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ATM Protein Kinase Activates Akt and Regulates Glucose Transporter 4 Translocation by Insulin in Muscle Cells
Author(s) -
Yang DaQing,
Halaby MarieJo,
Hibma Jody,
He Jinghua
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.313
Subject(s) - glut4 , insulin resistance , protein kinase b , medicine , endocrinology , glucose transporter , insulin , insulin receptor , glucose uptake , ataxia telangiectasia , transfection , biology , chemistry , phosphorylation , microbiology and biotechnology , biochemistry , gene , dna , dna damage
Ataxia‐telangiectasia (A‐T) is an autosomal recessive disorder mainly characterized by cerebellar ataxia. Patients with A‐T also have high incidences of type 2 diabetes mellitus. The gene mutated in this disease, ATM (A‐T, mutated), encodes a protein kinase. Previous studies have demonstrated that cytoplasmic ATM is an insulin‐responsive protein and a major upstream activator of Akt following insulin treatment. In our study, insulin resistance was induced in rats by feeding them a high‐fat diet. Muscle tissue of rats with insulin resistance had both dramatically reduced ATM levels and substantially decreased Akt phosphorylation at Ser473 compared to that of regular chow‐fed controls. The decreased ATM expression suggests that ATM is involved in the development of insulin resistance through down‐regulation of Akt. Furthermore, a 2‐deoxyglucose incorporation assay showed that this inhibitor also caused a significant reduction in insulin‐mediated glucose uptake in L6 cells. An immunofluorescence experiment demonstrated that in L6 cells transfected with wild type (WT)‐ATM, insulin caused a dramatic increase of the cell surface glucose transporter 4 (GLUT4), while in cells transfected with kinase dead (KD)‐ATM, translocation of GLUT4 to the cell surface in response to insulin was markedly inhibited. Funding of this project was supported by an Innovation Award received from American Diabetes Association.