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 (PTPs) play key roles in regulating tyrosine phosphorylation levels in cells. Since the discovery of PTP1B as a major drug target for diabetes and obesity, PTPs have emerged as a new and promising class of signaling targets for drug development in a variety of therapeutic areas. The routine use of generic substrate 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) in our hands led to the discovery of very similar and often not very selective molecules. Therefore, to increase the chances to discover novel chemical scaffolds, a side-by-side comparison between the DiFMUP assay and a chip-based mobility shift assay with a specific phosphopeptide was performed, on 1 PTP, using a focused set of compounds. Assay robustness and sensitivity were comparable for both the DiFMUP and mobility shift assays. The off-chip mobility shift assay required a longer development time because of identification, synthesis, and characterization of a specific peptide, and its cost per point was higher. However, although most potent scaffolds found with the DiFMUP assay were confirmed in the mobility shift format, the off-chip mobility shift assay led to the identification of previously unidentified chemical scaffolds with improved druglike properties.
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PMID:A microfluidics-based mobility shift assay to discover new tyrosine phosphatase inhibitors. 1709 20

PTP1B plays an important role as a negative regulator in insulin and leptin signaling pathways. Potent and orally active PTP1B inhibitors can act as potential agents for the treatment of Type 2 diabetes and obesity. CoMFA (Comparative Molecular Field Analysis) and de novo ligand design using LeapFrog (LF) studies were performed on pyridazine analogs, reported to be selective and non-competitive inhibitors of PTP1B. A robust model was developed which produced statistically significant results with cross-validated and conventional correlation coefficients of 0.619 and 0.990, respectively. Further, the robustness of the model was verified by bootstrapping analysis. LeapFrog (LF) program is a de novo drug discovery tool, which uses CoMFA maps to generate hypothetical cavity and ligands. As the crystal structure of PTP1B-pyridazine complex is not yet known, the contours of CoMFA model was used to serve as a pharmacophoric model to generate hypothetical cavity for LeapFrog calculations. Ligands were optimized using this concept.
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PMID:CoMFA based de novo design of pyridazine analogs as PTP1B inhibitors. 1714 Aug 31

Protein-tyrosine phosphatase (PTP)1B is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes. In this study, we have assessed the role of PTP1B in the insulin sensitivity of skeletal muscle under physiological and insulin-resistant conditions. Immortalized myocytes have been generated from PTP1B-deficient and wild-type neonatal mice. PTP1B(-/-) myocytes showed enhanced insulin-dependent activation of insulin receptor autophosphorylation and downstream signaling (tyrosine phosphorylation of insulin receptor substrate [IRS]-1 and IRS-2, activation of phosphatidylinositol 3-kinase, and serine phosphorylation of AKT), compared with wild-type cells. Accordingly, PTP1B(-/-) myocytes displayed higher insulin-dependent stimulation of glucose uptake and GLUT4 translocation to the plasma membrane than wild-type cells. Treatment with tumor necrosis factor-alpha (TNF-alpha) induced insulin resistance on glucose uptake, impaired insulin signaling, and increased PTP1B activity in wild-type cells. Conversely, the lack of PTP1B confers protection against insulin resistance by TNF-alpha in myocyte cell lines and in adult male mice. Wild-type mice treated with TNF-alpha developed a pronounced hyperglycemia along the glucose tolerance test, accompanied by an impaired insulin signaling and increased PTP1B activity in muscle. However, mice lacking PTP1B maintained a rapid clearance of glucose and insulin sensitivity and displayed normal muscle insulin signaling regardless the presence of TNF-alpha.
Diabetes 2007 Feb
PMID:Protein-tyrosine phosphatase 1B-deficient myocytes show increased insulin sensitivity and protection against tumor necrosis factor-alpha-induced insulin resistance. 3291 64

The protein tyrosine phosphatase PTP1B, previously recognized for its role in downregulating insulin and leptin signaling, has now been shown to function as a positive regulator of signaling events associated with breast tumorigenesis. Inhibitors of PTP1B that have been developed as drug candidates for treatment of diabetes and obesity may offer new avenues for the treatment of breast cancer.
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PMID:A brake becomes an accelerator: PTP1B--a new therapeutic target for breast cancer. 1734 79

Protein tyrosine phosphatases (PTPs) are important signaling enzymes that control such fundamental processes as proliferation, differentiation, survival/apoptosis, as well as adhesion and motility. Potent and selective PTP inhibitors serve not only as powerful research tools, but also as potential therapeutics against a variety illness including cancer and diabetes. PTP activity-based assays are widely used in high throughput screening (HTS) campaigns for PTP inhibitor discovery. These assays suffer from a major weakness, in that the reactivity of the active site Cys can cause serious problems as highly reactive oxidizing and alkylating agents may surface as hits. We describe the development of a fluorescence polarization (FP)-based displacement assay that makes the use of an active site Cys to Ser mutant PTP (e.g., PTP1B/C215S) that retains the wild-type binding affinity. The potency of library compounds is assessed by their ability to compete with the fluorescently labeled active site ligand for binding to the Cys to Ser PTP mutant. Finally, the substitution of the active site Cys by a Ser renders the mutant PTP insensitive to oxidation and alkylation and thus will likely eliminate "false" positives due to modification of the active site Cys that destroy the phosphatase activity.
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PMID:An affinity-based fluorescence polarization assay for protein tyrosine phosphatases. 1753 13

