Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein tyrosine phosphatases (PTPases) are important targets for the treatment of insulin resistance in patients with type II diabetes and as antibacterial agents. As a result, there is a growing interest in the development of potent and specific inhibitors for these enzymes. This paper describes a series of inhibitors that contain two or three alpha-ketocarboxylic acid groups that are designed to form multiple contacts with residues inside or near the active site of phosphatases. The inhibitors have been assayed against three PTPases: the Yersinia PTPase, PTP1B, and LAR. The best of the inhibitors has IC(50) values against the Yersinia PTPase and PTP1B of 0.7 and 2.7 microM, respectively. These divalent and trivalent compounds are significantly more potent than their corresponding monovalent analogues. In addition, they show good selectivity for PTP1B and the Yersinia PTPase as compared to LAR.
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PMID:Divalent and trivalent alpha-ketocarboxylic acids as inhibitors of protein tyrosine phosphatases. 1219 Mar 16

Protein tyrosine phosphatases (PTPases) have been suggested to modulate the insulin receptor signal transduction pathways. We studied PTPases in Psammomys obesus, an animal model of nutritionally induced insulin resistance. No changes in the protein expression level of src homology PTPase 2 (SHP-2) (muscle, liver) or leukocyte antigen receptor (LAR) (liver) were detected. In contrast, the expression level of PTPase 1B (PTP 1B) in the skeletal muscle, but not in liver, was increased by 83% in the diabetic animals, compared with a diabetes-resistant line. However, PTP 1B-specific activity (activity/protein) significantly decreased (50% to 56%) in skeletal muscle of diabetic animals, compared with both the diabetes-resistant line and diabetes-prone animals. In addition, PTP 1B activity was inversely correlated to serum glucose level (r = -.434, P < .02). These findings suggest that PTP 1B, though overexpressed, is not involved in the susceptibility to insulin resistance in Psammomys obesus and is secondarily attenuated by hyperglycemia or other factors in the diabetic milieu.
Int J Exp Diabetes Res
PMID:Protein tyrosine phosphatase 1B is impaired in skeletal muscle of diabetic Psammomys obesus. 1245 63

HIV protease inhibitor treatment is associated with insulin resistance. We have recently demonstrated that the HIV protease inhibitor indinavir influences initial insulin signaling steps in HepG2 cells. Here we investigated in the same cell model whether indinavir alters insulin-stimulated glycogen synthesis. Since an altered phosphotyrosine phosphatase activity could represent a mechanism by which insulin signaling is influenced, we also assessed potential indinavir effects on protein tyrosine phosphatase activity directed against tyrosine phosphorylated insulin receptor substrate-1. HepG2 cells were incubated for 48 h without or with indinavir (100 micro mol/l). Subsequently, the insulin-stimulated incorporation of 14C-glucose into glycogen was measured. In indinavir-treated cells the insulin effect on glycogen synthesis was reduced by 30 +/- 4.5 %. Dephosphorylation of immobilized tyrosine-phosphorylated insulin-receptor substrate-1 by the cell extracts was determined using a microwell plate-based method, and indinavir treatment did not alter this dephosphorylation. In conclusion, our data suggest that indinavir affects insulin-stimulation of glycogen synthesis in liver cells, and this may be related to the previously observed alterations in insulin signaling. Direct effects of indinavir on the GLUT4 transport system, that have been suggested from data in other cell systems, are unlikely in HepG2 cells that express no or almost no GLUT4 transport system. Finally, our data do not support the hypothesis that indinavir alters insulin signaling by influencing protein tyrosine phosphatase activity directed against insulin receptor substrate-1.
Exp Clin Endocrinol Diabetes 2003 Feb
PMID:The HIV protease inhibitor indinavir impairs glycogen synthesis in HepG2 hepatoma cells. 1260 45

Protein tyrosine phosphatases (PTPases) regulate intracellular signal transduction pathways by controlling the level of tyrosine phosphorylation in cells. These enzymes play an important role in a variety of diseases including type II diabetes and infection by the bacterium Yersinia pestis, which is the causative agent of bubonic plague. This report describes the synthesis, using parallel solution-phase methods, of a library of 104 potential inhibitors of PTPases. The library members are based on the bis(aryl alpha-ketocarboxylic acid) motif that incorporates a carboxylic acid on the central benzene linker. This carboxylic acid was coupled with a variety of different aromatic amines through an amide linkage. The aromatic component of the resulting amides is designed to make contacts with residues that surround the active site of the PTPase. The library was screened against the Yersinia PTPase and PTP1B. Based upon the screening results, four members of the library were selected for further study. These four compounds were evaluated against the Yersinia PTPase, PTP1B, TCPTP, CD45, and LAR. Compound 14 has an IC(50) value of 590nM against PTP1B and is a reversible competitive inhibitor. This affinity represents a greater than 120-fold increase in potency over compound 2, the parent structure upon which the library was based. A second inhibitor, compound 12, has an IC(50) value of 240nM against the Yersinia PTPase. In general, the selectivity of the inhibitors for PTP1B was good compared to LAR, but modest when compared to TCPTP and CD45.
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PMID:Parallel synthesis of a library of bidentate protein tyrosine phosphatase inhibitors based on the alpha-ketoacid motif. 1515 97

