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Glyceollin improves endoplasmic reticulum stress-induced insulin resistance through CaMKK-AMPK pathway in L6 myotubes.
J Nutr Biochem. 2013 Jun; 24(6):1053-61.JN

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+Show Affiliations

Department of Food Science and Biotechnology, Kyungpook National University, Daegu 702-701, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23313043

Citation

Yoon, Eun-Kyung, et al. "Glyceollin Improves Endoplasmic Reticulum Stress-induced Insulin Resistance Through CaMKK-AMPK Pathway in L6 Myotubes." The Journal of Nutritional Biochemistry, vol. 24, no. 6, 2013, pp. 1053-61.
Yoon EK, Jeong YT, Li X, et al. Glyceollin improves endoplasmic reticulum stress-induced insulin resistance through CaMKK-AMPK pathway in L6 myotubes. J Nutr Biochem. 2013;24(6):1053-61.
Yoon, E. K., Jeong, Y. T., Li, X., Song-Cui, ., Park, D. C., Kim, Y. H., Kim, Y. D., Chang, H. W., Lee, S. H., & Hwang, S. L. (2013). Glyceollin improves endoplasmic reticulum stress-induced insulin resistance through CaMKK-AMPK pathway in L6 myotubes. The Journal of Nutritional Biochemistry, 24(6), 1053-61. https://doi.org/10.1016/j.jnutbio.2012.08.003
Yoon EK, et al. Glyceollin Improves Endoplasmic Reticulum Stress-induced Insulin Resistance Through CaMKK-AMPK Pathway in L6 Myotubes. J Nutr Biochem. 2013;24(6):1053-61. PubMed PMID: 23313043.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glyceollin improves endoplasmic reticulum stress-induced insulin resistance through CaMKK-AMPK pathway in L6 myotubes. AU - Yoon,Eun-Kyung, AU - Jeong,Yong-Tae, AU - Li,Xian, AU - Song-Cui,, AU - Park,Dong-Chan, AU - Kim,Yong-Hoon, AU - Kim,Yong Deuk, AU - Chang,Hyeun Wook, AU - Lee,Sang-Han, AU - Hwang,Seung-Lark, Y1 - 2013/01/11/ PY - 2012/03/07/received PY - 2012/06/20/revised PY - 2012/08/05/accepted PY - 2013/1/15/entrez PY - 2013/1/15/pubmed PY - 2014/4/25/medline SP - 1053 EP - 61 JF - The Journal of nutritional biochemistry JO - J. Nutr. Biochem. VL - 24 IS - 6 N2 - 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. SN - 1873-4847 UR - https://www.unboundmedicine.com/medline/citation/23313043/Glyceollin_improves_endoplasmic_reticulum_stress_induced_insulin_resistance_through_CaMKK_AMPK_pathway_in_L6_myotubes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0955-2863(12)00210-0 DB - PRIME DP - Unbound Medicine ER -