title: 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.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Seung-Lark
authors.initials: SL
authors.lastname: Hwang
authors.forename: Yong-Tae
authors.initials: YT
authors.lastname: Jeong
authors.forename: Ju
authors.initials: J
authors.lastname: Hye Yang
authors.forename: Xian
authors.initials: X
authors.lastname: Li
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.forename: Jong Keun
authors.initials: JK
authors.lastname: Son
authors.forename: Hyeun Wook
authors.initials: HW
authors.lastname: Chang
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000037:antagonists & inhibitors / Q000502:physiology*; D004224:Diterpenes / Q000008:administration & dosage*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D055504:Insulin Receptor Substrate Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D055670:Medicine, Korean Traditional; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D029783:Thuja
chemical_list: D004224:Diterpenes; D007004:Hypoglycemic Agents; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010936:Plant Extracts; C101973:pinusolide; D003847:Deoxyglucose; D017346:Protein Serine-Threonine Kinases; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases
keywords: AMP-activated protein kinase; High glucose; Insulin resistance; L6 myotubes; Pinusolide