Insulin receptor regulation of cell surface integrins: a possible mechanism contributing to the development of diabetic complications.

Insulin plays a central role in regulating cellular growth in addition to its classic effects to regulate fuel metabolism. In a previous study, we have identified a patient who was homozygous for a deletion of the insulin receptor gene. In our current investigation, we used cultured skin fibroblasts from this patient as a model system in which to investigate the mechanisms whereby insulin regulates cellular growth in vitro. After cell division, skin fibroblasts from normal individuals migrate on the tissue culture plate and appear to be distributed randomly over the surface of the plate. In contrast, the patient's cells grew in clumps. Furthermore, the patient's fibroblasts exhibited a marked increase in the expression of several integrin subunits, especially the alpha5- and beta1-subunits that comprise the fibronectin receptor. Because the cellular growth pattern was restored to normal when cells were cultivated in the presence of blocking antibodies directed against either alpha5- or beta1-integrin subunits, we infer that increased expression of alpha5beta1-integrin may be the cause of the observed abnormality in the growth of the patient's cells in vitro. Furthermore, insulin stimulation led to downregulation of the levels of the alpha5- and beta1-integrin subunits in normal human fibroblasts but not in the patient's cells that lacked insulin receptors. Taken together, these data suggest that insulin's ability to regulate the expression of cell surface integrins may contribute to the mechanisms whereby insulin regulates cell growth. In light of the important role of integrins in mediating interactions between cells and the basement membrane, we suggest that dysregulation of integrin expression might contribute to the abnormalities in the structure of the basement membranes associated with the chronic microvascular complications of diabetes.