title: IGF-I mRNA and signaling in the diabetic retina.
abstract: 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 termed Akt. Because in diabetes vascular and neural cells of the retina undergo accelerated apoptosis, we examined IGF-I synthesis and signaling in the human and rat diabetic retina. In retinas obtained postmortem from six donors aged 64 +/- 8 years with a diabetes duration of 7 +/- 5 years, IGF-I mRNA levels were threefold lower than in the retinas of six age-matched nondiabetic 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 of control rats, but after 5 months of diabetes they failed to increase to the levels recorded in age-matched controls (P < 0.02). Retinal IGF-I expression was not altered by hypophysectomy, proving to be growth-hormone independent. 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, and 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 microvascular 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 controls, whereas IGF-IR activation and signaling are not affected, at least for some time. This finding suggests that in the diabetic retina, the activation of the IGF-IR is modulated by influences that compensate for, or are compensated by, decreased IGF-I synthesis.
authors.affiliation: Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: C
authors.initials: C
authors.lastname: Gerhardinger
authors.forename: K D
authors.initials: KD
authors.lastname: McClure
authors.forename: G
authors.initials: G
authors.lastname: Romeo
authors.forename: F
authors.initials: F
authors.lastname: Podestà
authors.forename: M
authors.initials: M
authors.lastname: Lorenzi
mesh_terms: D000368:Aged; D000375:Aging / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002102:Cadaver; D002196:Capillaries / Q000473:pathology / Q000503:physiopathology; D003920:Diabetes Mellitus / Q000378:metabolism / Q000503:physiopathology*; D013006:Growth Hormone / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017451:Receptors, Somatomedin / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000503:physiopathology*; D012171:Retinal Vessels / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt