FORUM REVIEW ARTICLE MicroRNA and Diabetic Complications: A Clinical Perspective Baoqi Fan, 1 Andrea On Yan Luk, 1,2 Juliana Chung Ngor Chan, 1–4 and Ronald Ching Wan Ma 1–4 Abstract Significance: The rising global prevalence of diabetes and its debilitating complications give rise to significant disability and premature mortality. Due to the silent nature of diabetes and its vascular complications, and limitations in current methods for detection, there is a need for novel biomarkers for early detection and prognosis. Recent Advances: Metabolic memory and epigenetic factors are important in the pathogenesis of diabetic complications and interact with genetic variants, metabolic factors, and clinical risk factors. Micro(mi)RNAs interact with epigenetic mechanisms and pleiotropically mediate the effects of hyperglycemia on the vascu- lature. Utilizing mature profiling techniques and platforms, an increasing number of miRNA signatures and interaction networks have been identified for diabetes and its related cardiorenal complications. As a result, these short, single-stranded molecules are emerging as potential diagnostic and predictive tools in human studies, and may function as disease biomarkers, as well as treatment targets. Critical Issues: However, there is complex interaction between the genome and epigenome. The regulation of miRNAs may differ across species and tissues. Most profiling studies to date lack validation, often requiring large, well-characterized cohorts and reliable normalization strategies. Furthermore, the incremental benefits of miRNAs as biomarkers, beyond prediction provided by traditional risk factors, are critical issues to consider, yet often neglected in published studies. Future Directions: All in all, the future for miRNA-based diagnostics and therapeutics for diabetic com- plications appears promising. Improved understanding of the complex mechanisms underlying miRNA dys- regulation, and more well-designed studies utilizing prospective samples would facilitate the translation to clinical use. Antioxid. Redox Signal. 29, 1041–1063. Keywords: microRNA, diabetes, diabetic complications, epigenetics, gene regulation, oxidative stress, biomarkers Introduction on Diabetic Complications D iabetes mellitus (DM) is characterized by chronic hyperglycemia due to impaired production and function of insulin. According to the International Diabetes Founda- tion, the number of people with diabetes will increase from 415 million in 2015 to 642 million by 2040 (67a). Half of this population will come from Asia, where rapid changes in the ecosystem with consumption of energy-dense diet, physical inactivity, psychosocial stress, and pollutants all contribute toward an obesogenic environment, unmasking diabetes in people with genetic predisposition (67a, 107). People with DM are at high risk of developing widespread vasculopathy. Microvascular complications include diabetic kidney disease (DKD), retinopathy, and neuropathy, whereas macrovascular diseases consist of coronary artery disease 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, China. 2 Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Shatin, China. 3 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, China. 4 The Chinese University of Hong Kong—Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Shatin, China. ANTIOXIDANTS & REDOX SIGNALING Volume 29, Number 11, 2018 ª Mary Ann Liebert, Inc. DOI: 10.1089/ars.2017.7318 1041 Downloaded by 168.151.28.11 from www.liebertpub.com at 11/02/18. For personal use only.