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Regulation of IGF-I Signaling in Retinal Endothelial Cells by Hyperglycemia

From the Division of Endocrinology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

PURPOSE. To investigate the role of hyperglycemia in regulating the proliferative response of retinal endothelial cells (RECs) to insulin-like growth factor (IGF)-I.

METHODS. The regulation of IGF-I signaling by glucose concentration was assessed by biochemical analysis of primary RECs grown in media containing normal (5 mM) and high (25 mM) glucose. Cell counting was used to asses the proliferative response to IGF-I.

RESULTS. Glucose (25 mM) enhanced the proliferative response of RECs to IGF-I. Phosphorylation of the adaptor protein Shc (Src homology 2 domain containing) transforming protein 1) was increased in RECs grown in high glucose. For Shc to be phosphorylated, it must be recruited to the cytoplasmic domain of the transmembrane protein SHPS-1 (SHP substrate-1). Shc recruitment to SHPS-1 was increased when RECs were grown in high glucose. The difference in Shc recruitment to SHPS-1 was attributable to a difference in SHPS-1 phosphorylation that is required for Shc recruitment. This, in turn, was attributable to an increase in SHPS-1 association with integrin-associated protein (IAP), which is necessary for SHPS-1 phosphorylation. The difference in response under the two different glucose conditions appeared to be attributable to changes in the activation of the integrin Vß3, since blocking Vß3 in high glucose inhibited the response to IGF-I, whereas addition of the active region of vitronectin to RECs grown in normal glucose enhanced their response.

CONCLUSIONS. This study demonstrates that hyperglycemic conditions enhance the response of RECs to IGF-I by increasing the association of IAP with SHPS-1 permitting the formation of the SHPS-1–Shc signaling complex, which is required for the proliferative response to IGF-I.