Diabetes mellitus (DM) is a complex, multisystem metabolic disorder that is widely recognized as a major health threat of this century (Shaw et al. 2010). The worldwide prevalence is estimated at almost 400 million (International Diabetes Federation 2013). Diabetes is characterized by chronic hyperglycaemia secondary to impaired insulin secretion and/or a decreased responsiveness of target tissues to insulin. The main forms of DM are type 1 DM (T1DM) and type 2 DM (T2DM). DM may also be triggered by pregnancy (gestational DM), the use of drugs and infections (American Diabetes Association 2005). T1DM results from autoimmune pancreatic p-cell destruction, with a consequent failure to produce insulin (Ilonen and Akerblom 1999). T2DM is characterized by peripheral insulin resistance accompanied by insufficient compensatory insulin secretion (Kahn 2001). Although T2DM is far more prevalent (accounting for at least 90% of diabetes), both types can result in complications (Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 2003). Many of these complications are vascular in origin and can be microvascular (e.g. nephropathy, retinopathy) or macrovascular (e.g. ischaemic heart disease, peripheral vascular disease) (Winer and Sowers 2004; Brownlee 2001). Cardiovascular disease (CVD) is the major cause of death in diabetes, and the risk of CVD is doubled with diabetes (Emerging Risk Factors Coalition et al. 2010).
The pathophysiology of the vascular complications of diabetes is complex and, to date, not completely understood. Hyperglycaemia-induced vascular damage is the principal overarching mechanism, although coexisting processes are essential. Interestingly, recent studies suggest that microRNAs (miRNAs, miRs) play important roles in this context. As introduced elsewhere in this book, microRNAs are small (~22 nucleotides) noncoding RNA molecules that are synthesized endogenously. They can modulate both physiological and pathological pathways by post-transcriptionally inhibiting the expression of several target genes (van Rooij 2011). MicroRNAs are highly expressed in the vasculature, and their involvement in angiogenesis and endothelial function is well described (Caporali and Emanueli 2011; Condorelli et al. 2014). Of particular relevance to this chapter, some miRNAs have been associated with the development and/or progression of diabetic vascular complications, although a complete understanding of their actions is still lacking (Shantikumar et al. 2012). It could be hypothesized that miRNAs act as mediators of the damaging effects of hyperglycaemia and/or that they are expressionally dys- regulated as a consequence of them. It is noteworthy that other biological factors are at play in diabetes, including alterations in lipid profiles, oxidative stress and an increase in pro-inflammatory cytokines (Tabak et al. 2011), and these factors are likely to be associated with microRNAs.
In this chapter, we review recent findings regarding the role of miRNAs in the pathophysiology of diabetes, but we highlight their actions specifically in microvascular and macrovascular complications. We describe known mechanisms of action of miRNAs in the diabetic milieu on diverse cell types such as pancreatic, adipose, endothelial and cardiac cells. Finally, the potential therapeutic and prognostic value of miRNAs in diabetes and its vascular complications will be discussed.