The PTPN1 gene codes for protein tyrosine phosphatase 1B (PTP1B) (EC 3.1.3.48), which negatively regulates insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase activation segment. PTPN1 is located in 20q13, a genomic region linked to type 2 diabetes in multiple genetic studies. Surveys of the gene have previously identified only a few uncommon coding single nucleotide polymorphisms (SNPs). We have carried out a detailed association analysis of 23 noncoding SNPs spanning the 161-kb genomic region, which includes the PTPN1 gene. These SNPs have been assessed for association with type 2 diabetes in two independently ascertained collections of Caucasian subjects with type 2 diabetes and two control groups. Association is observed between multiple SNPs and type 2 diabetes. The most consistent evidence for association occurred with SNPs spanning the 3' end of intron 1 of PTPN1 through intron 8 (P values ranging from 0.043 to 0.004 in one case-control set and 0.038-0.002 in a second case-control set). Analysis of the combined case-control data increased the evidence of SNP association with type 2 diabetes (P = 0.005-0.0016). All of the associated SNPs lie in a single 100-kb haplotype block that encompasses the PTPN1 gene. Analysis of haplotypes indicates a significant difference between haplotype frequencies in type 2 diabetes case and control subjects (P = 0.0035-0.0056), with one common haplotype (36%) contributing strongly to the evidence for association with type 2 diabetes. Odds ratios calculated from single SNP or haplotype data are in the proximity of 1.3. Haplotype-based calculation of population-attributable risk (PAR) results in an estimated PAR of 17-20% based on different models and assumptions. These results suggest that PTPN1 is a significant contributor to type 2 diabetes susceptibility in the Caucasian population. This risk is likely due to noncoding polymorphisms.
Diabetes 2004 Nov
PMID:Association of protein tyrosine phosphatase 1B gene polymorphisms with type 2 diabetes. 1550 84

Compounds of the trace element vanadium exert various insulin-like effects in in vitro and in vivo systems. These include their ability to improve glucose homeostasis and insulin resistance in animal models of Type 1 and Type 2 diabetes mellitus. In addition to animal studies, several reports have documented improvements in liver and muscle insulin sensitivity in a limited number of patients with Type 2 diabetes. These effects are, however, not as dramatic as those observed in animal experiments, probably because lower doses of vanadium were used and the duration of therapy was short in human studies as compared with animal work. The ability of these compounds to stimulate glucose uptake, glycogen and lipid synthesis in muscle, adipose and hepatic tissues and to inhibit gluconeogenesis, and the activities of the gluconeogenic enzymes: phosphoenol pyruvate carboxykinase and glucose-6-phosphatase in the liver and kidney as well as lipolysis in fat cells contributes as potential mechanisms to their anti-diabetic insulin-like effects. At the cellular level, vanadium activates several key elements of the insulin signal transduction pathway, such as the tyrosine phosphorylation of insulin receptor substrate-1, and extracellular signal-regulated kinase 1 and 2, phosphatidylinositol 3-kinase and protein kinase B activation. These pathways are believed to mediate the metabolic actions of insulin. Because protein tyrosine phosphatases (PTPases) are considered to be negative regulators of the insulin-signalling pathway, it is suggested that vanadium can enhance insulin signalling and action by virtue of its capacity to inhibit PTPase activity and increase tyrosine phosphorylation of substrate proteins. There are some concerns about the potential toxicity of available inorganic vanadium salts at higher doses and during long-term therapy. Therefore, new organo-vanadium compounds with higher potency and less toxicity need to be evaluated for their efficacy as potential treatment of human diabetes.
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PMID:Insulino-mimetic and anti-diabetic effects of vanadium compounds. 1560 84

