Des(1-3)IGF-1 treatment normalizes type 1 IGF receptor and phospho-Akt (Thr 308) immunoreactivity in predegenerative retina of diabetic rats.

A Kummer,B E Pulford,G M Seigel,D N Ishii

doi:10.1080/15438600303729

Abstract

Little is known about interventions that may prevent predegenerative changes in the diabetic retina. This study tested the hypothesis that immediate, systemic treatment with an insulin-like growth factor (IGF)-1 analog can prevent abnormal accumulations of type 1 IGF receptor, and phospho-Akt (Thr 308) immunoreactivity in predegenerative retinas of streptozotocin (STZ) diabetic rats. Type 1 IGF receptor immunoreactivity increased approximately 3-fold in both inner nuclear layer (INL) and ganglion cell layer (GCL) in retinas from STZ rats versus nondiabetic controls. Phospho-Akt (Thr 308) immunoreactivity increased 5-fold in GCL and 8-fold in INL of STZ rat retinas. In all cases, immunoreactive cells were significantly reduced in STZ des(1–3)IGF-1–treated versus STZ rats. Preliminary results suggested that vascular endothelial growth factor (VEGF) levels may also be reduced. Hyperglycemia/ failure of weight gain in diabetic rats continued despite systemic des(1–3)IGF-1. These data show that an IGF-1 analog can prevent early retinal biochemical abnormalities implicated in the progression of diabetic retinopathy, despite ongoing hyperglycemia.

Highlights

The pathogenesis of diabetic retinopathy is a complex process involving ischemic/hyperglycemic and growth factor retinal insults that can result in neovascularization and vision loss
Type 1 insulin-like growth factor (IGF) receptor and phospho-Akt (Thr 308) immunoreactivity were increased in the ganglion cell layer (GCL) and inner nuclear layer (INL) of the rat retina 2 weeks after induction of diabetes with STZ
These changes, seen at 2 weeks, are among the earliest biochemical abnormalities that have been detected in the eye in diabetes, which coincide with vascular endothelial growth factor (VEGF) up-regulation and blood-retinal barrier (BRB) breakdown [3, 4]

Summary

Introduction

The pathogenesis of diabetic retinopathy is a complex process involving ischemic/hyperglycemic and growth factor retinal insults that can result in neovascularization and vision loss. Administration of low replacement doses of IGF-1 (20 to 40 μg/kg/day) for 24 weeks did not cause progression of retinopathy in a phase II trial of 53 type 1 diabetic patients [20] These data show that IGF-1 administration is relatively safe, and early IGF-1 treatment might prevent diabetic complications in the eyes as well as nerves. Des(1–3)IGF-1 is an IGF-1 analogue lacking the N-terminal tripeptide, which has greatly reduced affinity for IGFBPs. Additional studies are needed to determine the early biochemical pathology in the diabetic eye. The purpose of this study was to test the hypotheses that administration of des(1–3)IGF-1 at the time of onset of diabetes can (i) normalize the type 1 IGF receptor levels in retina, (ii) inhibit the phospho-Akt (Thr 308) retinal stress response, and (iii) prevent these predegenerative biochemical abnormalities independently of poor glycemic control. By using des(1–3)IGF-1, this study tests the hypothesis that IGF-1 sequestration to IGFBP is not essential for preventing at least certain diabetic complications

Objectives

Results

Conclusion