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Diabetes reversal by inhibition of the low molecular weight tyrosine phosphatase

Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low molecular weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in...

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Autores principales: Stanford, Stephanie M, Aleshin, Alexander E, Zhang, Vida, Ardecky, Robert J, Hedrick, Michael P, Zou, Jiwen, Ganji, Santhi R., Bliss, Matthew R, Yamamoto, Fusayo, Bobkov, Andrey A., Kiselar, Janna, Liu, Yingge, Cadwell, Gregory W, Khare, Shilpi, Yu, Jinghua, Barquilla, Antonio, Chung, Thomas DY, Mustelin, Tomas, Schenk, Simon, Bankston, Laurie A, Liddington, Robert C, Pinkerton, Anthony B, Bottini, Nunzio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435566/
https://www.ncbi.nlm.nih.gov/pubmed/28346406
http://dx.doi.org/10.1038/nchembio.2344
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author Stanford, Stephanie M
Aleshin, Alexander E
Zhang, Vida
Ardecky, Robert J
Hedrick, Michael P
Zou, Jiwen
Ganji, Santhi R.
Bliss, Matthew R
Yamamoto, Fusayo
Bobkov, Andrey A.
Kiselar, Janna
Liu, Yingge
Cadwell, Gregory W
Khare, Shilpi
Yu, Jinghua
Barquilla, Antonio
Chung, Thomas DY
Mustelin, Tomas
Schenk, Simon
Bankston, Laurie A
Liddington, Robert C
Pinkerton, Anthony B
Bottini, Nunzio
author_facet Stanford, Stephanie M
Aleshin, Alexander E
Zhang, Vida
Ardecky, Robert J
Hedrick, Michael P
Zou, Jiwen
Ganji, Santhi R.
Bliss, Matthew R
Yamamoto, Fusayo
Bobkov, Andrey A.
Kiselar, Janna
Liu, Yingge
Cadwell, Gregory W
Khare, Shilpi
Yu, Jinghua
Barquilla, Antonio
Chung, Thomas DY
Mustelin, Tomas
Schenk, Simon
Bankston, Laurie A
Liddington, Robert C
Pinkerton, Anthony B
Bottini, Nunzio
author_sort Stanford, Stephanie M
collection PubMed
description Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low molecular weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, increases liver IR phosphorylation in vivo, and reverses high-fat diet induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes.
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spelling pubmed-54355662017-09-27 Diabetes reversal by inhibition of the low molecular weight tyrosine phosphatase Stanford, Stephanie M Aleshin, Alexander E Zhang, Vida Ardecky, Robert J Hedrick, Michael P Zou, Jiwen Ganji, Santhi R. Bliss, Matthew R Yamamoto, Fusayo Bobkov, Andrey A. Kiselar, Janna Liu, Yingge Cadwell, Gregory W Khare, Shilpi Yu, Jinghua Barquilla, Antonio Chung, Thomas DY Mustelin, Tomas Schenk, Simon Bankston, Laurie A Liddington, Robert C Pinkerton, Anthony B Bottini, Nunzio Nat Chem Biol Article Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low molecular weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, increases liver IR phosphorylation in vivo, and reverses high-fat diet induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes. 2017-03-27 2017-06 /pmc/articles/PMC5435566/ /pubmed/28346406 http://dx.doi.org/10.1038/nchembio.2344 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Stanford, Stephanie M
Aleshin, Alexander E
Zhang, Vida
Ardecky, Robert J
Hedrick, Michael P
Zou, Jiwen
Ganji, Santhi R.
Bliss, Matthew R
Yamamoto, Fusayo
Bobkov, Andrey A.
Kiselar, Janna
Liu, Yingge
Cadwell, Gregory W
Khare, Shilpi
Yu, Jinghua
Barquilla, Antonio
Chung, Thomas DY
Mustelin, Tomas
Schenk, Simon
Bankston, Laurie A
Liddington, Robert C
Pinkerton, Anthony B
Bottini, Nunzio
Diabetes reversal by inhibition of the low molecular weight tyrosine phosphatase
title Diabetes reversal by inhibition of the low molecular weight tyrosine phosphatase
title_full Diabetes reversal by inhibition of the low molecular weight tyrosine phosphatase
title_fullStr Diabetes reversal by inhibition of the low molecular weight tyrosine phosphatase
title_full_unstemmed Diabetes reversal by inhibition of the low molecular weight tyrosine phosphatase
title_short Diabetes reversal by inhibition of the low molecular weight tyrosine phosphatase
title_sort diabetes reversal by inhibition of the low molecular weight tyrosine phosphatase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435566/
https://www.ncbi.nlm.nih.gov/pubmed/28346406
http://dx.doi.org/10.1038/nchembio.2344
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