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)

Protein tyrosine phosphatase-1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B-/- mice was also evident in glucose and insulin tolerance tests. The PTP-1B-/- mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B-/- and PTP-1B+/- mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity.
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PMID:Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. 1020 63

Protein tyrosine phosphatases (PTPs) are required for the dephosphorylation of the insulin receptor (IR) and its initial cellular substrates, and it has recently been reported that PTP-1B may play a role in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus (DM). We therefore determined the amount and activity of PTP-1B in abdominal adipose tissue obtained from lean nondiabetic subjects (lean control (LC)), obese nondiabetic subjects (obese control (OC)), and subjects with both type 2 DM (DM2) and obesity (obese diabetic (OD)). PTP-1B protein levels were 3-fold higher in OC than in LC (1444 +/- 195 U vs 500 +/- 146 U (mean +/- SEM), P < .015), while OD exhibited a 5.5-fold increase (2728 +/- 286 U, P < .01). PTP activity was assayed by measuring the dephosphorylating activity toward a phosphorus 32-labeled synthetic dodecapeptide. In contrast to the increased PTP-1B protein levels, PTP-1B activity per unit of PTP-1B protein was markedly reduced, by 71% and 88% in OC and OD, respectively. Non-PTP-1B tyrosine phosphatase activity was comparable in all three groups. Similar results were obtained when PTP-1B activity was measured against intact human IR. A significant correlation was found between body mass index (BMI) and PTP-1B level (r = 0.672, P < .02), whereas BMI and PTP-1B activity per unit of PTP-1B showed a strong inverse correlation (r = -0.801, P < .002). These data suggest that the insulin resistance of obesity and DM2 is characterized by the increased expression of a catalytically impaired PTP-1B in adipose tissue and that impaired PTP-1B activity may be pathogenic for insulin resistance in these conditions.
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PMID:Marked impairment of protein tyrosine phosphatase 1B activity in adipose tissue of obese subjects with and without type 2 diabetes mellitus. 1044 21

Protein tyrosine phosphatase-1B (PTP-1B), a negative regulator of insulin signaling, may be an attractive therapeutic target for type 2 diabetes mellitus. High throughput screening (HTS) for PTP-1B inhibitors using compounds from the Korea Chemical Bank identified several hits (active compounds). Among them, a hit with 1,2-naphthoquinone scaffold was chosen for lead development. KR61639, [4-[1-(1H-indol-3-yl)-3,4-dioxo-3,4-dihydro-naphthalen-2-ylmethyl]-phenoxy]-acetic acid tert-butyl ester, inhibited human recombinant PTP-1B with an IC(50) value of 0.65 microM in a noncompetitive manner. KR61639 showed modest selectivity over several phosphatases and increased insulin-stimulated glycogen synthesis in HepG2 cells and stimulated 2-deoxyglucose uptake in 3T3/L1 adipocytes. In addition, in vivo study using ob/ob mouse demonstrated that KR61639 exerted a hypoglycemic action when given orally. Thus, KR61639 may be a good starting point for lead optimization in developing a novel antidiabetic agent.
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PMID:Discovery of a novel protein tyrosine phosphatase-1B inhibitor, KR61639: potential development as an antihyperglycemic agent. 1475 58

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

Protein tyrosine phosphatase (PTP)-1B, encoded by the PTPN1 gene, inactivates the insulin signal transduction cascade by dephosphorylating phosphotyrosine residues in insulin signaling molecules. Due to its chromosomal location under a chromosome 20 linkage peak and the metabolic effects of its absence in knockout mice, it is a candidate gene for type 2 diabetes. Recent studies have associated common sequence variants in PTPN1 with type 2 diabetes and diabetes-related phenotypes. We sought to replicate the association of common single nucleotide polymorphisms (SNPs) and haplotypes in PTPN1 with type 2 diabetes, fasting plasma glucose, and insulin sensitivity in a large collection of subjects. We assessed linkage disequilibrium, selected tag SNPs, and typed these markers in 3,347 cases of type 2 diabetes and 3,347 control subjects as well as 1,189 siblings discordant for type 2 diabetes. Despite power estimated at >95% to replicate the previously reported associations, no statistically significant evidence of association was observed between PTPN1 SNPs or common haplotypes with type 2 diabetes or with diabetic phenotypes.
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PMID:Association testing of the protein tyrosine phosphatase 1B gene (PTPN1) with type 2 diabetes in 7,883 people. 1591 13

Protein tyrosine phosphatase activity depends on a catalytic thiolate group on an acidic cysteine residue that is sensitive to reactive oxygen species. Representative of this family of enzymes is protein tyrosine phosphatase 1B (PTP1B), a major target for type 2 diabetes therapy. PTP1B is sensitive to hydrogen peroxide (H2O2) in vitro and in cells. It is also sensitive to glutathionylation by glutathione disulfide (GSSG). The sensitivity of PTP1B to the redox state of its environment was partially characterized in vitro by examination of phosphatase activity in the presence of various concentrations of glutathione (GSH) and GSSG. Enzyme sensitivity to glutathionylation was dependent on the amount of available thiol groups and increased as GSH concentration was increased. The half-inhibitory concentration for H2O2 was much less than that of GSSG in the presence of low concentrations of GSH, indicating that reaction with H2O2 is much more likely than is glutathionylation by GSSG. PTP1B and a related oxidant-sensitive phosphatase, PTEN, were also sensitive to the lipid peroxidation by-product 4-hydroxynonenal. Furthermore, PTP1B was inhibited by cytochrome c and microperoxidase. Taken together, these data suggest that not only H2O2, but also a variety of redox-active metabolites and hemes can oxidatively inactivate PTPs with potentially profound implications for signal transduction.
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PMID:Sensitivity of protein tyrosine phosphatase activity to the redox environment, cytochrome C, and microperoxidase. 1599 63

