Free Insulin Growth Factor-I and Vascular Endothelial Growth Factor in the Vitreous Fluid of Patients With Proliferative Diabetic Retinopathy RAFAEL SIMO ´ , MD, ALBERT LECUBE, MD, ROSA M. SEGURA, MD, JOSE ´ GARCI ´ A ARUMI ´ , MD, AND CRISTINA HERNA ´ NDEZ, MD ● PURPOSE: To investigate the relationship between insulin-like growth factor-I (IGF-I) and vascular endo- thelial growth factor (VEGF) in the vitreous fluid of diabetic patients with proliferative diabetic retinopathy (PDR). ● DESIGN: Observational case-control study. ● METHODS: In a prospective study, 37 consecutive diabetic patients with PDR (14 type I and 23 type II diabetes mellitus) in whom a vitrectomy was performed were compared with 21 nondiabetic patients with other conditions requiring vitrectomy (control group). Free IGF-I and VEGF were measured by ELISA. ● RESULTS: Vitreal levels of both free IGF-1 and VEGF were higher in diabetic patients with PDR than in control subjects (P < .01, and P < .0001, respectively). After adjusting for total intravitreous protein concentration, VEGF (ng/mg of proteins) remained significantly higher in diabetic patients with PDR than in the control group (P < .0001), whereas free IGF-I (ng/mg of proteins) was lower in diabetic patients than in control subjects (P < .0001). The vitreous concentrations of VEGF were higher in patients with active PDR than in patients with quiescent PDR (P < .005), whereas vitreous free IGF-I was not related to PDR activity. Finally, we did not observe a correlation between the vitreal levels of free IGF-I and VEGF. ● CONCLUSIONS: We conclude that free IGF-I and VEGF are both increased, but not related, within the vitreous fluid of diabetic patients with PDR. In addition, our results support the current concept that VEGF is directly involved in the pathogenesis of PDR, whereas the precise role of free IGF-I remains to be established. (Am J Ophthalmol 2002;134:376 –382. © 2002 by Elsevier Science Inc. All rights reserved.) R ETINAL NEOVASCULARIZATION, THE FINAL COMMON pathway in diabetic retinopathy (DR), remains the leading cause of legal blindness among working-age individuals. 1 There is a mounting body of evidence that suggests a major role for vascular endothelial growth factor (VEGF) in the etiopathogenesis of DR. 2–9 By contrast, although extensive claims have been made for the stimu- lating or accelerating role of insulin-like growth factor-I (IGF-I), the results of both clinical and experimental studies are controversial. 10 –17 Although some experimen- tal studies suggest that IGF-I regulates VEGF in several cell lines, 18 –22 there is little information about the relationship between IGF-I and VEGF in DR and no data are available for humans. Punglia and associates 23 demonstrated that elevated IGF-I increased VEGF expression in retinal pig- ment epithelial cells and that this effect was additive with hypoxia. Kaven and associates 24 showed a decrease in retinal epithelial cell proliferation when IGF-I and VEGF were used simultaneously as compared with when they were used separately. Smith and associates 25 have demon- strated, in transgenic mice expressing a growth hormone (GH) antagonist gene and in normal mice given an inhibitor of GH secretion (MK678), that retinal neovas- cularization was inhibited in inverse proportion to serum levels of GH and IGF-I. However, GH inhibition did not reduce the hypoxia-induced VEGF mRNA or its protein levels. Finally, the essential role of IGF-I in regulating not only retinal neovascularization, but also VEGF action, has Accepted for publication April 2, 2002. From the Division of Endocrinology, Diabetes Research Unit (R.S., A.L., R.M.S., C.H.) and Department of Ophthalmology (J.G.A.), Hos- pital General Universitari Vall d’Hebron, Barcelona, Spain. This work was supported by grants from the Ministerio de Sanidad y Consumo (FIS 98/1270), the Ministerio de Ciencia y Tecnologı ´a (PM 99 to 0136), the Associacio ´ Catalana de Diabetis (Ajut/la Recerca 1999) and Novo Nordisk S.A. (01/0066). Reprint requests to Rafael Simo ´ , MD, Diabetes Unit, Hospital General Universitari Vall d’Hebron, Pg. Vall d’Hebron 119-129, 08035 Barce- lona, Spain; fax: (+34) 932746238/34 or 932746058; e-mail: rsimo@hg. vhebron.es © 2002 BY ELSEVIER SCIENCE INC.ALL RIGHTS RESERVED. 376 0002-9394/02/$22.00 PII S0002-9394(02)01538-6