Overweight and obesity are major problems in today’s society, driving the prevalence of diabetes and its related complications. It is important to understand the molecular mechanisms underlying the chronic complications in diabetes in order to develop better therapeutic approaches for these conditions. Some of the most important complications include macrovascular abnormalities, e.g., heart disease and atherosclerosis, and microvascular abnormalities, e.g., retinopathy, nephropathy and neuropathy, in particular diabetic foot ulceration. The highly conserved endogenous small non-coding RNA molecules, the micro RNAs (miRNAs) have in recent years been found to be involved in a number of biological processes, including the pathogenesis of disease. Their main function is to regulate post-transcriptional gene expression by binding to their target messenger RNAs (mRNAs), leading to mRNA degradation, suppression of translation or even gene activation. These molecules are promising therapeutic targets and demonstrate great potential as diagnostic biomarkers for disease. This review aims to describe the most recent findings regarding the important roles of miRNAs in diabetes and its complications, with special attention given to the different phases of diabetic wound healing.

World Health Organization considered diabetes as one of the 21st century epidemics, estimating that over 10% of the world population is diabetic or at high risk. Self-assessment studies indicate that diabetic patients consider chronic wounds to affect their quality of life more dramatically than vision loss or renal failure. In addition to being the main reason for diabetic patients hospitalization, the economic burden of diabetic chronic wounds is close to 1% of UK and USA health systems budgets, which exceeds the funds allocated to the treatment of some types of cancer in both countries. Among the factors preceding the emergence of chronic diabetic wounds, also designated diabetic foot ulcers (DFU), hygiene and pressure in specific areas are under patient control, while others are still far from being understood. A triple impairment in the innervation, immune responses and vascularization associated to DFU have been extensively studied by the scientific community. However, the skin natural microbiota has only recently emerged as having a tremendous impact on DFU emergence and evolution to chronicity. Despite the great inter- and intra-variability of microbial colonizers, ongoing efforts are now focused on deciphering the impact of commensal and pathogenic microbiota on DFU etiology, as well as the mechanisms of interkingdom microbial-host communication. This review summarizes recent work in this context and offers new microbiological perspectives that may hold potential in the prevention and treatment of chronic diabetic wounds.

Treatment for chronic diabetic foot ulcers is limited by the inability to simultaneously address the excessive inflammation and impaired re-epithelization and remodeling. Impaired re-epithelization leads to significantly delayed wound closure and excessive inflammation causes tissue destruction, both enhancing wound pathogen colonization. Among many differentially expressed microRNAs, miR-155 is significantly upregulated and fibroblast growth factor 7 (FGF7) mRNA (target of miR-155) and protein are suppressed in diabetic skin, when compared to controls, leading us to hypothesize that topical miR-155 inhibition would improve diabetic wound healing by restoring FGF7 expression.In vitroinhibition of miR-155 increased human keratinocyte scratch closure and topical inhibition of miR-155in vivoin wounds increased murine FGF7 protein expression and significantly enhanced diabetic wound healing. Moreover, we show that miR-155 inhibition leads to a reduction in wound inflammation, in accordance with known pro-inflammatory actions of miR-155. Our results demonstrate, for the first time, that topical miR-155 inhibition increases diabetic wound fibroblast growth factor 7 expression in diabetic wounds, which, in turn, increases re-epithelization and, consequently, accelerates wound closure. Topical miR-155 inhibition targets both excessive inflammation and impaired re-epithelization and remodeling, being a potentially new and effective treatment for chronic diabetic foot ulcers.