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 SAR from our peptide libraries was exploited to design a series of potent deoxybenzoin PTP-1B inhibitors. The introduction of an ortho bromo substituent next to the difluoromethylphosphonate warhead gave up to 20-fold increase in potency compared to the desbromo analogues. In addition, these compounds were orally bioavailable and active in the animal models of non-insulin dependent diabetes mellitus (NIDDM).
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PMID:The development of potent non-peptidic PTP-1B inhibitors. 1501 19

Isis is developing ISIS-113715, an antisense inhibitor of the PTP1B gene, for the potential treatment of type 2 diabetes and obesity. ISIS-113715 is undergoing phase II clinical trials.
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PMID:Technology evaluation: ISIS-113715, Isis. 1526 36

The majority of the presentations a the conference were on three highly sought-after targets for type 2 diabetes mellitus, namely PTP1B, PPARs and DPP-IV, reflecting the current focus and trend in the industry. A couple of novel targets were discussed, including the potential of myostatin as a type 2 diabetes mellitus target and a novel GPCR target. While small molecules were dominant, several biological-based approaches were covered: antibody therapeutics and oligonucleotide-based approaches (ASO and siRNA). In searching for small-molecule leads, structure-based rational design and focused combination chemistry appear to produce better results than a random high-throughput approach over the entire chemical library. The biggest challenges for diabetes and obesity drugs remain similar to those mentioned in previous meetings: increasing specificity to reduce side effects and maintaining long-term effect while maintaining or increasing efficacy. Due to the tremendous interest of the pharmaceutical industry in metabolic disease drug development, our knowledge of food intake and metabolism regulation has increased exponentially. Overall, the prospect of better drugs for, and better control of, type 2 diabetes mellitus and obesity is promising.
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PMID:Metabolic Diseases Drug Discovery-Strategic Research Institute's Third International World Summit. Dipeptidyl peptidase-IV inhibitors 26-27 July 2004, San Diego, CA, USA. 1547 Jun

Protein tyrosine phosphatase (PTP)-1B, encoded by the PTPN1 gene, catalyzes the dephosphorylation of proteins at tyrosyl residues. PTP-1B has been implicated in negatively regulating insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor. The genetic contribution of PTPN1 to measures of glucose homeostasis has been assessed in 811 Hispanic subjects from the Insulin Resistance Atherosclerosis Study Family Study (IRASFS). Thirty-five single nucleotide polymorphisms (SNPs) spanning 161 kb and containing the PTPN1 gene were genotyped and tested for association. All 20 SNPs with minor allele frequencies >0.1 in a single haplotype block covering the PTPN1 genomic sequence show significant association with the insulin sensitivity index (S(i)) (P = 0.044-0.003) and fasting glucose (P = 0.029 to <0.001). In contrast, there is no evidence for association of PTPN1 polymorphisms with acute insulin response (a measure of beta-cell function). Haplotype analysis of eight SNP haplotypes that have independently been shown to be associated with type 2 diabetes risk and protection in Caucasian type 2 diabetic subjects are associated with lower (P = 0.007) and higher (P = 0.0002) S(i) and higher (P = 0.00007) and lower (P = 0.001) fasting glucose, respectively, in the IRASFS. This comprehensive genetic analysis of PTPN1 reveals significant association with metabolic traits consistent with the proposed in vivo role for the PTP-1B protein.
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PMID:Association of protein tyrosine phosphatase 1B gene polymorphisms with measures of glucose homeostasis in Hispanic Americans: the insulin resistance atherosclerosis study (IRAS) family study. 1550 85

The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes. Our previous studies have shown that the closely related tyrosine phosphatase TCPTP might also contribute to the regulation of insulin receptor (IR) signaling in vivo (S. Galic, M. Klingler-Hoffmann, M. T. Fodero-Tavoletti, M. A. Puryer, T. C. Meng, N. K. Tonks, and T. Tiganis, Mol. Cell. Biol. 23:2096-2108, 2003). Here we show that PTP1B and TCPTP function in a coordinated and temporally distinct manner to achieve an overall regulation of IR phosphorylation and signaling. Whereas insulin-induced phosphatidylinositol 3-kinase/Akt signaling was prolonged in both TCPTP-/- and PTP1B-/- immortalized mouse embryo fibroblasts (MEFs), mitogen-activated protein kinase ERK1/2 signaling was elevated only in PTP1B-null MEFs. By using phosphorylation-specific antibodies, we demonstrate that both IR beta-subunit Y1162/Y1163 and Y972 phosphorylation are elevated in PTP1B-/- MEFs, whereas Y972 phosphorylation was elevated and Y1162/Y1163 phosphorylation was sustained in TCPTP-/- MEFs, indicating that PTP1B and TCPTP differentially contribute to the regulation of IR phosphorylation and signaling. Consistent with this, suppression of TCPTP protein levels by RNA interference in PTP1B-/- MEFs resulted in no change in ERK1/2 signaling but caused prolonged Akt activation and Y1162/Y1163 phosphorylation. These results demonstrate that PTP1B and TCPTP are not redundant in insulin signaling and that they act to control both common as well as distinct insulin signaling pathways in the same cell.
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PMID:Coordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTP. 1563 81

