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 phosphatases (PTPases) have been postulated to balance the steady-state phosphorylation and the activation state of the insulin receptor and its substrate proteins. To explore whether PTP1B, a widely expressed, non-receptor-type PTPase, regulates insulin signaling, we used osmotic shock to load rat KRC-7 hepatoma cells with affinity-purified neutralizing antibodies that immunoprecipitate and inactivate the enzymatic activity of recombinant rat PTP1B in vitro. In cells loaded with PTP1B antibody, insulin-stimulated DNA synthesis and phosphatidylinositol 3'-kinase activity were increased by 42% and 38%, respectively, compared with control cells loaded with preimmune IgG (p < 0.005). In order to characterize the potential site(s) of action of PTP1B in insulin signaling, we also determined that insulin-stimulated receptor autophosphorylation and insulin receptor substrate 1 tyrosine phosphorylation were increased 2.2- and 2.0-fold, respectively, and that insulin-stimulated receptor kinase activity toward an exogenous peptide substrate was increased by 57% in the PTP1B antibody-loaded cells. Osmotic loading did not alter the cellular content of PTP1B protein, suggesting that the antibody acts in the cell by sterically blocking catalytic interactions between PTP1B and its physiological substrates. These studies demonstrate that PTP1B has a role in the negative regulation of insulin signaling and acts, at least in part, directly at the level of the insulin receptor. These results also show that insulin signaling can be enhanced by the inhibition of specific PTPases, a maneuver that has potential clinical relevance in the treatment of insulin resistance and Type II diabetes mellitus.
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PMID:Osmotic loading of neutralizing antibodies demonstrates a role for protein-tyrosine phosphatase 1B in negative regulation of the insulin action pathway. 754 90

To measure possible changes in basal and insulin-stimulated phosphotyrosine phosphatase (PTPase) activity in skeletal muscle from insulin-resistant individuals, soluble and particulate muscle fractions were prepared from biopsies taken before and after a 3-h hyperinsulinaemic euglycaemic clamp in eight non-insulin-dependent diabetic (NIDDM) patients and nine control subjects. We used a sensitive sandwich-immunofluorescence assay and the human insulin receptor as the substrate. PTPase activity was expressed as percentage of dephosphorylation of phosphotyrosyl-residues in immobilized insulin receptors per 2 h incubation time per 83 micrograms and 19 micrograms muscle fraction protein (soluble and particulate fraction, respectively). In the diabetic soluble muscle fractions, the basal PTPase activity was decreased compared with that of control subjects (11.5 +/- 5.5 vs 27.5 +/- 3.3, p < 0.04, mean +/- SEM). In the particulate muscle fractions from the control subjects, PTPase activity was increased after 3 h hyperinsulinaemia (20.0 +/- 3.2 vs 30.2 +/- 3.6, p < 0.03) and in the corresponding soluble fractions PTPase activity seemed decreased (27.5 +/- 3.3 vs 19.9 +/- 5.9, NS). No effect of insulin on PTPase activity was found in NIDDM patients (25.1 +/- 4.1 vs 27.2 +/- 5.2, 11.5 +/- 5.5 vs 15.1 +/- 4.5 [particulate and soluble fractions], NS). In conclusion, we found that the basal PTPase activity in soluble muscle fractions was decreased in NIDDM patients; furthermore, insulin stimulation was unable to increase PTPase activities in the particulate fractions, as opposed to the effect of insulin in control subjects.
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PMID:Altered basal and insulin-stimulated phosphotyrosine phosphatase (PTPase) activity in skeletal muscle from NIDDM patients compared with control subjects. 889 9

Vanadium and its compounds exhibit a wide variety of insulin-like effects. In this review, these effects are discussed with respect to the treatment of type I and type II diabetes in animal models, in vitro actions, antineoplastic role, treatment of IDDM and NIDDM patients, toxicity, and the possible mechanism(s) involved. Newly established CytPTK plays a major role in the bioresponses of vanadium. It has a molecular weight of approximately 53 kDa and is active in the presence of Co2+ rather than Mn2+. Among the protein-tyrosine kinase blockers, staurosporine is found to be a potent inhibitor of CytPTK but a poor inhibitor of InsRTK. Vanadium inhibits PTPase activity, and this in turn enhances the activity of protein tyrosine kinases. Our data show that inhibition of PTPase and protein tyrosine kinase activation has a major role in the therapeutic efficacy of vanadium in treating diabetes mellitus.
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PMID:Vanadium salts as insulin substitutes: mechanisms of action, a scientific and therapeutic tool in diabetes mellitus research. 899 1

