Pinusolide improves high glucose-induced insulin resistance via activation of AMP-activated protein kinase.

Abstract

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a crucial role in the maintenance of cellular energy homeostasis, and several natural compounds that activate AMPK possibly enhance glucose uptake by muscle cells. In this study, we found that pinusolide stimulated AMPK phosphorylation and glucose uptake and these effects were significantly reduced by siRNA LKB1 or compound C, suggesting that enhanced glucose uptake by pinusolide is predominantly accomplished via an LKB1-mediated AMPK activation pathway. An insulin resistance state was induced by exposing cells to 30mM glucose, as indicated by reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and glucose uptake. Under these conditions, the phosphorylation of AMPK and ACC were decreased. Surprisingly, disrupted insulin signaling and decreased AMPK activity by high glucose concentrations were prevented by pinusolide. Moreover, this treatment increased insulin-stimulated glucose uptake via AMPK activation. Taken together, our findings suggest a link between high glucose and insulin resistance in muscle cells, and provide further evidence that pinusolide attenuates blockade of insulin signaling by enhancing IRS-1 tyrosine phosphorylation by the activating the AMPK pathway. In addition, this study indicates the targeting of AMPK represents a new therapeutic strategy for hyperglycemia-induced insulin resistance and type 2 diabetes.

• Authors: Seung-Lark Hwang, Yong-Tae Jeong, Ju Hye Yang, Xian Li, Yue Lu, Jong Keun Son, Hyeun Wook Chang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 437 Issue 3 Pg. 374-9 (Aug 02 2013) ISSN: 1090-2104 [Electronic] United States
• PMID: 23831466 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Chemical References

• Diterpenes
• Hypoglycemic Agents
• IRS1 protein, human
• Insulin Receptor Substrate Proteins
• Plant Extracts
• pinusolide
• Deoxyglucose
• Protein Serine-Threonine Kinases
• Stk11 protein, rat
• AMP-Activated Protein Kinase Kinases

Topics

• AMP-Activated Protein Kinase Kinases
• Animals
• Cells, Cultured
• Deoxyglucose (antagonists & inhibitors, physiology)
• Diterpenes (administration & dosage)
• Enzyme Activation (physiology)
• Humans
• Hypoglycemic Agents (administration & dosage)
• Insulin Receptor Substrate Proteins (antagonists & inhibitors, metabolism)
• Insulin Resistance (physiology)
• Medicine, Korean Traditional
• Muscle Fibers, Skeletal (enzymology, metabolism)
• Phosphorylation
• Plant Extracts (administration & dosage, chemistry)
• Protein Serine-Threonine Kinases
• Rats
• Signal Transduction (physiology)
• Thuja