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 re its classic effects to regulate fuel metabolism. In a previous stu dy, we have identified a patient who was homozygous for a deletion of the insulin receptor gene. In our current investigation, we used cultu red skin fibroblasts fi om this patient as a model system in which to investigate the mechanisms whereby insulin regulates cellular growth i n vitro. After cell division, skin fibroblasts from normal individuals migrate on the tissue culture plate and appear to be distributed rand omly over the surface of the plate. In contrast, the patient's cells g rew in clumps. Furthermore, the patient's fibroblasts exhibited a mark ed increase in the expression of several integrin subunits, especially the alpha 5- and beta 1-subunits that comprise the fibronectin recept or. Because the cellular growth pattern was restored to normal when ce lls were cultivated in the presence of blocking antibodies directed ag ainst either alpha 5- or beta 1-integrin subunits, we infer that incre ased expression of alpha 5 beta 1-integrin may be the cause of the obs erved abnormality in the growth of the patient's cells in vitro. Furth ermore, insulin stimulation led to downregulation of the levels of the a5- and pl-integrin subunits in normal human fibroblasts but not in t he patient's cells that lacked insulin receptors. Taken together, thes e data suggest that insulin's ability to regulate the expression of ce ll 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 sug gest that dysregulation of integrin expression might contribute to the abnormalities in the structure of the basement membranes associated w ith the chronic microvascular complications of diabetes.