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)

The involvement of tyrosine phosphorylation in insulin action led us to hypothesize that increased activity of protein tyrosine phosphatases (PTPases) might contribute to insulin resistance in alloxan diabetes in the rat. Hepatic PTPase activity was measured using two artificial substrates phosphorylated on tyrosine: reduced, carboxyamidomethylated, and maleylated lysozyme (P-Tyr-RCML) and myelin basic protein (P-Tyr-MBP), as well as an autophosphorylated 48-kD insulin receptor tyrosine kinase domain (P-Tyr-IRKD). Rats that were made alloxan diabetic exhibited a significant increase in hepatic membrane (detergent-soluble) PTPase activity measured with P-Tyr-MBP, without a change in activity measured with P-Tyr-RCML or the P-Tyr-IRKD. The PTPase active with P-Tyr-MBP behaved as a high molecular weight peak during gel filtration chromatography. Characterization of this enzyme indicated it shared properties with CD45, the prototype for a class of transmembrane, receptor-like PTPases. Our results indicate that alloxan diabetes in the rat is associated with an increase in the activity of a large, membrane-associated PTPase which accounts for only a small proportion of insulin receptor tyrosine dephosphorylation. Nonetheless, increased activity of this PTPase may oppose tyrosine kinase-mediated insulin signal transmission, thus contributing to insulin resistance.
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PMID:Differential regulation of multiple hepatic protein tyrosine phosphatases in alloxan diabetic rats. 132 40

Phosphotyrosine phosphatase (PTPase) activity in rat liver was measured using a phosphopeptide substrate containing sequence identity to the major site of insulin receptor autophosphorylation. PTPase activity was detected in both cytosolic and particulate fractions of rat liver and produced linear dephosphorylation over a 15-min time course. In rats made insulin-deficient diabetic by streptozotocin treatment (STZ), cytosolic PTPase activity increased to 180% of the control values after 2 d of diabetes and remained elevated at 30 d (P less than 0.02). Gel filtration on Sephadex-75 revealed a single peak of activity in the cytosol in both control and diabetic animals and confirmed the increased levels. In BB diabetic rats, another model of insulin deficiency, the PTPase activity in the cytosolic fraction was increased to approximately 230% of control values. PTPase activity in the particulate fraction of liver was also increased by 30 and 80% after 2 and 8 d of STZ diabetes, respectively. However, this increase was not sustained and after 30 d of STZ diabetes, PTPase activity associated with the particulate fraction in the BB diabetic rat was reduced to approximately 70% of the control levels. Treatment of STZ diabetic rats with subcutaneous insulin or vanadate in their drinking water for 3 d reduced tyrosine PTPase activity in the particulate, but not in the cytosolic fraction. This was associated with a change in blood glucose toward normal. These data indicate insulin deficient diabetes is accompanied by significant changes in hepatic PTPase activity. Since tyrosine phosphorylation plays a central role in the cellular action of insulin receptor, an increase in PTPase activity may be an important factor in the altered insulin action associated with these diabetic states.
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PMID:Hepatic phosphotyrosine phosphatase activity and its alterations in diabetic rats. 254 42

Resistance to the biological action of insulin in its target tissues is a cardinal feature of non-insulin-dependent diabetes mellitus. Protein-tyrosine phosphatases (PTPases) have been postulated to play a key role in the regulation of the insulin action pathway, especially in skeletal muscle, the major site of insulin-mediated glucose disposal in vivo. To evaluate whether changes in the activity and/or abundance of candidate skeletal muscle PTPases is associated with severe resistance to insulin in an animal model, we measured PTPase enzyme activity and PTPase protein level by immunoblotting in subcellular fractions of skeletal muscle in lean (+/?), insulin-resistant obese (fa/fa), and diabetic (ZDF/Drt-fa/fa) Zucker rats. Using a phosphotyrosylmyelin basic protein substrate, the solubilized-particulate fraction PTPase activity was increased by 65% and 74% (P < .05) and in vitro dephosphorylation of a recombinant rat insulin receptor kinase domain was increased by 104% and 114% in obese and diabetic animals, respectively (P < .01). These changes in PTPase activity were associated with an increase in specific immunoreactivity of leukocyte common antigen-related PTPase ([LAR] by 42% and 50%), PTPase 1B (by 61% and 69%), and the SHZ domain containing PTPase (SH-PTP2) (by 44% and 48%) in the solubilized-particulate fraction of obese and diabetic animals, respectively (P < .05). In diabetic muscle, increased SH-PTP2 abundance was also associated with a shift of SH-PTP2 to a plasma membrane component, which may have important consequences for the activation of this enzyme in the insulin-resistant state. These results provide evidence that specific PTPases play a role in the insulin resistance of this genetic model of obesity and non-insulin-dependent diabetes.
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PMID:Increased abundance of specific skeletal muscle protein-tyrosine phosphatases in a genetic model of insulin-resistant obesity and diabetes mellitus. 766 92