The molecular basis of insulin resistance, a major risk factor for development of Type II diabetes, involves defective insulin signaling. Insulin-mediated signal transduction is negatively regulated by the phosphotyrosine phosphatase, PTP1B, and numerous studies have demonstrated that organo-vanadium compounds, which are nonselective phosphotyrosine phosphatase inhibitors, have insulin-mimetic properties. However, whether or not vanadium compounds can prevent the transition from insulin resistance to overt diabetes is unknown. We compared the ability of bis(maltolato)oxovanadium(IV) (BMOV), an orally bioavailable organo-vanadium compound, and rosiglitazone maleate (RSG), a known insulin sensitizer, to prevent development of diabetes in Zucker diabetic fatty (ZDF) rats. Treatment began at 6 weeks of age when animals are insulin resistant and hyperinsulinemic, but not yet hyperglycemic, and ended at 12 weeks of age, which is 4 weeks after ZDF rats typically develop overt diabetes. BMOV-treated ZDF rats did not develop hyperglycemia, showed significant improvement in insulin sensitivity, and retained normal pancreatic islet morphology and endocrine cell distribution, similar to RSG-treated animals. BMOV and RSG treatment also prevented the hyper-phagia and polydipsia present in untreated ZDF rats; however, BMOV-treated ZDF rats gained much less weight than did RSG-treated animals. Circulating levels of adiponectin decreased in untreated ZDF rats compared to lean controls, but these levels remained normal in BMOV-treated ZDF rats. In contrast, in RSG-treated ZDF rats, plasma adiponectin levels were nearly 4-fold higher than in lean control rats, primarily as a result of a large increase in the amount of low-molecular weight forms of adiponectin in circulation. These data demonstrate that phosphatase inhibition offers a new approach to diabetes prevention, one that may have advantages over current approaches.
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PMID:A nonspecific phosphotyrosine phosphatase inhibitor, bis(maltolato)oxovanadium(IV), improves glucose tolerance and prevents diabetes in Zucker diabetic fatty rats. 1663 95

Protein tyrosine phosphatases (PTPases) and protein tyrosine kinase (PTKases) regulate the phosphorylation and dephosphorylation of tyrosine residues in proteins, events that are essential for a variety of cellular functions. PTPases such as PTP1B and the Yersinia PTPase play an important role in diseases including type II diabetes and bubonic plague. A library of 67 bidentate PTPase inhibitors that are based on the alpha-ketocarboxylic acid motif has been synthesized using parallel solution-phase methods. Two aryl alpha-ketocarboxylic acids were tethered to a variety of different diamine linkers through amide bonds. The compounds were assayed in crude form against the Yersinia PTPase, PTP1B, and TCPTP. Six compounds were selected for further evaluation, in purified form, against the Yersinia PTPase, PTP1B, TCPTP, LAR, and CD45. These compounds had IC50 values in the low micromolar range against the Yersinia PTPase, PTP1B, and TCPTP, showed good selectivity for PTP1B over LAR, and modest selectivity over CD45. The correlation between linker structure and inhibitor activity shows that aromatic groups in the linker can play an important role in determining binding affinity in this class of inhibitors.
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PMID:Investigations of linker structure on the potency of a series of bidentate protein tyrosine phosphatase inhibitors. 1578 8

Protein tyrosine phosphatases (PTPases) are the enzymes responsible for the selective dephosphorylation of tyrosine residues. PTPases function to regulate a wide array of biological responses mediated by growth factors and other stimuli by balancing the cellular level of phosphotyrosine in concert with their counterparts, protein tyrosine kinases. The important roles which PTPases play in regulating intracellular signalling and, ultimately, biological function along with the recent availability of information regarding their structural features has highlighted them as potential targets for pharmacological modulation. This is demonstrated by the increased level of activity directed towards the identification of novel small-molecule PTPase inhibitors. The rationale and potential utility of this drug discovery approach is discussed here, with particular emphasis on its application for the treatment of insulin resistance and Type 2 diabetes.
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PMID:Protein tyrosine phosphatases: their role in insulin action and potential as drug targets. 1599 69

Leprechaunism features a clinical constellation characterized by extreme insulin resistance, growth retardation, and several distinct developmental abnormalities. One puzzling observation about leprechaunism is that mutations in the insulin receptor gene frequently associated with this syndrome cannot account for the aberrant responses of cultured cells to other growth factors. Here we report that the generation of reactive oxygen species (ROS) is impaired in cells from leprechaunism patients, thus shedding new light on this issue. Stimulation of patients' skin fibroblast cells with platelet-derived growth factor (PDGF) resulted in a lower-level tyrosine phosphorylation of cytosolic proteins compared with that seen in normal cells. In addition, consistent with the hypothesis that ROS mediate the level of tyrosine phosphorylation of cytosolic proteins through inactivation of protein tyrosine phosphatases (PTPases), patient fibroblast cells showed a significantly higher phosphatase activity than normal cells. We further showed that the lower-level tyrosine phosphorylation in response to growth factors results from the downregulation of an NADPH oxidase, Nox4, which in turn results in the reduction of ROS generation. Ectopic expression of Nox4 in the patient fibroblast cells consistently restored PDGF-induced ROS production and regulation of PTPase activities. Taken together, these data provide insight into the mechanisms through which growth retardation is associated with leprechaunism syndrome.
Diabetes 2005 Nov
PMID:Impaired generation of reactive oxygen species in leprechaunism through downregulation of Nox4. 1624 42


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