Diabetes Rapidly Impairs Global Rates of Protein Synthesis in the Retina: A Potential Mechanism for Cellular Dysfunction

Abstract

Purpose:: To investigate the regulation of protein synthesis in the retina of two rodent models of type 1 diabetes. The retina has a high metabolic rate and requires continual protein synthesis to maintain cellular integrity and visual processes. Diabetes impairs protein metabolism in many tissues but changes in the retina have not been examined previously.

Methods:: Global rates of protein synthesis were compared in retinas, gastrocnemius muscles and livers of streptozotocin-diabetic rats and Ins2Akita mice and age-matched controls. The flooding dose technique was used to measure incorporation of H3-phenylalanine into protein following intra-femoral or intra-peritoneal administration. Transcriptional profiles were assessed using whole genome Codelink microarrays (GE Healthcare). Expression and localization of the 18S and 28S ribosomal RNAs were also studied using real-time RT-PCR and fluorescence in situ hybridization (FISH) in control and diabetic rats.

Results:: The global rate of retinal protein synthesis (Ks) was progressively reduced (70 to 50% of control values) after 8 and 12 weeks of diabetes in the diabetic rats, and after 4 weeks of diabetes in the Ins2Akita mice. Systemic insulin therapy restored the Ks to control values. Additionally, microarray analysis of retinal RNA expression demonstrated decreases in protein synthesis transcripts (e.g. ribosomal proteins, translation initiation factors) in the Ins2Akita mice whereas they were generally increased in the rats. The expression and localization of the 18S and 28S RNAs were unchanged in 8 week diabetic rat retinas.

Conclusions:: This study shows for the first time that diabetes disrupts an insulin sensitive anabolic process in the retina. Reduced protein synthesis may impair retinal function by disturbing processes that require high protein turnover, such as photoreceptor regeneration, synaptic plasticity or neurotransmission. Characterization of the mechanisms responsible may lead to new potential therapeutic targets for diabetic retinopathy.

Keywords: diabetic retinopathy • ribosomal RNA • metabolism