Diabetes Modulates Iodothyronine Deiodinase 2 Expression in the Mouse Retina: A Role for Thyroid Hormone in the Pathogenesis of Diabetic Retinopathy

Abstract

Purpose Clinical investigations associate hypothyroidism with an increased risk for microvascular complications, yet the mechanism by which thyroid hormone regulates the development of diabetic retinopathy is not clearly understood. We investigated the role of iodothyronine deiodinase 2 (DIO2) in the pathogenesis of diabetic retinopathy. Methods Retinas from streptozotocin-induced diabetic and nondiabetic mice were evaluated by RNA sequencing, RT-PCR, and immunostaining. Media and cell lysates from mouse retinal microvascular endothelial cells and retinal astrocytes exposed to physiologic (5 mM) and high glucose (25 mM) containing media were assessed by liquid chromatography-tandem mass spectrometry to measure tetraiodothyronine (T4) and tri-iodothyronine (T3) concentrations and by Western blot analysis to determine the relationship of T4/T3 to oxidative stress and inflammatory mediators. Cell death was determined by Trypan Blue exclusion assay. Results At 12 weeks of diabetes duration, retinas from diabetic mice compared with nondiabetic mice demonstrated a significant decrease in Dio2 transcripts and Dio2 gene and protein ( P < 0.05) expression. When cultured in the presence of high glucose, both mouse retinal astrocytes and microvascular endothelial cells demonstrated a significant reduction of DIO2 protein compared with cells cultured in physiologic glucose. High glucose inhibited generation of T3, leading to a significantly increased T4/T3 ( P < 0.0079). Supplementation of cells with T3, but not T4, prevented the high glucose-induced rise in endothelial nitric oxide synthase, intercellular cell adhesion molecule 1, and endothelial cell death ( P < 0.0079). Conclusions Decreased intraretinal T3 owing to diabetes-induced loss of DIO2 may lead to dysfunction and death of cells in the retina, thereby contributing to the pathogenesis of early diabetic retinopathy.

Correlation Between Thyroid-Related Hormones and Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients with Normal Thyroid Function: A Retrospective Study

“…The decrease of T3 level can induce retinal cell dysfunction and death by aggravating the oxidative stress and inflammation in the eyes, thus promoting the onset of early diabetic retinopathy. 22 In addition, low T3 level may have a protective effect on retinal stress in the early stage of diabetic retinopathy. 23 Thus, timely correction of TSH and FT3 levels in T2DM patients may be helpful to prevent the occurrence or progress of DR.…”

“…This reduced the conversion from thyroxine (T4) to triiodothyronine (T3), thereby resulting in reduced FT3 production. 22 Due to the insufficient synthesis and secretion of THs, the human body secretes a large amount of TSH to maintain the normal function of the thyroid gland, thus resulting in a significant increase in serum TSH levels. It was reported that the increase of TSH significantly increased the expression of interleukin-6 and anti-tumor necrosis factor-α in adipocytes, enhanced lipolysis and insulin resistance, and thus promoted the increase of TG level.…”

“…19 Notably, THs are essential for retinal retinopathy. 22 In addition, low T3 level may have a protective effect on retinal stress in the early stage of diabetic retinopathy. 23 Thus, timely correction of TSH and FT3 levels in T2DM patients may be helpful to prevent the occurrence or progress of DR. FBG only represents the blood glucose level at the time of blood drawing.…”