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Title: Evidence for organic cation transporter-mediated metformin transport and 5'-adenosine monophosphate-activated protein kinase activation in rat skeletal muscles.
Authors: Oshima, Rieko
Yamada, Mayumi
Kurogi, Eriko
Ogino, Yohei
Serizawa, Yasuhiro
Tsuda, Satoshi
Ma, Xiao
Egawa, Tatsuro  kyouindb  KAKEN_id  orcid (unconfirmed)
Hayashi, Tatsuya  kyouindb  KAKEN_id  orcid (unconfirmed)
Author's alias: 大島, 里詠子
林, 達也
Keywords: Metformin
5′-adenosine monophosphate-activated protein kinase
Organic cation transporter
Glucose transport
Skeletal muscle
Issue Date: Feb-2015
Publisher: Elsevier Inc.
Journal title: Metabolism
Volume: 64
Issue: 2
Start page: 296
End page: 304
Abstract: [Objective] 5′-adenosine monophosphate-activated protein kinase (AMPK) is a key molecule of metabolic enhancement in skeletal muscle. We investigated whether metformin (MET) acts directly on skeletal muscle, is transported into skeletal muscle via organic cation transporters (OCTs), and activates AMPK. [Materials/Methods] Isolated rat epitrochlearis and soleus muscles were incubated in vitro either in the absence or in the presence of MET. The activation status of AMPK, the intracellular energy status, and glucose and MET transport activity were then evaluated. The effect of cimetidine, which is an OCT inhibitor, on AMPK activation was also examined. [Results] MET (10 mmol/L, ≥ 60 min) increased the phosphorylation of Thr172 at the catalytic α subunit of AMPK in both muscles. AMPK activity assays showed that both AMPKα1 and AMPKα2 activity increased significantly. The AMPK activation was associated with energy deprivation, which was estimated from the ATP, phosphocreatine (PCr), and glycogen content, and with increased rates of 3-O-methyl-D-glucose (3MG) transport. MET did not change the basal phosphorylation status of insulin receptor signaling molecules. MET was transported into the cytoplasm in a time-dependent manner, and cimetidine suppressed MET-induced AMPK phosphorylation and 3MG transport. [Conclusion] These results suggest that MET is acutely transported into skeletal muscle by OCTs, and stimulates AMPKα1 and α2 activity in both fast- and slow-twitch muscle types, at least in part by reducing the energy state.
Rights: © 2015 Elsevier Inc.
This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。
DOI(Published Version): 10.1016/j.metabol.2014.10.037
PubMed ID: 25433920
Appears in Collections:Journal Articles

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