance (IGT) or type 2 diabetes in the Oji-Cree of Sandy Lake, Ontario, Canada. Six hundred and fifty-three subjects were genotyped using PCR amplification of exon 8, followed by digestion with the restriction enzyme AvaI. Sixty-eight subjects were heterozygotes, and none was a homozygote. Thus, the overall frequencies of the C allele and the T allele were 0.948 and 0.052, respectively. Subjects with the PTP-1B 981T/981C genotype were approximately 40% less likely to have IGT or diabetes as subjects with the 981C/981C genotype (P = 0.040). There was no difference in quantitative traits among subjects grouped according to the PTP-1B 981C-->T SNP genotype. These very preliminary findings suggest that genomic variation in PTP-1B is associated with a reduced risk of diabetes and are consistent with the idea that this protein is important in metabolism.
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PMID:A single nucleotide polymorphism in protein tyrosine phosphatase PTP-1B is associated with protection from diabetes or impaired glucose tolerance in Oji-Cree. 1183 11

Indirect evidence implicates leptin resistance in the pathogenesis of the lipotoxicity that complicates obesity and results in the metabolic syndrome. In this issue of Developmental Cell, two groups identify protein tyrosine phosphatase 1B (PTP1B) as a cause of leptin resistance through dephosphorylation of Jak2.
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PMID:Protein tyrosine phosphatase 1B: a potential leptin resistance factor of obesity. 1197 Aug 99

Common obesity is primarily characterized by resistance to the actions of the hormone leptin. Mice deficient in protein tyrosine phosphatase 1B (PTP1B) are resistant to diabetes and diet-induced obesity, prompting us to further define the relationship between PTP1B and leptin in modulating obesity. Leptin-deficient (Lep(ob/ob)) mice lacking PTP1B exhibit an attenuated weight gain, a decrease in adipose tissue, and an increase in resting metabolic rate. Furthermore, PTP1B-deficient mice show an enhanced response toward leptin-mediated weight loss and suppression of feeding. Hypothalami from these mice also display markedly increased leptin-induced Stat3 phosphorylation. Finally, substrate-trapping experiments demonstrate that leptin-activated Jak2, but not Stat3 or the leptin receptor, is a substrate of PTP1B. These results suggest that PTP1B negatively regulates leptin signaling, and provide one mechanism by which it may regulate obesity.
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PMID:Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. 1197 Aug 89

Coordinated tyrosine phosphorylation is essential for signalling pathways regulated by insulin and leptin. Type 2 diabetes and obesity are characterised by resistance to hormones insulin and leptin, possibly due to attenuated or diminished signalling from the receptors. Pharmacological agents capable of inhibiting the negative regulator(s) of the signalling pathways are expected to potentiate the action of insulin and leptin and therefore be beneficial for the treatment of Type 2 diabetes and obesity. A large body of data from cellular, biochemical, mouse and human genetic and chemical inhibitor studies have identified protein tyrosine phosphatase 1B (PTP1B) as a major negative regulator of both insulin and leptin signalling. In addition, evidence suggests that insulin and leptin action can be enhanced by the inhibition of PTP1B. Consequently, PTP1B has emerged as an attractive novel target for the treatment of both Type 2 diabetes and obesity. The link between PTP1B and diabetes and obesity has led to an avalanche of research dedicated to finding inhibitors of this phosphatase. With the combined use of structure and medicinal chemistry, several groups have demonstrated that it is feasible to obtain small-molecule PTP1B inhibitors with the requisite potency and selectivity. The challenge for the future will be to transform potent and selective small molecule PTP1B inhibitors into orally available drugs with desirable physicochemical properties and in vivo efficacies.
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PMID:PTP1B inhibitors as potential therapeutics in the treatment of type 2 diabetes and obesity. 1255 16

Recent studies have demonstrated that protein tyrosine phosphatase 1B (PTP1B) is involved in the down regulation of insulin signaling. Selective inhibitors of PTP1B hold much promise for the treatment of type 2 diabetes mellitus and obesity. Consequently much effort, by both industry and academia, has been devoted towards the development of PTP1B specific inhibitors. This article gives an overview of reports that have appeared in the primary scientific literature on the development of PTP1B inhibitors, starting from the days of early development up to September of 2002.
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PMID:Inhibitors of protein tyrosine phosphatase 1B (PTP1B). 1267 43

Protein tyrosine phosphatases regulate signal transduction pathways involving tyrosine phosphorylation and have been implicated in the development of cancer, diabetes, rheumatoid arthritis and hypertension. Increasing evidence suggests that the cellular redox state is involved in regulating tyrosine phosphatase activity through the reversible oxidization of the catalytic cysteine to sulphenic acid (Cys-SOH). But how further oxidation to the irreversible sulphinic (Cys-SO2H) and sulphonic (Cys-SO3H) forms is prevented remains unclear. Here we report the crystal structures of the regulatory sulphenic and irreversible sulphinic and sulphonic acids of protein tyrosine phosphatase 1B (PTP1B), an important enzyme in the negative regulation of the insulin receptor and a therapeutic target in type II diabetes and obesity. We also identify a sulphenyl-amide species that is formed through oxidation of its catalytic cysteine. Formation of the sulphenyl-amide causes large changes in the PTP1B active site, which are reversible by reduction with the cellular reducing agent glutathione. The sulphenyl-amide is a protective intermediate in the oxidative inhibition of PTP1B. In addition, it may facilitate reactivation of PTP1B by biological thiols and signal a unique state of the protein.
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PMID:Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B. 1280 39

