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.
Authors	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
Journal	Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 17777 (12 19 2017) ISSN: 2045-2322 [Electronic] England
PMID	29259227 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Furans Hypoglycemic Agents Insulin Insulin Receptor Substrate Proteins Irs1 protein, mouse Phenanthrenes Quinones dihydrotanshinone I AMP-Activated Protein Kinases Protein Tyrosine Phosphatases Glucose
Topics	AMP-Activated Protein Kinases (metabolism) Animals Cell Line Enzyme Activation (drug effects) Furans Glucose (metabolism) Glucose Tolerance Test (methods) Humans Hypoglycemic Agents (pharmacology) Insulin (metabolism) Insulin Receptor Substrate Proteins (metabolism) Insulin Resistance (physiology) Male Metabolic Syndrome (drug therapy, metabolism) Mice Mice, Inbred C57BL Muscle, Skeletal (drug effects, metabolism) Muscular Atrophy (drug therapy, metabolism) Phenanthrenes (pharmacology) Protein Tyrosine Phosphatases (antagonists & inhibitors) Quinones Signal Transduction (drug effects)

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