Alterations in skeletal muscle protein-tyrosine phosphatase activity and expression in insulin-resistant human obesity and diabetes.

Ahmad, Faiyaz; Azevedo, J. L.; Cortright, Ronald N.; Dohm, G. Lynis; Goldstein, Barry J.

doi:10.1172/jci119552

Cited by 264 publications

(198 citation statements)

References 54 publications

(38 reference statements)

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“…In insulin-resistant states such as obesity and type 2 diabetes, insulin signaling is impaired. Several studies of obese humans and rodents report that the expression and͞or activity of specific PTPs, including leukocyte antigen-related phosphatase (LAR), protein-tyrosine phosphatase 1B (PTP1B), and srchomology phosphatase-2 (SHP2), are increased in muscle and adipose tissue (11)(12)(13)(14)(15). We have also observed increased levels of LAR expression in immunoblots of liver extracts from Zucker rats (J.M.Z., unpublished observations).…”

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confidence: 62%

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Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance

Zabolotny

Kim

Peroni

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

111

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Previous reports indicate that the expression and͞or activity of the protein-tyrosine phosphatase (PTP) LAR are increased in insulinresponsive tissues of obese, insulin-resistant humans and rodents, but it is not known whether these alterations contribute to the pathogenesis of insulin resistance. To address this question, we generated transgenic mice that overexpress human LAR, specifically in muscle, to levels comparable to those reported in insulinresistant humans. In LAR-transgenic mice, fasting plasma insulin was increased 2.5-fold compared with wild-type controls, whereas fasting glucose was normal. Whole-body glucose disposal and glucose uptake into muscle in vivo were reduced by 39 -50%. Insulin injection resulted in normal tyrosyl phosphorylation of the insulin receptor and insulin receptor substrate 1 (IRS-1) in muscle of transgenic mice. However, phosphorylation of IRS-2 was reduced by 62%, PI3 kinase activity associated with phosphotyrosine, IRS-1, or IRS-2 was reduced by 34 -57%, and association of p85␣ with both IRS proteins was reduced by 39 -52%. Thus, overexpression of LAR in muscle causes whole-body insulin resistance, most likely due to dephosphorylation of specific regulatory phosphotyrosines on IRS proteins. Our data suggest that increased expression and͞or activity of LAR or related PTPs in insulin target tissues of obese humans may contribute to the pathogenesis of insulin resistance.

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confidence: 62%

“…We have also observed increased levels of LAR expression in immunoblots of liver extracts from Zucker rats (J.M.Z., unpublished observations). Immunodepletion experiments suggest that a 2-3-fold elevation of LAR accounts for most of the enhanced PTP activity in both adipose tissue (12) and muscle (13) of obese humans.…”

mentioning

confidence: 99%

Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance

Zabolotny

Kim

Peroni

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

111

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“…To investigate the potential mechanism(s) associated with this glucose intolerance, we examined the levels of PTP1B, a well-known negative regulator of insulin and leptin receptor signalling [32] whose levels are elevated in obesity in humans [33,34] and rodents, and under inflammatory conditions [22,35,36]. Mice lacking PTP1B globally or specifically in the brain [35,37,38] are lean, while those lacking muscle-or liver-PTP1B are protected against HFD-induced insulin resistance and glucose intolerance [18,19].…”

Section: Discussionmentioning

confidence: 99%

Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

et al. 2011

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Aims/hypothesis Obesity is a major risk factor for development of insulin resistance, a proximal cause of type 2 diabetes and is also associated with an increased relative risk of Alzheimer's disease. We therefore investigated the susceptibility of transgenic mice carrying human mutated transgenes for amyloid precursor protein (APP SWE ) and presenilin 1 (PSEN1 A246E ) (APP/PSEN1), or PSEN1 A246E alone, which are well-characterised animal models of Alzheimer's disease, to develop obesity, glucose intolerance and insulin resistance, and whether this was age-and/or diet-dependent. Methods We analysed the effects of age and/or diet on body weight of wild-type, PSEN1 and APP/PSEN1 mice. We also analysed the effects of diet on glucose homeostasis and insulin signalling in these mice. Results While there were no body weight differences between 16-17-and 20-21-month-old PSEN1 mice, APP/PSEN1 mice and their wild-type controls on standard, low-fat, chow diet, the APP/PSEN1 mice still exhibited impaired glucose homeostasis, as investigated by glucose tolerance tests. This was associated with increased brain protein tyrosine phosphatase 1B protein levels in APP/PSEN1 mice. Interestingly, short-term high-fat diet (HFD) feeding of wild-type, PSEN1and APP/PSEN1 mice for a period of 8 weeks led to higher body weight gain in APP/PSEN1 than in PSEN1 mice and wild-type controls. In addition, HFD-feeding caused fasting hyperglycaemia and worsening of glucose maintenance in PSEN1 mice, the former being further exacerbated in APP/ PSEN1 mice. The mechanism(s) behind this glucose intolerance in PSEN1 and APP/PSEN1 mice appeared to involve increased levels of brain retinol-binding protein 4 and basal phosphorylation of S6 ribosomal protein, and decreased insulin-stimulated phosphorylation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 in the brain. Conclusions/interpretation Our results indicate that Alzheimer's disease increases susceptibility to body weight gain induced by HFD, and to the associated glucose intolerance and insulin resistance.