To test whether protein tyrosine phosphatases (PTPases) may play a role in the insulin resistance of insulinopenic diabetes, we assessed PTPase activity as well as the protein and mRNA abundance of three major candidate PTPases in subcellular fractions of liver and skeletal muscle of streptozotocin-diabetic rats before and after insulin treatment. PTPase activity against the insulin receptor in liver and muscle cytosol increased to 120-125% of control in the diabetic animals and by an additional 5-10% after insulin treatment. In the particulate fraction, PTPase activity decreased to 65-70% of control in diabetic liver and muscle and increased to 115-120% of control after insulin treatment. Protein for the leukocyte common antigen-related PTPase paralleled the changes in the PTPase activity in the particulate fraction. SH-PTP2/syp and PTPase 1B were both significantly increased in diabetes. SH-PTP2/syp also exhibited an increased ratio of particulate to cytosol distribution in diabetic tissues (1.8-1.9) that was reversed after insulin treatment (0.79-0.95). Northern analysis suggested that the PTPases were regulated at a pretranslational level. These changes in the abundance and distribution of specific PTPases may be involved in the pathogenesis of insulin resistance in insulinopenic diabetes.
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PMID:Alterations in specific protein-tyrosine phosphatases accompany insulin resistance of streptozotocin diabetes. 776 48

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

Tumor necrosis factor-alpha (TNF-alpha) can modulate the signalling capacity of tyrosine kinase receptors; in particular, TNF-alpha has been shown to mediate the insulin resistance associated with animal models of obesity and noninsulin-dependent diabetes mellitus. In order to determine whether the effects of TNF-alpha might involve alterations in the expression of specific protein-tyrosine phosphatases (PTPases) that have been implicated in the regulation of growth factor receptor signalling, KRC-7 rat hepatoma cells were treated with TNF-alpha, and changes in overall tissue PTPase activity and the abundance of three major hepatic PTPases (LAR, PTP1B, and SH-PTP2) were measured in addition to effects of TNF-alpha on ligand-stimulated autophosphorylation of insulin and epidermal growth factor (EGF) receptors and insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation. TNF-alpha caused a dose-dependent decrease in insulin-stimulated IRS-1 phosphorylation and EGF-stimulated receptor autophosphorylation to 47-50% of control. Overall PTPase activity in the cytosol fraction did not change with TNF-alpha treatment, and PTPase activity in the particulate fraction was decreased by 55-66%, demonstrating that increases in total cellular PTPase activity did not account for the observed alterations in receptor signalling. However, immunoblot analysis showed that TNF-alpha treatment resulted in a 2.5-fold increase in the abundance of SH-PTP2, a 49% decrease in the transmembrane PTPase LAR, and no evident change in the expression of PTP1B. These data suggest that at least part of the TNF-alpha effect on pathways of reversible tyrosine phosphorylation may be exerted through the dynamic modulation of the expression of specific PTPases. Since SH-PTP2 has been shown to interact directly with both the EGF receptor and IRS-1, increased abundance of this PTPase, may mediate the TNF-alpha effect to inhibit signalling through these proteins. Furthermore, decreased abundance of the LAR PTPase, which has been implicated in the regulation of insulin receptor phosphorylation, may account for the less marked effect of TNF-alpha on the autophosphorylation state of the insulin receptor while postreceptor actions of insulin are inhibited.
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PMID:Effect of tumor necrosis factor-alpha on the phosphorylation of tyrosine kinase receptors is associated with dynamic alterations in specific protein-tyrosine phosphatases. 901 60

