| First Author | Sakagami H | Year | 2014 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 306 |
| Issue | 9 | Pages | E1065-76 |
| PubMed ID | 24619881 | Mgi Jnum | J:212496 |
| Mgi Id | MGI:5581574 | Doi | 10.1152/ajpendo.00597.2012 |
| Citation | Sakagami H, et al. (2014) Loss of HIF-1alpha impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells. Am J Physiol Endocrinol Metab 306(9):E1065-76 |
| abstractText | Defects in glucose uptake by the skeletal muscle cause diseases linked to metabolic disturbance such as type 2 diabetes. The molecular mechanism determining glucose disposal in the skeletal muscle in response to cellular stimuli including insulin, however, remains largely unknown. The hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor operating in the cellular adaptive response to hypoxic conditions. Recent studies have uncovered pleiotropic actions of HIF-1alpha in the homeostatic response to various cellular stimuli, including insulin under normoxic conditions. Thus we hypothesized HIF-1alpha is involved in the regulation of glucose metabolism stimulated by insulin in the skeletal muscle. To this end, we generated C2C12 myocytes in which HIF-1alpha is knocked down by short-hairpin RNA and examined the intracellular signaling cascade and glucose uptake subsequent to insulin stimulation. Knockdown of HIF-1alpha expression in the skeletal muscle cells resulted in abrogation of insulin-stimulated glucose uptake associated with impaired mobilization of glucose transporter 4 (GLUT4) to the plasma membrane. Such defect seemed to be caused by reduced phosphorylation of the protein kinase B substrate of 160 kDa (AS160). AS160 phosphorylation and GLUT4 translocation by AMP-activated protein kinase activation were abrogated as well. In addition, expression of the constitutively active mutant of HIF-1alpha (CA-HIF-1alpha) or upregulation of endogenous HIF-1alpha in C2C12 cells shows AS160 phosphorylation comparable to the insulin-stimulated level even in the absence of insulin. Accordingly GLUT4 translocation was increased in the cells expressing CA-HIF1alpha. Taken together, HIF-1alpha is a determinant for GLUT4-mediated glucose uptake in the skeletal muscle cells thus as a possible target to alleviate impaired glucose metabolism in, e.g., type 2 diabetes. |