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“…Indeed, increased expression and activity of several PTPs has been observed in skeletal muscle and adipose tissue in insulin-resistant, obese states in rodents and humans (16 -20). In obese humans, the increased PTP activity in skeletal muscle and adipose tissue has been reported to be due mainly to increased expression of two PTPs, the transmembrane (receptor-like) leukocyte antigen related phosphatase (LAR) and the nontransmembrane tyrosine phosphatase PTP1B (17,18). Whereas Src homology phosphatase 2 expression is also increased, immunodepletion (17,18) and substrate specificity (21) studies suggest it may be less important.…”

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confidence: 99%

“…In obese humans, the increased PTP activity in skeletal muscle and adipose tissue has been reported to be due mainly to increased expression of two PTPs, the transmembrane (receptor-like) leukocyte antigen related phosphatase (LAR) and the nontransmembrane tyrosine phosphatase PTP1B (17,18). Whereas Src homology phosphatase 2 expression is also increased, immunodepletion (17,18) and substrate specificity (21) studies suggest it may be less important. Consistent with the notion that increased PTP activity may contribute to insulin resistance, weight loss in obese humans results in a decrease in the level of these PTPs, concomitant with an increase in the glucose disposal rate (22).…”

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confidence: 99%

Overexpression of Protein-tyrosine Phosphatase-1B in Adipocytes Inhibits Insulin-stimulated Phosphoinositide 3-Kinase Activity without Altering Glucose Transport or Akt/Protein Kinase B Activation

Venable¹,

Frevert²,

Kim³

et al. 2000

Journal of Biological Chemistry

109

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Previous studies suggested that protein-tyrosine phosphatase 1B (PTP1B) antagonizes insulin action by catalyzing dephosphorylation of the insulin receptor (IR) and/or other key proteins in the insulin signaling pathway. In adipose tissue and muscle of obese humans and rodents, PTP1B expression is increased, which led to the hypothesis that PTP1B plays a role in the pathogenesis of insulin resistance. Consistent with this, mice in which the PTP1B gene was disrupted exhibit increased insulin sensitivity. To test whether increased expression of PTP1B in an insulin-sensitive cell type could contribute to insulin resistance, we overexpressed wild-type PTP1B in 3T3L1 adipocytes using adenovirusmediated gene delivery. PTP1B expression was increased ϳ3-5-fold above endogenous levels at 16 h, ϳ14-fold at 40 h, and ϳ20-fold at 72 h post-transduction. Total protein-tyrosine phosphatase activity was increased by 50% at 16 h, 3-4-fold at 40 h, and 5-6-fold at 72 h posttransduction. Compared with control cells, cells expressing high levels of PTP1B showed a 50 -60% decrease in maximally insulin-stimulated tyrosyl phosphorylation of IR and insulin receptor substrate-1 (IRS-1) and phosphoinositide 3-kinase (PI3K) activity associated with IRS-1 or with phosphotyrosine. Akt phosphorylation and activity were unchanged. Phosphorylation of p42 and p44 MAP kinase (MAPK) was reduced ϳ32%. Overexpression of PTP1B had no effect on basal, submaximally or maximally (100 nM) insulin-stimulated glucose transport or on the EC 50 for transport. Our results suggest that: 1) insulin stimulation of glucose transport in adipocytes requires <45% of maximal tyrosyl phosphorylation of IR or IRS-1 and <50% of maximal activation of PI3K, 2) a novel PI3K-independent pathway may play a role in insulin-induced glucose transport in adipocytes, and 3) overexpression of PTP1B alone in adipocytes does not impair glucose transport.

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Alterations in skeletal muscle protein-tyrosine phosphatase activity and expression in insulin-resistant human obesity and diabetes.

Cited by 264 publications

References 54 publications

Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance

Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance

Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

Overexpression of Protein-tyrosine Phosphatase-1B in Adipocytes Inhibits Insulin-stimulated Phosphoinositide 3-Kinase Activity without Altering Glucose Transport or Akt/Protein Kinase B Activation

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