Protein-tyrosine phosphatases (PTPases) play an integral role in the regulation of cellular insulin action. LAR, a transmembrane PTPase expressed in insulin-sensitive tissues, acts as a negative regulator of insulin signaling in intact cell models. The physiological role of LAR was studied in mice in which LAR expression was eradicated by insertional mutagenesis. In the fasting state, adult male homozygous LAR (-/-) mice had significantly lower plasma levels of insulin and glucose, as well as a reduced rate of hepatic glucose production compared with wild-type controls, suggesting a heightened level of insulin sensitivity. In euglycemic clamp studies, the LAR (-/-) mice exhibited a significant resistance to insulin-stimulated glucose disposal and suppression of hepatic glucose output. Examination of hepatic insulin action demonstrated that the major alteration involved a 47% reduction in insulin-stimulated phosphatidylinositol 3'-kinase (PI 3-kinase) activity in the knockout mice, indicating a post-receptor signaling defect. Taken together with previous work on the cellular effects of LAR, the present results are consistent with a physiological role for LAR in the negative regulation of insulin action, with secondary abnormalities that contribute to the resistance to insulin-stimulated signaling in the knockout mice. Overall, these data provide further evidence for an important role for LAR in the regulation of insulin action and glucose homeostasis in intact animals.
Diabetes 1998 Mar
PMID:Transgenic mice deficient in the LAR protein-tyrosine phosphatase exhibit profound defects in glucose homeostasis. 951 61

Biological actions of insulin are initiated by activation of the insulin receptor tyrosine kinase. Protein tyrosine phosphatases (PTPases) PTP1B and PTPalpha are known to dephosphorylate the insulin receptor and may contribute to insulin resistance in diseases such as diabetes. We previously reported that overexpression of PTP1B in rat adipose cells significantly impairs insulin-stimulated translocation of GLUT4 [Chen, H., et al. (1997) J. Biol. Chem. 272, 8026]. In the present study, we treated adipose cells with a PTPase inhibitor containing the phosphotyrosyl mimetic difluorophosphonomethyl phenylalanine (F2Pmp) to determine whether we could improve the insulin resistance caused by overexpression of PTP1B or PTPalpha. Rat adipose cells transfected by electroporation with either PTP1B or PTPalpha were treated without or with the inhibitor, and effects on insulin-stimulated translocation of a cotransfected epitope-tagged GLUT4 were studied. The IC50 of the F2Pmp-containing inhibitor is 180 nM for PTP1B and 10 mM for PTPalpha in vitro. As expected, in the absence of the inhibitor, overexpression of either PTP1B or PTPalpha caused a significant decrease in the amount of GLUT4 at the cell surface both in the absence and in the presence of insulin when compared with control cells transfected with epitope-tagged GLUT4 alone. Interestingly, the insulin resistance caused by overexpression of PTP1B (but not PTPalpha) was reversed by treating the transfected cells with the F2Pmp-containing inhibitor. Furthermore, the inhibitor blocked the insulin-stimulated association of PTP1B with the insulin receptor. We conclude that the F2Pmp-containing compound is a potent and specific inhibitor of overexpressed PTP1B that may be useful for designing rational therapies for treating insulin resistant diseases such as diabetes.
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PMID:A phosphotyrosyl mimetic peptide reverses impairment of insulin-stimulated translocation of GLUT4 caused by overexpression of PTP1B in rat adipose cells. 989 Sep 20

Type 2 diabetes is characterized by insulin resistance as well as impaired insulin secretion. Thus, the enhancement of insulin sensitivity is a possible treatment modality. The mechanism of insulin resistance is still unknown. However, some genetic backgrounds may be involved and modulated by environmental factors. Obesity is considered to be one of major factors to induce insulin resistance. Regarding mechanism of obesity-induced insulin resistance, the increased expression of Tumor necrosis factor alpha and abnormality in PTPase are postulated. Prolonged hyperglycemia also induces the impairment of insulin action, resulting in worsening glycemic control. Abnormal glucosamine biosynthesis and impaired receptor kinase are considered to be involved in the hyperglycemia-induced insulin resistance.
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PMID:[Molecular mechanism and clinical impact of insulin resistance in type 2 diabetes mellitus]. 1019 30

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


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