Peroxisome proliferator-activated receptor (PPAR)-gamma, a target in the treatment of diabetes, improves insulin sensitivity and exerts cardiovascular protective effects by mechanisms that are not completely elucidated. To investigate underlying molecular mechanisms responsible for PPAR-gamma-associated vascular insulin signaling in hypertension, we tested whether PPAR-gamma downregulation in vascular smooth muscle cells (VSMC) from WKY and SHRSP rats would decrease insulin signaling and glucose uptake and whether this response would be worsened by hyperglycemia to a greater extent in VSMC of hypertensive origin. Passaged mesenteric artery VSMC grown in euglycemic (5.5 mmol/L) or hyperglycemic media (25.0 mmol/L) were treated with PPAR-gamma-siRNA (5 nmol/L), PPAR-gamma antagonist (GW-9662, 10 micromol/L), or PPAR-gamma activator (rosiglitazone, 10 micromol/L) in the presence or absence of insulin (100 nmol/L). Immunoblotting revealed that hyperglycemia and PPAR-gamma inhibition significantly (P < 0.001) decreased insulin-stimulated insulin receptor (IR)-beta, Akt, and glycogen synthase kinase (GSK)-3beta phosphorylation, whereas phosphotyrosine phosphatase (PTP)-1B expression was increased in VSMC from both strains. These effects were more pronounced in SHRSP under hyperglycemia. Rosiglitazone tended to increase insulin-mediated IR-beta, Akt, and GSK-3beta phosphorylation in VSMC from both strains, whereas insulin-induced PTP-1B expression was reduced by hyperglycemia. Insulin-stimulated GLUT-4 expression and glucose transport were attenuated by hyperglycemia in both VSMC. These data suggest that PPAR-gamma inhibition results in decreased insulin signaling, particularly in SHR, in an IR-beta phosphorylation-dependent manner.
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PMID:Effects of PPAR-gamma knock-down and hyperglycemia on insulin signaling in vascular smooth muscle cells from hypertensive rats. 1757 98

Vanadium is a well known anti-diabetic agent which mimics most of the actions of insulin on mature adipocytes. We report here the effect of vanadium on proliferation and differentiation of 3T3-L1 preadipocytes. Like insulin, vanadium treatment leads to increased proliferation as evidenced by H(3)thymidine uptake studies and differentiation of 3T3-L1 cells into adipocytes as evidenced by oil-red-O staining. Adipogenic potential of vanadium can be attributed to CREB activation, as documented by phospho-CREB antibody staining. This adipogenic potential is of significance in an in vivo scenario as the new adipocytes are likely to be insulin sensitive as against resistant existing mature adipocytes and thus indirectly may help in reduction of insulin resistance. Till today decrease in insulin resistance by vanadium treatment has been mainly attributed to its potential to inhibit PTP-1B, however the present study opens a new dimension in vanadium treatment for diabetes due to its novel role in adipogenesis.
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PMID:Adipogenic action of vanadium: a new dimension in treating diabetes. 1767 28

The global epidemic of obesity and type-2 diabetes mellitus (T2DM) has highlighted the need for new therapeutic approaches. The association of insulin resistance with these disorders and the knowledge that insulin receptor signaling is mediated by tyrosine (Tyr) phosphorylation have generated great interest in the regulation of the balance between Tyr phosphorylation and dephosphorylation. Several protein Tyr phosphatases (PTPs) have been implicated in the regulation of insulin action, with the most convincing data for PTP1B. Murine models targeting PTP1B, PTP1B(-/-)mice, demonstrate enhanced insulin sensitivity without the weight gain seen with other insulin sensitizers such as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, probably due to a second action of PTP1B as a negative regulator of leptin signaling. Despite intensive efforts and recent progress, a safe, selective and efficacious PTP1B inhibitor has yet to be identified.
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PMID:Inhibition of the protein tyrosine phosphatase PTP1B: potential therapy for obesity, insulin resistance and type-2 diabetes mellitus. 1805 39

Diabetes mellitus is a chronic metabolic disorder, characterized by glucose overproduction and glucose underutilization. Current therapy for T2DM includes drugs, like metformin, glitazones, sulphonyl ureas, etc. Extensive research has been carried out world wide on molecular targets for T2DM like PPARgamma, PTP1B, DPP-IV, GSK-3, cannabinoid receptor, fructose-bisphosphatases, beta3 adrenoceptor, etc. in the development of newer anti-diabetic agents. These therapeutic targets are quite important and most of them are suitable for in silico analysis. Hence, many molecular modeling and informatics studies like, molecular docking, pharmacophore mapping, 3D-QSAR, virtual screening, quantum chemical studies, and pharmacoinformatics like bioinformatics and chemoinformatics studies have been performed on the drugs/leads/targets associated with T2DM. Several of these in silico efforts are exemplary studies; the methodologies adopted in these studies can be emulated in many other therapeutic areas. A review of the rational approaches reported in designing anti-diabetic agents is presented in this article.
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PMID:Modeling and informatics in designing anti-diabetic agents. 1822 Jul 88

Corosolic acid, a triterpenoid compound widely existing in many traditional Chinese medicinal herbs, has been proved to have antidiabetic effects on animal experiments and clinical trials. However, the underlying mechanisms remain unknown. Here, we investigate its cellular effects and related signaling pathway. We demonstrate that it enhances glucose uptake in L6 myotubes and facilitates glucose transporter isoform 4 translocation in CHO/hIR cells. These actions are mediated by insulin pathway activation and can be blocked by phosphatidylinositol 3-kinase (PI(3) Kinase) inhibitor wortmannin. Furthermore, Corosolic acid inhibits the enzymatic activities of several diabetes-related non-receptor protein tyrosine phosphatases (PTPs) in vitro, such as PTP1B, T-cell-PTP, src homology phosphatase-1 and src homology phosphatase-2.
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PMID:Corosolic acid stimulates glucose uptake via enhancing insulin receptor phosphorylation. 1834 86


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