title: Emodin regulates glucose utilization by activating AMP-activated protein kinase.
abstract: AMP-activated protein kinase has been described as a key signaling protein that can regulate energy homeostasis. Here, we aimed to characterize novel AMP-activated kinase (AMPK)-activating compounds that have a much lower effective concentration than metformin. As a result, emodin, a natural anthraquinone derivative, was shown to stimulate AMPK activity in skeletal muscle and liver cells. Emodin enhanced GLUT4 translocation and [(14)C]glucose uptake into the myotube in an AMPK-dependent manner. Also, emodin inhibited glucose production by suppressing the expression of key gluconeogenic genes, such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, in hepatocytes. Furthermore, we found that emodin can activate AMPK by inhibiting mitochondrial respiratory complex I activity, leading to increased reactive oxygen species and Ca(2+)/calmodulin-dependent protein kinase kinase activity. Finally, we confirmed that a single dose administration of emodin significantly decreased the fasting plasma glucose levels and improved glucose tolerance in C57Bl/6J mice. Increased insulin sensitivity was also confirmed after daily injection of emodin for 8 days using an insulin tolerance test and insulin-stimulated PI3K phosphorylation in wild type and high fat diet-induced diabetic mouse models. Our study suggests that emodin regulates glucose homeostasis in vivo by AMPK activation and that this may represent a novel therapeutic principle in the treatment of type 2 diabetic models.
authors.affiliation: Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea.
authors.forename: Parkyong
authors.initials: P
authors.lastname: Song
authors.forename: Jong Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Jaewang
authors.initials: J
authors.lastname: Ghim
authors.forename: Jong Hyuk
authors.initials: JH
authors.lastname: Yoon
authors.forename: Areum
authors.initials: A
authors.lastname: Lee
authors.forename: Yonghoon
authors.initials: Y
authors.lastname: Kwon
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Hyun
authors.forename: Hyo-Youl
authors.initials: HY
authors.lastname: Moon
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004642:Emodin / Q000494:pharmacology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000166:cytology; D032446:Myoblasts / Q000166:cytology
chemical_list: D001786:Blood Glucose; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D004642:Emodin; D002118:Calcium