IGF-I mRNA and signaling in the diabetic retina

IGF-I promotes the survival of multiple cell types by activating the IGF-I receptor (IGF-IR), which signals downstream to a serine/threonine kinase te rmed Akt. Because in diabetes vascular and neural cells of the retina under go accelerated apoptosis, we examined IGF-I synthesis and signaling in the human and rat diabetic retina. In retinas obtained postmortem from six dono rs aged 64 +/- 8 years with a diabetes duration of 7 +/- 5 years, IGF-I mRN A levels were threefold lower than in the retinas of six age-matched nondia betic donors (P = 0.005). In the retinas of rats with 2 months' duration of streptozotocin-induced diabetes, IGF-I mRNA levels were similar to those o f control rats, but after 5 months of diabetes they failed to increase to t he levels recorded in age-matched controls (P < 0.02). Retinal IGF-I expres sion was not altered by hypophysectomy, proving to be growth-hormone indepe ndent. IGF-IR levels were modestly increased in the human diabetic retinas (P = 0.02 vs. nondiabetic retinas) and were unchanged in the diabetic rats. Phosphorylation of the IGF-IR could be measured only in the rat retina, an d was not decreased in the diabetic rats (94 +/- 18% of control values). In the same diabetic rats, phosphorylation of Akt was 123 +/- 21% of control values. There was not yet evidence of increased apoptosis of retinal microv ascular cells after 5 months of streptozotocin-induced diabetes. Hence, in the retina of diabetic rats, as in the retina of diabetic human donors, IGF -I mRNA levels are substantially lower than in age-matched nondiabetic cont rols, whereas IGF-IR activation and signaling are not affected, at least fo r some time. This finding suggests that in the diabetic retina, the activat ion of the IGF-IR is modulated by influences that compensate for, or are co mpensated by, decreased IGF-I synthesis.