Noncoding RNAs regulating the insulin signaling pathway: a new therapeutic approach in diabetic retinopathy

Diabetic retinopathy (DR), one of the microvascular diseases of diabetes mellitus, remains one of the leading causes of blindness worldwide. Preclinical and limited human tissue studies indicate that dysregulation of insulin signaling is central to the pathophysiology of DR, at least at the retinal vascular level. Multiple independent preclinical studies have implicated noncoding RNAs (ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs)) as potent modulators of insulin signaling within retinal cells. The modulatory ncRNAs act by targeting essential components of the insulin cascade, like Insulin Receptor Substrate 1 (IRS1), Phosphoinositide 3-Kinase/Akt (Protein Kinase B) pathway (PI3K/Akt), Glucose Transporter Type 4 (GLUT4), Phosphatase and Tensin Homolog (PTEN), and Insulin-Like Growth Factor-1 Receptor (IGF-1R), to modulate glucose metabolism, oxidative stress response, angiogenesis, and apoptosis under hyperglycemic conditions. This review collates current data on the polyvalent functionality of ncRNAs in modulating insulin signaling and potentially acting as biomarkers and therapeutic targets for DR. The review also delves into how specific ncRNAs can directly and indirectly reduce disease progression by targeting the insulin cascade, versus those that can repress such progression. Since the treatment of DR has a limited scope and efficacy, targeting this ncRNA-insulin signaling axis may offer an intriguing new opportunity to discover novel therapeutics.