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.
Highlights
Type 2 diabetes is the most common form of diabetes, and insulin resistance in metabolic organs contributes to the development of this disease
protein tyrosine phosphatase (PTPase) are readily inactivated by reactive oxygen species (ROS) through the oxidation of catalytic cysteine[12]
NAC treatment prevented H2O2 and Menadione-induced insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, dihydrotanshinone I (DHTS)-induced IRS-1 tyrosine phosphorylation remained in the presence of NAC
Summary
Type 2 diabetes is the most common form of diabetes, and insulin resistance in metabolic organs contributes to the development of this disease. Reduced IRS-1 levels contribute to two pathological features of insulin resistance in skeletal muscle: impaired glucose metabolism and decreased muscle mass[7]. Overexpression of E3 ligases targeting IRS-1 induces pathological changes such as glucose intolerance or muscle atrophy[8,9,10,11], as both are under the control of IRS-1-mediated signaling. We revealed that C1-Ten promotes IRS-1 degradation via its protein tyrosine phosphatase (PTPase) activity towards IRS-1, thereby reducing glucose uptake and muscle mass[3]. With the unexpected finding that C1-Ten inhibition leads to activation of both IRS-1 and AMP-activated protein kinase (AMPK) pathways, we elucidated a new C1-Ten-mediated signaling pathway using the C1-Ten inhibitor, DHTS. Our study potentiates the importance of C1-Ten as a novel therapeutic target for metabolic disorders
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