MicroRNA-423 may regulate diabetic vasculopathy.

To test the hypothesis that microRNAs may play a role in diabetic retinopathy, we measured the levels of different markers [microRNAs, vascular endothelial growth factor (VEGF), nitric oxide (NO), and total antioxidant capacity (TAO)] in patients with type 2 diabetes mellitus (T2DM) and microvascular complications. Sixty-nine patients were recruited: 22 healthy subjects, ten T2DM patients without retinopathy, 22 with nonproliferative diabetic retinopathy, and 15 with proliferative diabetic retinopathy (PDR). Serum levels of NO, VEGF, TAO and 16 candidate microRNAs were measured. Additionally, the mRNA levels of endothelial nitric oxide synthase (eNOS), induced NOS (iNOS), C reactive protein (CRP), VEGF, tumor necrosis factor α (TNFα), PON2, p22, and SOD2 were measured in human vascular endothelial cells cultured in the presence of pooled sera from the subject groups. Plasma miR-423 levels showed a significant ~ twofold decrease in patients with PDR compared to controls. P lasma NO levels were significantly higher in retinopathy, VEGF levels were significantly lower, and TAO was significantly decreased. eNOS mRNA levels were lower in the cells of T2DM patients without retinopathy, but higher in PDR. PON2, p22, and SOD2 mRNA levels were all significantly lower in PDR. CRP, TNFα, iNOS, and VEGF mRNA levels showed no significant association with disease status. Lowered miR-423 levels in diabetic patients showed a correlation with VEGF and an inverse correlation between NO and eNOS expression. Our findings suggest a cross talk between miR-423 and VEGF signaling, affecting eNOS function. miR-423 may be involved in the regulation of diabetic vascular retinal proliferation.

Serum miR-122 levels correlate with diabetic retinopathy.

Diabetic retinopathy is the most severe ocular complication of diabetes and may lead to visual disability and blindness. Proliferative diabetic retinopathy (PDR) is characterized by ischemia-induced neovascularization with associated complications. An association was established between the presence of PDR, cardiovascular disease, and mortality among patients with type 1 diabetes mellitus and type 2 diabetes mellitus in epidemiological studies. However, the mechanism underlying increased cardiovascular risk in patients with PDR is still unknown. In recent years, a group of miRNAs has been linked to the pathology of diabetes mellitus. Besides, miRNAs in biofluids such as serum have been suggested as potential minimally invasive biomarkers of diabetes and vascular complications. This was a prospective study that recruited 40 human subjects: 10 healthy subjects, 10 with diabetes but without retinopathy (NDR), 10 with diabetic non-proliferative retinopathy (NPDR), and 10 with proliferative diabetic retinopathy (PDR). To examine whether serum miRNAs show altered levels at different stages of diabetic retinopathy, seven specific miRNA candidates (miR-126-3p, miR-130a-3p, miR-21-1, let-7f-5p, miR-122, miR-30c and miR-451a) were measured by qRT-PCR in RNA isolated from sera of all subjects. miR-122 levels increased in parallel with retinopathy severity: from healthy controls to NDR and from NDR to NPDR. However, when the disease progressed to PDR a marked decrease in miR-122 level was noted. This decrease was significant both compared to NPDR samples (p = 0.016) and to all non-PDR samples (p = 0.0002). Additionally, a positive trend was observed comparing miR-122 levels and the number of endothelial progenitor cells in the sera of all subjects. A significant increase in miR-122 was found in patients with diabetic retinopathy that may be related to its role in preventing angiogenesis and proliferation. The dramatic decline in patients with PDR may represent an inhibition or exhaustion of the anti-angiogenic anti-proliferative defense system. Further studies are needed to understand whether miRNA-122 has a role in the pathogenesis of diabetic retinopathy.

Levels of adhesion molecules in peripheral blood correlat with stages of diabetic retinopathy and may serve as bio markers for microvascular complications.

BACKGROUND: Proliferative diabetic retinopathy is a devastating complication of diabetes mellitus, developing within 15 years in 50% of patients with type 1 diabetes mellitus (DM) and in 10% of patients with type 2 DM. The correlation between levels of inflammatory markers in the peripheral blood and retinopathy staging has not been studied yet, and the purpose of this prospective study was to find a possible association between inflammation and staging of diabetic retinopathy. METHODS: A prospective (pilot) study that measured level of adhesion molecules in the peripheral blood of 10 healthy subjects and 30 patients with type 2 diabetes mellitus. Patients were grouped by the degree of retinopathy: 10 without retinopathy, 10 with non-proliferative retinopathy [NPDR] and 10 with proliferative retinopathy [PDR]. After signing the consent form, an ophthalmologic examination was performed, and 10 mL of blood was drawn. In order to assess adhesion molecules' level serum samples were collected, frozen, and stored at a temperature of -80 °C until analysis was performed as one batch. RESULTS: 10 healthy volunteers and 30 patients were enrolled. Healthy volunteers were younger (36.6 ±â€¯7.9 years) compared to patients (no retinopathy 64.5 ±â€¯10.8 years, NPDR 71.4 ±â€¯8.9 years, and PDR 63.3 ±â€¯11.6 years) (p = .0003 for all groups of patients in comparison with the healthy subjects). VCAM-1 levels were increased by retinopathy staging - starting from 81.86 ±â€¯3.80 ng/ml (healthy), 105.55 ±â€¯1.37 ng/ml (no retinopathy), 111.78 ±â€¯4.14 ng/ml (NPDR), and 123.45 ±â€¯3.99 ng/ml (PDR), with a significant difference between healthy and patients without retinopathy (p = .03), between no retinopathy and NPDR (p = .001), and between NPDR and PDR (p < .0001). E selectin was increased in correlation with severity of the retinopathy, with a significant difference between groups of patients (p = .03 between healthy subjects and T2DM patients without retinopathy, p = .001 between patients with T2DM no retinopathy and NPDR, p < .0001 between NPDR and PDR). CONCLUSIONS: We found a significant increase in levels of adhesion molecules (VCAM-1) and selectins (E-selectin) in parallel with increased severity of diabetic retinopathy, with a significant difference of inflammatory markers between stages of retinopathy.

[HAPTOGLOBIN POLYMORPHISM AS AN INDEPENDENT PREDICTOR OF DIABETIC NEPHROPATHY AND RETINOPATHY].

INTRODUCTION: The antioxidant protein haptoglobin (Hp) plays a major role in the development of diabetic complications such as diabetic nephropathy and retinopathy. In humans, two alleles of Hp were identified: 1 and 2 with three possible genotypes: 1-1, 2-1, and 2-2. The Hp protein products differ in their biochemical and biophysical properties, such as their antioxidant capacity. The Hp1 protein is superior to the Hp2 protein in binding to free hemoglobin and neutralizing its oxidative potential and the accompanying renal and retinal injury. Hence, diabetic patients with different Hp phenotypes have variable susceptibility to developing diabetic nephropathy and retinopathy. In diabetes, the kidney and the retinal injury progress gradually over time. Thus, understanding the factors that mediate the aggravation and progression of these complications is of critical importance. One of the latest hypotheses regarding the involvement of haptoglobin in the development of diabetic complications is its contribution to impaired vitamin D activation in the kidney. Over the last few years, great efforts were made in the field to explore this notion and decrypt the mechanism behind it. The goal in this area is that the research findings will be translated into clinical practice and lead to the development of a pharmacogenomics clinical approach that will deal with diabetic complications by selective administration of vitamin D according to the Hp genotype.