Insulin-Deficient Diabetes Reduces Insulin-Like Growth Factor 2 Levels: Implications for Diabetic Retinopathy
Abstract Number: 1005-P
Authors: THOMAS W. GARDNER, HISANORI IMAI, MANDY LOSIEWICZ, REEMA GOEL, PATRICE E. FORT
Institutions: Hershey, PA, Kobe, Japan
Results: Insulin-like growth factor 2 (IGF2) is a potent neurotrophin in the central nervous system during development, but its role in diabetic retinopathy has not been examined. The expression pattern of IGF2 isoforms was assessed in serum of patients with Type 1 diabetes and in tissues and serum of rats with streptozotocin-induced diabetes by western blot. The effects of IGF2 isoforms on insulin receptor (IR) and IGF1 receptor (IGF1R) autophosphorylation were determined in ex vivo retinas incubated with or without mature-, big-, or pro-IGF2 (1-100nM). The cell survival promoting effects of IGF2 isoforms were tested in differentiated R28 retinal neurons subjected to serum deprivation using caspase-3 activity assay and DNA fragmentation ELISA. These studies show that persons with Type 1 diabetes and diabetic rats exhibited significant reductions in all IGF2 isoforms in serum. In rat retinas mature IGF2 was not detected, but big- and pro-IGF2 levels were reduced after 12 weeks of diabetes. IGF2 treatment significantly increased IR and IGF1R autophosphorylation in ex vivo retinas and phosphorylation of GSK3beta, P70 6K, mTOR, MAPK and Akt in a dose dependent manner. IGF2 significantly decreased caspase-3 activity and DNA fragmentation induced by serum deprivation in vitro. Mature, big- and pro-IGF2 phosphorylated all pro-survival kinases (p<0.01) and decreased caspase-3 and DNA fragmentation. Intravitreal IGF2 administration in diabetic rats restored retinal Akt1 kinase activity and reduced cell death. Together, these data suggest that insulin-deficient diabetes impairs systemic and retinal IGF2 production and signaling, and may contribute to early stages of diabetic retinopathy. Ocular IGF2 treatment may diminish retinal damage from diabetes.