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Cell Signal. 2013 Dec;25(12):2558-65. doi: 10.1016/j.cellsig.2013.08.018. Epub 2013 Aug 29.

Tiam-1, a GEF for Rac1, plays a critical role in metformin-mediated glucose uptake in C2C12 cells.

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  • 1Department of Anatomy, Korea University College of Medicine, Seoul, Republic of Korea.


Metformin is known to stimulate glucose uptake, but the mechanism for this action is not fully understood. In this study, AMPK activators (AICAR and metformin) increased the expression of T-lymphoma invasion and metastasis-inducing protein-1 (Tiam-1), a Rac1 specific guanine nucleotide exchange factor (GEF), mRNA and protein in skeletal muscle C2C12 cells. Metformin increases the serine-phosphorylation of Tiam-1 by AMPK and induces interaction between Tiam-1 and 14-3-3. Pharmacologic inhibition of AMPK blocks this interaction, indicating that 14-3-3 may be required for induction of Tiam-1 by AMPK. Metformin also increases the phosphorylation of p21-activated kinase 1 (PAK1), a direct downstream target of Rac1, dependent on AMPK. Tiam-1 is down-regulated at high glucose concentrations in cultured cells and in the db/db mouse model of hyperglycemia. Furthermore, Tiam-1 knock-down blocked metformin-induced increase in glucose uptake. These findings suggest that metformin promotes cellular glucose uptake in part through Tiam-1 induction.

© 2013. Published by Elsevier Inc. All rights reserved.


5-aminoimidazole-4-carboxyamide-1-d-robofuranoside; ACC; AICAR; AMP-activated protein kinase; AMPK; GEF; Glucose uptake; PAK1; T-lymphoma invasion and metastasis-inducing protein-1; Tiam-1; acetyl-CoA carboxylase; guanine nucleotide exchange factor

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