Inhibition of internalization of glucose transporters and IGF-II receptors. Mechanism of action of MHC class I-derived peptides which augment the insulin response in rat adipose cells.

Peptides from the alpha 1 domain of the major histocompatibility complex class I antigen (MHC class I), e.g. Dk-(61-85) and Dk-(62-85), have been shown previously to augment glucose uptake in insulin-stimulated cells and to inhibit insulin receptor internalization (Stagsted, J., Reaven, G. M., Hansen, T., Goldstein, A., and Olsson, L. (1990) Cell 62, 297-307). We now report that these peptides inhibit by 80-100% the internalization of glucose transporters (GLUT4) and insulin-like growth factor II (IGF-II) receptors in insulin-stimulated cells and correspondingly double insulin-stimulated glucose transport activity and the number of GLUT4 and IGF-II receptors on the cell surface. In addition, the peptides enhance the apparent affinity about 3-fold of IGF-II binding to its receptor. It is concluded that the effects of the peptides on glucose transport and IGF-II binding are a consequence of the peptide-mediated inhibition of internalization of GLUT4 and IGF-II receptor. The active peptides are derived from the alpha 1 domain of a MHC class I molecule, suggesting that the latter is involved in regulation of internalization of cell surface integral membrane proteins such as the GLUT4 and IGF-II and insulin receptors.