Isodihydrocapsiate stimulates plasma glucose uptake by activation of AMP-activated protein kinase.
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.
Hwang
Seung-Lark
SL
TG Biotech Research Institute, Technobuilding, Kyungpook National University, Daegu 702-832, Republic of Korea.
Yang
Byung-Keun
BK
Lee
Jai-Youl
JY
Kim
Jeong-Han
JH
Kim
Byung-Dong
BD
Kim
Byung-Hong
BH
Suh
Ki-Hyoung
KH
Kim
Dae Young
DY
Kim
Dae-Yong
DY
Kim
Moon Sung
MS
Song
Hebok
H
Park
Byeoung-Soo
BS
Huh
Tae-Lin
TL
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
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