Endocrine Abstracts (2019) 65 EC1.2 | DOI: 10.1530/endoabs.65.EC1.2

From bench to bedside and beyond: a novel therapy to improve wound healing in type 2 diabetes

Ramzi Ajjan1, Elizabeth Hensor2, Afroze Abbas1, Francesco Del Galdo1, David Russell1, Kave Shams1, Paul Stewart2, Lorraine Webber3, Lindsey Pegg3, Adrian Freeman3, Janet Woods1, Sookhoe Eng1, Angela Taylor4, Wiebke Arlt5, Abd Tahrani5 & Ana Tiganescu2

1Leeds Teaching Hospitals Trust, Leeds, UK; 2University of Leeds, Leeds, UK; 3AstraZeneca, Cambridge, UK; 4University of Birmingham, Birmingham, UK; 5University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

The International Diabetes Federation estimates that type 2 diabetes mellitus (T2DM) will affect 642 million people by 2040. Chronically inflamed, hypoxic wounds are common in T2DM and represent a global unmet clinical need. Each year, diabetic foot ulcers cost the NHS £650 million and cause 1 in 200 UK deaths. This mortality is greater than colon, breast and prostate cancer combined. Glucocorticoids are used to treat a range of inflammatory conditions (e.g. asthma, eczema, polymyalgia rheumatica) although long-term therapy is precluded by their adverse side-effects including delayed wound repair and increased infection risk. Glucocorticoid excess drives impaired wound healing through the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which activates cortisol from cortisone in peripheral tissues including skin. In human skin fibroblasts, we found that 11β-HSD1 regulates over 600 genes in response to inflammation (e.g. suppression of angiogenesis which is essential for effective healing). In these cells, hypoxia (a hallmark of diabetic ulcers) induces 11β-HSD1, which prevents expression of pro-angiogenic vascular endothelial growth factor. In mice, we demonstrated that 11β-HSD1 activity increases during the inflammatory phase of wound healing and topical 11β-HSD1 inhibition improves wound healing during systemic glucocorticoid excess, in aged mice and models of diabetes (importantly, without exacerbation of normal inflammatory responses). Here, I present GC-SHEALD – the first randomized, double-blind, placebo-controlled trial to explore 11β-HSD1 inhibition as a novel therapy for wound healing in type 2 diabetes (https://doi.org/10.1186/ISRCTN74621291).