title: Isodihydrocapsiate stimulates plasma glucose uptake by activation of AMP-activated protein kinase.
abstract: AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is implicated as a key factor in controlling whole body homeostasis, including fatty acid oxidation and glucose uptake. We report that a synthetic structural isomer of dihydrocapsiate, isodihydrocapsiate (8-methylnonanoic acid 3-hydroxy-4-methoxy benzyl ester) improves type 2 diabetes by activating AMPK through the LKB1 pathway. In L6 myotube cells, phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) and glucose uptake were significantly increased, whereas these effects were attenuated by an AMPK inhibitor, compound C. In addition, increased phosphorylation of AMPK and ACC by isodihydrocapsiate was significantly reduced by radicicol, an LKB1 destabilizer, suggesting that increased glucose uptake in L6 cells with isodihydrocapsiate treatment is predominantly accomplished by a LKB1-mediated AMPK activation pathway. Oral administration of isodihydrocapsiate to diabetic (db/db) mice reduced blood glucose levels by 40% after a 4-week treatment period. Our results support the development of isodihydrocapsiate as a potential therapeutic agent to target AMPK in type 2 diabetes.
authors.affiliation: TG Biotech Research Institute, Technobuilding, Kyungpook National University, Daegu 702-832, Republic of Korea.
authors.forename: Seung-Lark
authors.initials: SL
authors.lastname: Hwang
authors.forename: Byung-Keun
authors.initials: BK
authors.lastname: Yang
authors.forename: Jai-Youl
authors.initials: JY
authors.lastname: Lee
authors.forename: Jeong-Han
authors.initials: JH
authors.lastname: Kim
authors.forename: Byung-Dong
authors.initials: BD
authors.lastname: Kim
authors.forename: Byung-Hong
authors.initials: BH
authors.lastname: Kim
authors.forename: Ki-Hyoung
authors.initials: KH
authors.lastname: Suh
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Kim
authors.forename: Dae-Yong
authors.initials: DY
authors.lastname: Kim
authors.forename: Moon Sung
authors.initials: MS
authors.lastname: Kim
authors.forename: Hebok
authors.initials: H
authors.lastname: Song
authors.forename: Byeoung-Soo
authors.initials: BS
authors.lastname: Park
authors.forename: Tae-Lin
authors.initials: TL
authors.lastname: Huh
mesh_terms: D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002211:Capsaicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009097:Multienzyme Complexes / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; C529521:isodihydrocapsiate; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D002211:Capsaicin