Α-Melanocyte-Stimulating Hormone Protects Early Diabetic Retina from Blood-Retinal Barrier Breakdown and Vascular Leakage via MC4R.

BACKGROUND/AIMS: Blood-retinal barrier (BRB) breakdown and vascular leakage is the leading cause of blindness of diabetic retinopathy (DR). Hyperglycemia-induced oxidative stress and inflammation are primary pathogenic factors of this severe DR complication. An effective interventional modality against the pathogenic factors during early DR is needed to curb BRB breakdown and vascular leakage. This study sought to examine the protective effects of α-Melanocyte-stimulating hormone (α-MSH) on early diabetic retina against vascular hyperpermeability, electrophysiological dysfunction, and morphological deterioration in a rat model of diabetes and probe the mechanisms underlying the α-MSH's anti-hyperpermeability in both rodent retinas and simian retinal vascular endothelial cells (RF6A). METHODS: Sprague Dawley rats were injected through tail vein with streptozotocin to induce diabetes. The rats were intravitreally injected with α-MSH or saline at Week 1 and 3 after hyperglycemia. In another 2 weeks, Evans blue assay, transmission electron microscopy, electroretinogram (ERG), and hematoxylin and eosin (H&E) staining were performed to examine the protective effects of α-MSH in diabetic retinas. The expression of pro-inflammatory factors and tight junction at mRNA and protein levels in retinas was analyzed. Finally, the α-MSH's anti-hyperpermeability was confirmed in a high glucose (HG)-treated RF6A cell monolayer transwell culture by transendothelial electrical resistance (TEER) measurement and a fluorescein isothiocyanate-Dextran assay. Universal or specific melanocortin receptor (MCR) blockers were also employed to elucidate the MCR subtype mediating α-MSH's protection. RESULTS: Evans blue assay showed that BRB breakdown and vascular leakage was detected, and rescued by α-MSH both qualitatively and quantitatively in early diabetic retinas; electron microscopy revealed substantially improved retinal and choroidal vessel ultrastructures in α-MSH-treated diabetic retinas; scotopic ERG suggested partial rescue of functional defects by α-MSH in diabetic retinas; and H&E staining revealed significantly increased thickness of all layers in α-MSH-treated diabetic retinas. Mechanistically, α-MSH corrected aberrant transcript and protein expression of pro-inflammatory factor and tight junction genes in the diseased retinas; moreover, it prevented abnormal changes in TEER and permeability in HG-stimulated RF6A cells, and this anti-hyperpermeability was abolished by a universal MCR blocker or an antagonist specific to MC4R. CONCLUSIONS: This study showed previously undescribed protective effects of α-MSH on inhibiting BRB breakdown and vascular leakage, improving electrophysiological functions and morphology in early diabetic retinas, which may be due to its down-regulating pro-inflammatory factors and augmenting tight junctions. α-MSH acts predominantly on MC4R to antagonize hyperpermeability in retinal microvessel endothelial cells.

The Effects of Diabetic Duration on Lacrimal Functional Unit in Patients with Type II Diabetes.

PURPOSE: To observe ocular surface changes in Type II diabetic patients with different disease durations and to understand the correlations between clinical parameters and diabetic durations. METHODS: In this cross-sectional, prospective study, 51 healthy controls and 91 patients with Type II diabetes were enrolled. The diabetics were divided into 3 subgroups according to the disease duration, including duration <10 y group, 10 to 20 y group, and ≥21 y group. All subjects underwent clinical ocular examinations, including lipid layer thickness (LLT), blinking rate, tear meniscus height (TMH), noninvasive tear film break-up time (NI-BUT), meibography, superficial punctate keratopathy (SPK) scoring, corneal sensitivity, and Schirmer I test. They were also evaluated using the standard patient evaluation of eye dryness (SPEED) questionnaire. RESULTS: SPEED score, meiboscore, SPK score, LLT, Schirmer I test, and corneal sensitivity differed significantly between the diabetic and healthy control groups. Further, SPEED score, Schirmer I test, corneal sensitivity, meiboscore, and blink rate significantly differed among the 3 diabetic subgroups and the control group. In diabetics, the SPEED score correlated with the SPK score, blink rate, TMH, and LLT; NI-BUT with TMH, LLT, and blink rate; TMH with the SPK score; Schirmer I test with the SPK score; and corneal sensitivity with the meiboscore. More importantly, the Schirmer I test, corneal sensitivity, and SPEED score negatively correlated with diabetic duration. CONCLUSION: Diabetic duration is an important factor that affects functions of the lacrimal functional unit in patients with Type II diabetes. The trends of changes in the ocular parameters vary along the course of diabetes.