PTP1B is a ubiquitously expressed intracellular protein tyrosine phosphatase. Several lines of evidence support an important role for protein tyrosine phosphatase 1B(PTP1B) in metabolism, and specially in type 2 diabetes and obesity. Overexpression of PTP1B protein has been observed in insulin-resistant states associated with obesity. PTP1B is a negative regulator of insulin and leptin signaling, PTP1B inhibitors might be efficacious in the treatment of type 2 diabetes and obesity by increasing insulin and leptin sensitivity.
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PMID:[Role of protein tyrosine phosphatase 1B in the type 2 diabetes and obesity]. 1564 Jan 30

Impaired insulin receptor (IR) signaling leads to insulin resistance and type 2 diabetes mellitus. Several inhibitors of the IR tyrosine kinase activity have recently been described and associated with human insulin resistance. Among these negative regulators, protein tyrosine phosphatases (PTPs) are likely to play a pivotal role in IR signaling. Transgenic studies revealed that PTP1B and TCPTP are primary candidates but IR of these animals can be finally dephosphorylated, suggesting that other PTPs are also involved in the dephosphorylation of IR. In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163 were primary targets of PTP epsilonM. Wild type as well as substrate-trapping DA forms of PTPepsilonM suppressed phosphorylation of IR downstream enzymes such as Akt, extracellular regulated kinase (ERK) and glycogen synthase kinase 3 (GSK3). It was also demonstrated that PTPepsilonM suppressed insulin-induced glycogen synthesis and inhibited insulin-induced suppression of phosphoenol pyruvate carboxykinase (PEPCK) expression in primary hepatocytes. Furthermore, adenovirally introduced PTPepsilonM also exhibited inhibitory activity against suppression of PEPCK expression in mouse liver. These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver.
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PMID:Receptor-type protein tyrosine phosphatase epsilon (PTPepsilonM) is a negative regulator of insulin signaling in primary hepatocytes and liver. 1573 37

Chromium has been recognized for decades as a nutritional factor that improves glucose tolerance by enhancing in vivo insulin action, but the molecular mechanism is unknown. Here we report pretreatment of CHO-IR cells with chromium enhances tyrosine phosphorylation of the insulin receptor. Different chromium(III) compounds were effective at enhancing insulin receptor phosphorylation in intact cells, but did not directly activate recombinant insulin receptor kinase. The level of insulin receptor phosphorylation in cells can be increased by inhibition of the opposing protein tyrosine phosphatase (PTP1B), a target for drug development. However, chromium did not inhibit recombinant human PTP1B using either p-nitrophenyl phosphate or the tyrosine-phosphorylated insulin receptor as the substrate. Chromium also did not alter reversible redox regulation of PTP1B. Purified plasma membranes exhibited insulin-dependent kinase activity in assays using substrate peptides mimicking sites of Tyr phosphorylation in the endogenous substrate IRS-1. Plasma membranes prepared from chromium-treated cells had higher specific activity of insulin-dependent kinase relative to controls. We conclude that cellular chromium potentiates insulin signaling by increasing insulin receptor kinase activity, separate from inhibition of PTPase. Our results suggest that nutritional and pharmacological therapies may complement one another to combat insulin resistance, a hallmark of type 2 diabetes.
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PMID:Cellular chromium enhances activation of insulin receptor kinase. 1592 36

Insulin resistance plays an important role in the development of such abnormalities as impaired glucose tolerance, type 2 diabetes, obesity, and hyperlipidemia. The rates of these diseases are increasing and their cardiovascular complications are among the most common causes of death worldwide. The discovery of protein tyrosine phosphatase (PTP-1B) seems to be a milestone in the investigation of insulin signaling transmission. PTP-1B is considered a negative regulator of insulin signaling, mainly through insulin receptor dephosphorylation. In animal model studies (Elchebly et al.) there was a significant increase in insulin sensitivity of PTP-1B knock-out mice. There is also evidence that higher expression of the PTP-1B gene causes insulin resistance in humans. PTP-1B inhibitors could thus be promising drugs for insulin resistance therapy. The object of this review is to present current evidence of PTP-1B's role in the pathophysiology of insulin resistance abnormalities and the potential treatment of these disorders.
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PMID:[The role of protein tyrosine phosphatase (PTP-1B) in insulin resistance]. 1592 4

PTP-1B represents an attractive target for the treatment of type 2 diabetes and obesity. Given the role that protein phosphatases play in the regulation of many biologically relevant processes, inhibitors against PTP-1B must be not only potent, but also selective. It has been extremely difficult to synthesize inhibitors that are selective over the highly homologous TCPTP. We have successfully exploited the conservative Leu119 to Val substitution between the two enzymes to synthesize a PTP-1B inhibitor that is an order of magnitude more selective over TCPTP. Structural analyses of PTP-1B/inhibitor complexes show a conformation-assisted inhibition mechanism as the basis for selectivity. Such an inhibitory mechanism may be applicable to other homologous enzymes.
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PMID:Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase. 1640 90


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