Diabetes Complications: The MicroRNA Perspective

There remains a critical need to better understand the underlying disease mechanisms responsible for diabetes complications in order to develop new and improved therapeutic strategies for these chronic conditions. These complications are broadly classified as microvascular, including neuropathy, nephropathy, and retinopathy, or macrovascular, including cardiovascular and peripheral vascular disease. The risk for developing complications is influenced by many factors including duration of diabetes and genetic factors. Current treatments have resulted in only a partial reduction in this risk, and the management of these conditions remains a major unmet need for those with diabetes. New insights have come from an unlikely ally, the worm C. elegans, in which research has identified a novel family of endogenous, small (;22 nucleotides), single stranded, noncoding RNA molecules known as microRNAs (miRNAs) as developmental regulators (1,2). These molecules, only identified in humans in the last decade, modulate physiological and pathological processes by the posttranscriptional inhibition of gene expression (3). Many excellent reviews have been written dealing with biogenesis (4) through to their role in development and disease (5), although this work has generally focused on cancer and infection rather than diabetes and its complications (6). The effect of miRNAs is via the incomplete binding of the “seed sequence” at the 59 end of the miRNA to the complementary target site in the 39 untranslated region (UTR) of the messenger RNA. Each miRNA species can inhibit the expression of many genes, while each mRNA can be potentially targeted by several miRNAs. Recent studies have demonstrated clear links between altered miRNA expression and certain diabetes complications, as described later in this article. These findings further highlight the complex nature of diabetes and the huge challenge in better understanding the various vascular complications associated with this disorder. Here we discuss some recent studies demonstrating the role of miRNAs in diabetes complications and at sites where complications occur, with the anticipation that these studies are likely to influence the treatment, diagnosis, and management of complications. We also explore the huge clinical challenge before us in attempting the targeted modulation of these rather promiscuous molecules in specific tissues in order to achieve better therapeutic outcomes.