Protein tyrosine phosphatases (PTPs) are important regulators of signal transduction pathways. Potent and selective PTP inhibitors are useful for probing these pathways and also may serve as drugs for the treatment of a variety of diseases including type 2 diabetes and infection by the bacterium Yersinia pestis. In this report Cu(I)-catalyzed 'click' cycloaddition reactions between azides and alkynes were employed to generate two sequential libraries of PTP inhibitors. In the first round library methyl 4-azidobenzoylformate was reacted with 56 mono- and diynes. After hydrolysis of the methyl esters, the resulting alpha-ketocarboxylic acids were assayed in crude form against the Yersinia PTP and PTP1B. Four compounds were selected for further evaluation, and one compound was chosen as the lead for generation of the second round library. This lead compound was modified by conversion of an alcohol into an azide group, and the resulting azide was reacted with the same 56 mono- and diynes that were used in the first generation library. After screening the crude inhibitors against the Yersinia PTP and PTP1B, four compounds were selected and evaluated in pure form against the Yersinia PTP, PTP1B, TCPTP, LAR, and CD45. The best bis(alpha-ketocarboxylic acid) inhibitor 34 had an IC(50) value of 550nM against the Yersinia PTP and an IC(50) value of 710nM against TCPTP. The most potent inhibitor containing a single alpha-ketocarboxylic acid group 32 had IC(50) values of 2.1, 5.7, and 2.6 microM against the Yersinia PTP, PTP1B, and TCPTP, respectively.
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PMID:A two stage click-based library of protein tyrosine phosphatase inhibitors. 1704 67

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is considered an important regulator of T-cell activation. Polymorphisms within the PTPN22 gene have been suggested to confer susceptibility to autoimmune endocrine disorders. To evaluate the impact of a functional variation in the PTPN22 gene in type 1 (T1D) and type 2 diabetes (T2D), the PTPN22 C1858T single nucleotide polymorphism (SNP) was studied in the population of Estonian origin, including 170 T1D patients, 244 T2D patients and 230 controls. Using two methods for PTPN22 C1858T detection in parallel, we found that not only T1D but also T2D is associated with the PTPN22 1858T allele. The role of PTPN22 gene in the pathogenesis of T2D is yet unclear and needs further investigation.
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PMID:Protein tyrosine phosphatase non-receptor type 22 gene variants at position 1858 are associated with type 1 and type 2 diabetes in Estonian population. 1876 13

Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates. First, PTP-1B ASO (ISIS 113715) dose-dependently inhibited PTP-1B mRNA and protein expression in cultured monkey hepatocytes. Subcutaneous administration of ISIS 113715 reduced PTP-1B mRNA expression in liver and adipose tissue of normal-weight monkeys by 40-50% and improved insulin sensitivity during an iv glucose tolerance test (IVGTT). In obese, insulin-resistant rhesus monkeys, treatment with 20 mg/kg ISIS 113715 for 4 wk reduced fasting concentrations of insulin and glucose and reduced insulin responses during an IVGTT. In these animals, adiponectin concentrations were also increased by 70%, most of which was an increase of high-molecular-weight oligomers. These effects were not observed in monkeys on a lower, dose-escalation regimen (1-10 mg/kg over 9 wk). Overall, the increase of adiponectin concentrations during ISIS 113715 treatment was correlated with the lowering of insulin responses during IVGTT (r = -0.47, P = 0.042). These results indicate that inhibition of PTP-1B with ASOs such as ISIS 113715 may be a viable approach for the treatment and prevention of obesity-associated insulin resistance and type 2 diabetes because they potently increase adiponectin concentrations in addition to improving insulin sensitivity.
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PMID:Inhibition of protein tyrosine phosphatase-1B with antisense oligonucleotides improves insulin sensitivity and increases adiponectin concentrations in monkeys. 1916 74

Protein tyrosine phosphatase 1beta (PTP1beta) acts as a negative regulator of insulin signaling. Selective inhibition of PTP1beta has served as a potential drug target for the treatment of type 2 diabetes mellitus. We evaluated the inhibitory effect of Phellinus linteus against PTP1beta as part of our ongoing search for natural therapeutic and preventive agents for diabetes mellitus. Fractions of the P. linteus extract were found to exhibit significant inhibitory activities against PTP1beta. In an attempt to identify bioactive components, we isolated, from the most active ethyl acetate fraction, five hispidin derivatives (phelligridimer A, davallialactone, hypholomine B, interfungins A, and inoscavin A) and four phenolic compounds (protocatechuic acid, protocatechualdehyde, caffeic acid, and ellagic acid). The chemical structures of these compounds were elucidated from spectroscopic evidence and by comparison with published data. All the compounds strongly inhibited PTP1beta activity in an in vitro assay; their IC50 values ranged from 9.0 +/- 0.01 to 58.2 +/- 0.3 microM. Our results indicated that the hispidin skeleton may be an important moiety for inhibitory activity of the above compounds against PTP1beta. Thus, hispidin derivatives could be a potent new class of natural PTP1beta inhibitors.
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PMID:Inhibition of protein tyrosine phosphatase 1beta by hispidin derivatives isolated from the fruiting body of Phellinus linteus. 2129 22


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