SFEBES2019 EARLY CAREERS AND PLENARY ORALS Early Career Prize Lecture Translational (1 abstracts)
From bench to bedside and beyond: a novel therapy to improve wound healing in type 2 diabetes
Ramzi Ajjan 1 , Elizabeth Hensor 2 , Afroze Abbas 1 , Francesco Del Galdo 1 , David Russell 1 , Kave Shams 1 , Paul Stewart 2 , Lorraine Webber 3 , Lindsey Pegg 3 , Adrian Freeman 3 , Janet Woods 1 , Sookhoe Eng 1 , Angela Taylor 4 , Wiebke Arlt 5 , Abd Tahrani 5 & Ana Tiganescu 2
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).
Volume 65
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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