Abnormalities of Platelet-Derived Growth Factors in Insulin-Dependent Diabetes Pavel Hamet, Hidekatsu Sugimoto, Fumio Umeda, Louise Lecavalier, Douglas J. Franks, David N. Orth, and Jean-louis Chiasson Platelets are involved in homeostasis of the vascular wall at various levels. An important feature of this involvement is the potential for platelet proliferation. Platelets from normal subjects contain platelet-derived growth factor (PDGF). epithelial growth factor (EGF). and transforming growth factor. We have detected the presence of an excessive growth-promoting activity in the heated supernatant fraction derived from the platelets of young, insulin-dependent diabetics. This activity is most pronounced when measured in cultures of smooth muscle cells and fibroblasts. This activity may be further separated into cationic and anionic fractions by ion exchange chromatography of the platelet-rich supernatant. The cationic factor corresponds to PDGF. whereas the anionic factor appears to be identical to EGF. Chronic. intensive insulin therapy normalizes the excessive growth-promoting activity of platelets from diabetics. Further studies are needed to evaluate the differential release of those growth-promoting factors found in platelets of normal subjects and in patients with vascular disease. e 1985 by Grun. & Stratton. Inc. P LATELETS HAVE BEEN implicated in the pathogenesis of macroangiopathy in diabetics and in the development of atherosclerosis in nondia- betics. Platelets interact with vascular walls in several ways and can affect vascular contractility, prostanoid metabolism, and cell proliferation. I Major interest in the involvement of platelets in the pathogenesis of vascular disease was aroused following the proposal of the hypothesis of Ross and Glomset. 2 They suggested a sequence of events leading to the development of vascular disease including endothelial damage, which allows platelets to adhere to the vascular endothelium and release their contents; increased permeability of the vascular endothelium to plasma factors; and the migration and proliferation of vascular smooth muscle cells. Platelets contain major proliferative factors, and vascular smooth muscle is one target tissue of these factors. 3 The most thoroughly documented growth factor of platelets is platelet-derived growth factor (PDG F)4 and other factors such as epithelial growth factor (EGF) and transforming growth factor (TGF) have also been described. 3 PDGF is a mixture of two highly basic glycoproteins 4 : PDGF-l (31,000 molecu- lar weight-mol wt) with a 7% carbohydrate content and PDGF-2 (28,000 mol wt) with a 4% carbohydrate content. Both are equally active growth promoters, and each is composed of an A-chain (15,000 to 17,000 mol wt) and a B-chain (14,000 mol wt). These chains are linked by disulfide bonds, and reduction of these disulfide linkages destroys the mitogenic activity of the protein. PDGF and other growth factors are contained in the alpha granules of platelets and are released during platelet aggregation. In the circulation, PDGF binds to a-macroglobulin,s which appears to serve as a buffer for the powerful mitogenic activity of PDGF, much in the same manner as it buffers the activity of other compounds (eg, tonin).6 MetIIboIism. Vol 34. No 12. Suppl1 (December). 1985: pp 25-31 In vivo, the half-life of radiolabeled PDGF is extremely short (about two minutes), and there is no detectable accumulation on circulating elements of the blood. PDGF is virtually absent in plasma, although measurable levels are detectable in whole blood and in serum in which platelets have released their contents (about 17 ng/mL).' PDGF binds to specific receptors on vascular smooth muscle cells and other cells, includ- ing fibroblasts.8-IO These receptors are linked to tyro- sine kinase, which autophosphorylates and phosphoryl- ates endogenous substrates, events potentially related with cell growth. II In fact, PDGF is not a complete growth factor since it only initiates the progression of target cells from G-O or G-I phase into S-phase by inducing specific genes,12 and other factors such as EGF are needed to complete the cell cycle.· Recently, some exciting research has shown that an analogous relationship exists between PDGF and the transforming proteins of oncogenes. Direct support for this similarity has been provided by the discovery of a high degree of homology between the amino acid composition of the A-chain of PDGF and the amino acid sequence of P28,v,'i', which is the putative trans- forming region (v-sis) of simian sarcoma virus (SSV).13.14 The gene that codes for PDGF is also partially identical to the c-sis gene. IS Rat kidney cells, transformed by SSV, secrete a mitogen that appears to be identical to PDGF. 16 In addition to' its growth- From the Clinical Research Institute of Montreal and tM Department of Medicine. Vanderbilt University. Nashville. Tenn. Supported in part by NIH Grant AM 21299 and a grant from the Medical Research Council of Canada. Address reprint requests to Pavel Hamet. MD. Clinical Research Institute of Montreal. 110 Pine Ave W. Montreal. Quebec. H2W IR7. Canada. c:> 1985 by Grune cI Stratton. Inc. 0026-0495/85/3412-1005$03.00/0 25