Back to Search
Start Over
Metformin induces Rab4 through AMPK and modulates GLUT4 translocation in skeletal muscle cells
- Source :
- Journal of Cellular Physiology. 226:974-981
- Publication Year :
- 2011
- Publisher :
- Wiley, 2011.
-
Abstract
- Metformin is a major oral anti-diabetic drug and is known as an insulin sensitizer. However, the mechanism by which metformin acts is unclear. In this study, we found that AICAR, an AMPK activator, and metformin increased the expression of Rab4 mRNA and protein levels in skeletal muscle C2C12 cells. The promoter activity of Rab4 was increased by metformin in an AMPK-dependent manner. Metformin stimulated the phosphorylation of AS160, Akt substrate, and Rab GTPase activating protein (GAP), and also increased the phosphorylation of PKC-zeta, which is a critical molecule for glucose uptake. Knockdown of AMPK blocked the metformin-induced phosphorylation of AS160/PKC-zeta. In addition, a colorimetric absorbance assay showed that insulin-induced translocation of GLUT4 was suppressed in Rab4 knockdown cells. Moreover, Rab4 interacted with PKC-zeta but not with GLUT4. The C-terminal-deleted Rab4 mutant, Rab4ΔCT, showed diffuse sub-cellular localization, while wild-type Rab4 localized exclusively to the perinuclear membrane. Unlike Rab4ΔCT, wild-type Rab4 co-localized with PKC-zeta. Together, these results demonstrate that metformin induces Rab4 expression via AMPK-AS160-PKC-zeta and modulates insulin-mediated GLUT4 translocation.
- Subjects :
- medicine.medical_specialty
endocrine system diseases
Physiology
Glucose uptake
Clinical Biochemistry
Biology
Cell Line
Mice
Phosphoserine
Internal medicine
medicine
Animals
Humans
Insulin
Myocyte
RNA, Messenger
Phosphorylation
Muscle, Skeletal
Promoter Regions, Genetic
Protein kinase B
Protein Kinase C
Muscle Cells
Glucose Transporter Type 4
rab4 GTP-Binding Proteins
Adenylate Kinase
nutritional and metabolic diseases
Skeletal muscle
AMPK
Cell Biology
Ribonucleotides
Aminoimidazole Carboxamide
Metformin
Protein Structure, Tertiary
Protein Transport
medicine.anatomical_structure
Endocrinology
Gene Expression Regulation
biology.protein
Mutant Proteins
hormones, hormone substitutes, and hormone antagonists
GLUT4
HeLa Cells
Protein Binding
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 00219541
- Volume :
- 226
- Database :
- OpenAIRE
- Journal :
- Journal of Cellular Physiology
- Accession number :
- edsair.doi.dedup.....092fb56afddcb099b41e4678179c6f6c