This review outlines the physiology of protein tyrosine phosphatase 1B (PTP1B) and its potential involvement in the states of insulin resistance that characterizes both obesity and type 2 diabetes. The primary focus of this review is upon the elucidation of the role and control of PTP1B enzyme activity in obesity and type 2 diabetes. Furthermore, since selectivity and cell permeability are the two most important requirements for the development of successful PTP1B inhibitors, recent progress in finding compounds meeting these criteria are discussed.
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PMID:Protein tyrosine phosphatase 1B inhibitors for the treatment of type 2 diabetes and obesity: recent advances. 1464 9

Type 2 diabetes and obesity are characterised by insulin and leptin resistance. Studies suggest that these may be due to defects in the insulin and leptin signalling pathways. Over the last decade, a considerable body of evidence has been amassed indicating that protein tyrosine phosphatase 1B (PTP1B) is involved in the downregulation of insulin and leptin signalling. Consequently, compounds that inhibit PTP1B have potential as therapeutics for treating Type 2 diabetes and obesity. This review covers recent advances in PTP1B inhibitors with an emphasis on recent attempts to create potent, selective and cell-permeable small-molecule inhibitors.
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PMID:Recent advances in protein tyrosine phosphatase 1B inhibitors. 1501 40

We have evaluated the possible association of polycystic ovary syndrome (PCOS) with 15 genomic variants previously described to influence insulin resistance, obesity, and/or type 2 diabetes mellitus. Seventy-two PCOS patients and 42 healthy controls were genotyped for 15 variants in the genes encoding for paraoxonase (three variants), plasma cell differentiation antigen glycoprotein, human sorbin and SH3 domain containing 1, plasminogen activator inhibitor-1, peroxisome proliferator-activated receptor-gamma2, protein tyrosine phosphatase 1B (two variants), adiponectin (two variants), IGF1, IGF2, IGF1 receptor, and IGF2 receptor. Compared with controls, PCOS patients were more frequently homozygous for the -108T variant in paraoxonase (36.6% vs. 9.5%; P = 0.002) and homozygous for G alleles of the ApaI variant in IGF2 (62.9% vs. 38.1%; P = 0.018). Paraoxonase is a serum antioxidant enzyme and, because -108T alleles result in decreased paraoxonase expression, this increase in oxidative stress might result in insulin resistance. G alleles of the ApaI variant in IGF2 may increase IGF2 expression, and IGF2 stimulates adrenal and ovarian androgen secretion. In conclusion, the paraoxonase -108 C-->T variant and the ApaI polymorphism in the IGF2 gene are associated with PCOS and might contribute to increased oxidative stress, insulin resistance, and hyperandrogenism in this prevalent disorder.
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PMID:Association of the polycystic ovary syndrome with genomic variants related to insulin resistance, type 2 diabetes mellitus, and obesity. 1518 Oct 35

Sucrose- and fructose-enriched diets produce hepatic insulin resistance in rats independently of obesity. In humans, fructose infusion results in impaired insulin regulation of glucose production. The aim of the present study was to identify intrahepatic mediators of sucrose- and fructose-induced hepatic insulin resistance. In study 1, male rats were fed a control diet (STD, 68% of energy from corn starch, 12% from corn oil) or a sucrose-enriched diet (HSD, 68% sucrose, 12% corn oil) for 1, 2, or 5 wk. HSD produced hepatic insulin resistance at all time points. Hepatic protein tyrosine phosphatase 1B protein levels and activity were increased at 5 wk only, whereas c-jun NH(2)-terminal kinase (JNK) activity was increased at all time points. Normalization of JNK activity in hepatocytes isolated from HSD rats improved insulin-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS) proteins and insulin suppression of glucose release. In study 2, male rats were provided STD for 1 wk and then were either fasted or fasted and refed either STD or HSD for 3 or 6 h. Rats refed HSD were characterized by increased hepatic JNK activity and phosphorylation of IRS1 on Ser(307) after 6 h only. In study 3, hyperglycemic, hyperinsulinemic pancreatic clamps were performed for 3 or 6 h in the presence or absence of low or high intraportal fructose infusions. High intraportal fructose infusions, which increased portal vein fructose concentration to approximately 1 mM, increased hepatic JNK activity and phosphorylation of IRS1 on Ser(307) at 6 h only. These data suggest that sucrose- and fructose-induced hepatic insulin resistance are mediated, in part, via activation of JNK activity. Thus high rates of fructose metabolism in the liver appear to acutely activate stress pathways.
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PMID:Hepatospecific effects of fructose on c-jun NH2-terminal kinase: implications for hepatic insulin resistance. 1519 36


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