Diabetes reduces basal retinal insulin receptor signaling: reversal with systemic and local insulin.
Diabetic retinopathy is characterized by early onset of neuronal cell death. We previously showed that insulin mediates a prosurvival pathway in retinal neurons and that normal retina expresses a highly active basal insulin receptor/Akt signaling pathway that is stable throughout feeding and fasting. Using the streptozotocin-induced diabetic rat model, we tested the hypothesis that diabetes diminishes basal retinal insulin receptor signaling concomitantly with increased diabetes-induced retinal apoptosis. The expression, phosphorylation status, and/or kinase activity of the insulin receptor and downstream signaling proteins were investigated in retinas of age-matched control, diabetic, and insulin-treated diabetic rats. Four weeks of diabetes reduced basal insulin receptor kinase, insulin receptor substrate (IRS)-1/2-associated phosphatidylinositol 3-kinase, and Akt kinase activity without altering insulin receptor or IRS-1/2 expression or tyrosine phosphorylation. After 12 weeks of diabetes, constitutive insulin receptor autophosphorylation and IRS-2 expression were reduced, without changes in p42/p44 mitogen-activated protein kinase or IRS-1. Sustained systemic insulin treatment of diabetic rats prevented loss of insulin receptor and Akt kinase activity, and acute intravitreal insulin administration restored insulin receptor kinase activity. Insulin treatment restored insulin receptor-beta autophosphorylation in rat retinas maintained ex vivo, demonstrating functional receptors and suggesting loss of ligand as a cause for reduced retinal insulin receptor/Akt pathway activity. These results demonstrate that diabetes progressively impairs the constitutive retinal insulin receptor signaling pathway through Akt and suggests that loss of this survival pathway may contribute to the initial stages of diabetic retinopathy.
Dept. of Cellular and Molecular Physiology, Juvenile Diabetes Research Foundation Diabetic Retinopathy Center, Penn State College of Medicine, Hershey, PA 17033, USA
Chad E N
CE
Reiter
Xiaohua
X
Wu
Lakshman
L
Sandirasegarane
Makoto
M
Nakamura
Kirk A
KA
Gilbert
Ravi S J
RS
Singh
Patrice E
PE
Fort
David A
DA
Antonetti
Thomas W
TW
Gardner
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000503:physiopathology*; D007328:Insulin / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000187:drug effects / Q000502:physiology*; D012160:Retina / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D007328:Insulin; D011972:Receptor, Insulin