Protein-tyrosine phosphatases (PTPases) have been implicated in the physiological regulation of the insulin signalling pathway. In cellular and molecular studies, the transmembrane, receptor-type PTPase LAR and the intracellular, non-receptor enzyme PTP1B have been shown to have a direct impact on insulin action in intact cell models. Since insulin signalling can be enhanced by reducing the abundance or activity of specific PTPases, pharmaceutical agents directed at blocking the interaction between individual PTPases and the insulin receptor may have potential clinical relevance to the treatment of insulin-resistant states such as obesity and Type II diabetes mellitus.
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PMID:Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases. 960 18

Insulin signaling involves a dynamic cascade of protein tyrosine phosphorylation and dephosphorylation. Most of our understanding of this process comes from studies focusing on tyrosine kinases, which are signal activators. Our knowledge of the role of protein-tyrosine phosphatases (PTPases), signal attenuators, in regulating insulin signal transduction remains rather limited. Protein-tyrosine phosphatase 1B (PTP-1B), the prototypical PTPase, is ubiquitously and abundantly expressed. Work from several laboratories, including our own, has implicated PTP-1B as a negative regulator of insulin action and as a potentially important mediator in the pathogenesis of insulin-resistance and non-insulin dependent diabetes mellitus (NIDDM).
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PMID:Protein-tyrosine phosphatase-1B acts as a negative regulator of insulin signal transduction. 960 19

In this review, tumor necrosis factor-alpha (TNF-alpha) is identified as the uniting principle linking the pathogenesis of insulin-dependent diabetes mellitus (IDDM), non-insulin dependent diabetes mellitus (NIDDM) and carcinoma. Elevated TNF-alpha initially increases, and then inhibits, the activity of a number of key enzymes involved in energy metabolism and major histocompatibility (MHC) class I molecule expression. These enzymes include: protein-tyrosine kinase (PTKase) and protein-tyrosine phosphatase (PTPase--enzymes involved in energy metabolism, cell proliferation and stimulation of the MHC class I molecule pathway. Of primary importance is the inhibiting effect of TNF-alpha on PTKase, since this induces insulin resistance in NIDDM and carcinoma, and PTPase, which inhibits MHC class I molecule expression. Studies have shown that IDDM is associated with an increase in PTPase activity which leads to overexpression of MHC class I molecules and a concomitant destruction of pancreatic beta cells. Conversely, carcinoma is associated with an inhibition of PTPase activity, which reduces the expression of MHC class I antigen expression on the cell surface thereby allowing malignant cells to escape immune surveillance. It will be argued that there is continuum of liability between these three conditions, initiated by the effect of TNF-alpha on these key enzymes.
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PMID:Tumor necrosis factor-alpha: a continuum of liability between insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus and carcinoma (review). 1046 70

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.
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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

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

Tyrosine phosphorylation of the insulin receptor is the initial event following receptor binding to insulin, and it induces further tyrosine phosphorylation of various intracellular molecules. This signaling is countered by protein tyrosine phosphatases (PTPases), which reportedly are associated with insulin resistance that can be reduced by regulation of PTPases. Protein tyrosine phosphatase 1B (PTP1B) and leukocyte antigen-related PTPase (LAR) are the PTPases implicated most frequently in insulin resistance and diabetes mellitus. Here, we show that PTP1B and LAR are expressed in human fibroblasts, and we examine the regulation of PTPase activity in fibroblasts from patients with an insulin receptor gene mutation as an in vitro model of insulin resistance. Total PTPase activity was significantly lower in the cytosolic and membrane fractions of fibroblasts with mutations compared with controls (p<0.05). Insulin stimulation of fibroblasts with mutations resulted in a significantly smaller increase in PTP1B activity compared with stimulation of wild-type fibroblasts (p<0.05). This indicates that insulin receptor gene mutations blunt increases in PTPase activity in response to insulin, possibly via a negative feedback mechanism. Our data suggest that the PTPase activity in patients with insulin receptor gene mutation and severe insulin resistance may differ from that in ordinary type 2 diabetes.
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PMID:Protein tyrosine phosphatase regulation in fibroblasts from patients with an insulin receptor gene mutation. 1892 40


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