The Link Between Glycemic Control Measures and Eye Microvascular Complications in a Clinical Cohort of Type 2 Diabetes with MicroRNA-223 Signature

Abstract

Abstract Background: Type 2 diabetes (T2D) is a critical healthcare challenge and priority in Qatar which is listed amongst the top 10 countries in the world, with its prevalence presently at 17% double the global average. MicroRNAs (miRNAs) are implicated in the pathogenesis of (T2D) and long-term microvascular complications including diabetic retinopathy (DR). Methods: In this study, a T2D cohort that accurately matches the characteristics of the general population was employed to find microRNA (miRNA) signatures that are correlated with glycemic and β cell function measurements. Targeted miRNA profiling was performed in (471) T2D individuals with or without DR and (491) (non-diabetic) healthy controls from the Qatar Biobank. Discovery analysis identified 20 differentially expressed miRNAs in T2D compared to controls, of which miR-223 was significantly upregulated (fold change:5.16, p=3.6e-02) and positively correlated with glucose and hemoglobin A1c (HbA1c) levels (p-value = 9.88e-04 and 1.64e-05, respectively), but did not show any significant associations with insulin or C-peptide. Accordingly, we performed functional validation using a miR-223 mimic (overexpression) under control and hyperglycemia-induced conditions in a zebrafish model. Results: Over-expression of miR-223 alone was associated with significantly higher glucose (42.7mg/dL, n=75 vs 38.7mg/dL, n=75, p=0.02) and degenerated retinal vasculature, and altered retinal morphology involving changes in the ganglion cell layer and inner and outer nuclear layers. Assessment of retinal angiogenesis revealed significant upregulation in the expression of vascular endothelial growth factor and its receptors, including kinase insert domain receptor. Further, the pancreatic markers, pancreatic and duodenal homeobox 1, and the insulin gene expressions were upregulated in the miR-223 group. Conclusion: Our zebrafish model validates a novel correlation between miR-223 and DR development. Targeting miR-223 in T2D patients may serve as a promising therapeutic strategy to control DR in at-risk individuals.