Retinopatia diabética: influência do perfil de metilação do microRNA-9-3, nível de atividade física, consumo alimentar e de parâmetros bioquímicos

Abstract

Diabetes mellitus type 2 (DM2) is a metabolic disorder that causes persistent hyperglycemia due to insufficient insulin production or failure in its action. This hyperglycemia is associated with chronic complications, including microvascular and macrovascular issues, with diabetic retinopathy (DR) being a common microvascular complication that represents a significant risk of blindness. There is growing interest in identifying markers to detect patients with diabetes at higher risk of developing DR early on. Epigenetics, especially DNA methylation, has been explored in studying chronic complications of DM2. The expression of miR-9 can be regulated by DNA methylation, and previous studies have indicated an association between the methylated profile of the miR-9 promoter and DR. However, these studies did not examine the relationship between methylation and clinical stages of retinopathy or modifiable factors such as physical activity, diet, and oxidative stress. The aim of this study was to analyze the methylation profile of miR-9-3 in patients with DM2, both with and without DR, and to compare the stages of the complication with physical, dietary, and biochemical parameters. A cross-sectional study was conducted with 170 participants divided into a control group (DM2, n = 64) and a DR group (n = 106), which was further subdivided into non-proliferative diabetic retinopathy (NPDR, n = 58) and proliferative diabetic retinopathy (PDR, n = 48). Epidemiological, clinical, anthropometric, physical activity level (PAL), dietary intake, and biochemical parameters were analyzed. DNA extracted from leukocytes was used to analyze the methylation of miR-9-3 using MSP-PCR. The results showed that the hypermethylated profile of miR-9-3 was significantly more frequent in the DR group (p = 0.001) and in the PDR subgroup compared to the control group (p = 0.001). Logistic regression revealed that the hypermethylation of miR-9-3 increased the chances of developing DR (OR: 2.826; p = 0.002) and PDR (OR: 5.472; p = 0.001). Additionally, hypermethylation in the DR and NPDR groups was associated with elevated serum levels of VEGF-A (p = 0.012 and p = 0.025, respectively). Insufficient PAL was a significant risk factor for the methylation of miR-9-3 (OR = 2.592; p = 0.006), while a higher total antioxidant capacity (TAC) was identified as a protective variable (OR = 0.409; p = 0.018). Carbohydrate intake (kcal) was an independent risk factor for the methylation of miR-9-3 (OR = 5.243; p = 0.000). These data indicate that the hypermethylation of miR-9-3 is associated with the development and progression of DR, particularly in the proliferative form, possibly due to its link with elevated levels of VEGF-A and pathological angiogenesis. Moreover, insufficient PAL is a risk factor for hypermethylation, while higher TAC serves as a protective factor, suggesting that interventions in physical activity and antioxidant status may be effective in prevention. Finally, the association between carbohydrate intake and methylation of miR-9-3 suggests that diet may impact microvascular complications, highlighting the importance of dietary interventions in the management of DR.