title: Tiam-1, a GEF for Rac1, plays a critical role in metformin-mediated glucose uptake in C2C12 cells.
abstract: 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.
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ga Young
authors.initials: GY
authors.lastname: You
authors.forename: Jung Ok
authors.initials: JO
authors.lastname: Lee
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Kim
authors.forename: Nami
authors.initials: N
authors.lastname: Kim
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Lee
authors.forename: Ji Wook
authors.initials: JW
authors.lastname: Moon
authors.forename: Sha
authors.initials: S
authors.lastname: Jie
authors.forename: Hye Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Park
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D005947:Glucose / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D012265:Ribonucleotides / Q000494:pharmacology; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D015854:Up-Regulation / Q000187:drug effects; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D012265:Ribonucleotides; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513260:Tiam1 protein, mouse; D000620:Aminoimidazole Carboxamide; D008687:Metformin; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D055372:AMP-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; C031143:AICA ribonucleotide; D005947:Glucose
keywords: 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