Glyceollin improves endoplasmic reticulum stress-induced insulin resistance through CaMKK-AMPK pathway in L6 myotubes.

Abstract

Glyceollin has been shown to have antidiabetic properties, although its molecular mechanism is not known. Here, we have investigated the metabolic effects of glyceollin in animal models of insulin resistance and in endoplasmic reticulum (ER) stress-responsive muscle cells. db/db mice were treated with glyceollin for 4weeks and triglycerides, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels were measured. Glyceollin reduced serum insulin and triglycerides and increased HDL levels in db/db mice. Furthermore, glyceollin caused a significant improvement in glucose homeostasis without altering body weight and food intake in db/db mice. In muscle cells, glyceollin increased the activity of AMP-activated protein kinase (AMPK) as well as cellular glucose uptake. Fatty acid oxidation was also increased. In parallel, phosphorylation of acetyl-CoA carboxylase (ACC) at Ser-79 was increased, consistent with decreased ACC activity. An insulin-resistant state was induced by exposing cells to 5μg/ml of tunicamycin as indicated by decreased insulin-mediated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and glucose uptake. Inhibition of insulin-mediated tyrosine phosphorylation of IRS-1 and glucose uptake under ER stress was prevented by glyceollin. Strikingly, glyceollin reduced ER stress-induced, c-Jun NH2-terminal kinase activation and subsequently increased insulin signaling via stimulation of AMPK activity in L6 myotubes. Pharmacologic inhibition or knockdown of Ca(2+)/calmodulin-dependent protein kinase kinase blocked glyceollin-increased AMPK phosphorylation and insulin sensitivity under ER stress conditions. Taken together, these results indicate that glyceollin-mediated enhancement of insulin sensitivity under ER stress conditions is predominantly accomplished by activating AMPK, thereby having beneficial effects on hyperglycemia and insulin resistance.

• Authors: Eun-Kyung Yoon, Yong-Tae Jeong, Xian Li, Song-Cui, Dong-Chan Park, Yong-Hoon Kim, Yong Deuk Kim, Hyeun Wook Chang, Sang-Han Lee, Seung-Lark Hwang
• Journal: The Journal of nutritional biochemistry (J Nutr Biochem) Vol. 24 Issue 6 Pg. 1053-61 (Jun 2013) ISSN: 1873-4847 [Electronic] United States
• PMID: 23313043 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Fatty Acids
• Hypoglycemic Agents
• Insulin
• Insulin Receptor Substrate Proteins
• Lipoproteins, HDL
• Lipoproteins, LDL
• Pterocarpans
• glyceollin
• Calcium-Calmodulin-Dependent Protein Kinase Kinase
• AMP-Activated Protein Kinases
• Glucose

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Kinase (metabolism)
• Cell Line
• Endoplasmic Reticulum Stress (physiology)
• Enzyme Activation
• Fatty Acids (metabolism)
• Glucose (metabolism)
• Hypoglycemic Agents (pharmacology)
• Insulin (metabolism)
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin Resistance
• Lipoproteins, HDL (metabolism)
• Lipoproteins, LDL (metabolism)
• Male
• Mice
• Muscle Fibers, Skeletal (drug effects, metabolism)
• Oxidation-Reduction
• Phosphorylation
• Pterocarpans (pharmacology)