Inhibition of C1-Ten PTPase activity reduces insulin resistance through IRS-1 and AMPK pathways

Heeyoon Jeong; Ara Koh; Jiyoun Lee; Dohyun Park; Jung Ok Lee; Mi Nam Lee; Kyung Jin Jo; Huynh Nguyen Khanh Tran; Eui Kim; Byung Sun Min; Hyeon Soo Kim; Per Olof Berggren; Sung Ho Ryu

doi:10.1038/s41598-017-18081-8

Inhibition of C1-Ten PTPase activity reduces insulin resistance through IRS-1 and AMPK pathways

Heeyoon Jeong, Ara Koh, Jiyoun Lee, Dohyun Park, Jung Ok Lee, Mi Nam Lee, Kyung Jin Jo, Huynh Nguyen Khanh Tran, Eui Kim, Byung Sun Min, Hyeon Soo Kim, Per Olof Berggren, Sung Ho Ryu

Department of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

Insulin resistance causes type 2 diabetes; therefore, increasing insulin sensitivity is a therapeutic approach against type 2 diabetes. Activating AMP-activated protein kinase (AMPK) is an effective approach for treating diabetes, and reduced insulin receptor substrate-1 (IRS-1) protein levels have been suggested as a molecular mechanism causing insulin resistance. Thus, dual targeting of AMPK and IRS-1 might provide an ideal way to treat diabetes. We found that 15,16-dihydrotanshinone I (DHTS), as a C1-Ten protein tyrosine phosphatase inhibitor, increased IRS-1 stability, improved glucose tolerance and reduced muscle atrophy. Identification of DHTS as a C1-Ten inhibitor revealed a new function of C1-Ten in AMPK inhibition, possibly through regulation of IRS-1. These findings suggest that C1-Ten inhibition by DHTS could provide a novel therapeutic strategy for insulin resistance-associated metabolic syndrome through dual targeting of IRS-1 and AMPK.

Original language	English
Article number	17777
Journal	Scientific reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-18081-8
Publication status	Published - 2017 Dec 1

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title = "Inhibition of C1-Ten PTPase activity reduces insulin resistance through IRS-1 and AMPK pathways",

abstract = "Insulin resistance causes type 2 diabetes; therefore, increasing insulin sensitivity is a therapeutic approach against type 2 diabetes. Activating AMP-activated protein kinase (AMPK) is an effective approach for treating diabetes, and reduced insulin receptor substrate-1 (IRS-1) protein levels have been suggested as a molecular mechanism causing insulin resistance. Thus, dual targeting of AMPK and IRS-1 might provide an ideal way to treat diabetes. We found that 15,16-dihydrotanshinone I (DHTS), as a C1-Ten protein tyrosine phosphatase inhibitor, increased IRS-1 stability, improved glucose tolerance and reduced muscle atrophy. Identification of DHTS as a C1-Ten inhibitor revealed a new function of C1-Ten in AMPK inhibition, possibly through regulation of IRS-1. These findings suggest that C1-Ten inhibition by DHTS could provide a novel therapeutic strategy for insulin resistance-associated metabolic syndrome through dual targeting of IRS-1 and AMPK.",

author = "Heeyoon Jeong and Ara Koh and Jiyoun Lee and Dohyun Park and Lee, {Jung Ok} and Lee, {Mi Nam} and Jo, {Kyung Jin} and Tran, {Huynh Nguyen Khanh} and Eui Kim and Min, {Byung Sun} and Kim, {Hyeon Soo} and Berggren, {Per Olof} and Ryu, {Sung Ho}",

note = "Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. NRF-2016K1A1A2912722). Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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AU - Jeong, Heeyoon

AU - Koh, Ara

AU - Lee, Jiyoun

AU - Park, Dohyun

AU - Lee, Jung Ok

AU - Lee, Mi Nam

AU - Jo, Kyung Jin

AU - Tran, Huynh Nguyen Khanh

AU - Kim, Eui

AU - Min, Byung Sun

AU - Kim, Hyeon Soo

AU - Berggren, Per Olof

AU - Ryu, Sung Ho

N1 - Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. NRF-2016K1A1A2912722). Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Insulin resistance causes type 2 diabetes; therefore, increasing insulin sensitivity is a therapeutic approach against type 2 diabetes. Activating AMP-activated protein kinase (AMPK) is an effective approach for treating diabetes, and reduced insulin receptor substrate-1 (IRS-1) protein levels have been suggested as a molecular mechanism causing insulin resistance. Thus, dual targeting of AMPK and IRS-1 might provide an ideal way to treat diabetes. We found that 15,16-dihydrotanshinone I (DHTS), as a C1-Ten protein tyrosine phosphatase inhibitor, increased IRS-1 stability, improved glucose tolerance and reduced muscle atrophy. Identification of DHTS as a C1-Ten inhibitor revealed a new function of C1-Ten in AMPK inhibition, possibly through regulation of IRS-1. These findings suggest that C1-Ten inhibition by DHTS could provide a novel therapeutic strategy for insulin resistance-associated metabolic syndrome through dual targeting of IRS-1 and AMPK.

AB - Insulin resistance causes type 2 diabetes; therefore, increasing insulin sensitivity is a therapeutic approach against type 2 diabetes. Activating AMP-activated protein kinase (AMPK) is an effective approach for treating diabetes, and reduced insulin receptor substrate-1 (IRS-1) protein levels have been suggested as a molecular mechanism causing insulin resistance. Thus, dual targeting of AMPK and IRS-1 might provide an ideal way to treat diabetes. We found that 15,16-dihydrotanshinone I (DHTS), as a C1-Ten protein tyrosine phosphatase inhibitor, increased IRS-1 stability, improved glucose tolerance and reduced muscle atrophy. Identification of DHTS as a C1-Ten inhibitor revealed a new function of C1-Ten in AMPK inhibition, possibly through regulation of IRS-1. These findings suggest that C1-Ten inhibition by DHTS could provide a novel therapeutic strategy for insulin resistance-associated metabolic syndrome through dual targeting of IRS-1 and AMPK.

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Inhibition of C1-Ten PTPase activity reduces insulin resistance through IRS-1 and AMPK pathways

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