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Beta-cell death and dysfunction drives hyperglycaemia in organ donors |
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| Authors: | Iestyn M. Shapey PhD Angela Summers BSc James O'Sullivan BSc Catherine Fullwood PhD Neil A. Hanley MBChB John Casey MBChB Shareen Forbes MBChB Miranda Rosenthal PhD Paul R. V. Johnson MBChB Pratik Choudhary MBBS James Bushnell MD James A. M. Shaw MBChB Daniel Neiman PhD Ruth Shemer PhD Benjamin Glaser MD Yuval Dor PhD Titus Augustine MS Martin K. Rutter MD David van Dellen MD |
| Affiliation: | 1. Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK;2. Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK Department of Renal and Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Manchester, UK;3. Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK;4. Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK Department of Research and Innovation (medical statistics), Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK;5. Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK;6. Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK Endocrinology Unit, University of Edinburgh, Edinburgh, UK;7. Diabetes Unit, Royal Free Hospital, London, UK;8. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK;9. Diabetes Research Group, King's College London, London, UK;10. Richard Bright Renal Unit, Southmead Hospital, Bristol, UK;11. Institute of Cellular Medicine, Newcastle University, Newcastle, UK;12. Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel;13. Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel;14. Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK Diabetes, Endocrinology and Metabolism Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK |
| Abstract: | BackgroundDonor hyperglycaemia following brain death has been attributed to reversible insulin resistance. However, our islet and pancreas transplant data suggest that other mechanisms may be predominant. We aimed to determine the relationships between donor insulin use and markers of beta-cell death and beta-cell function in pancreas donors after brain death.MethodsIn pancreas donors after brain death, we compared clinical and biochemical data in ‘insulin-treated’ and ‘not insulin-treated donors’ (IT vs. not-IT). We measured plasma glucose, C-peptide and levels of circulating unmethylated insulin gene promoter cell-free DNA (INS-cfDNA) and microRNA-375 (miR-375), as measures of beta-cell death. Relationships between markers of beta-cell death and islet isolation outcomes and post-transplant function were also evaluated.ResultsOf 92 pancreas donors, 40 (43%) required insulin. Glycaemic control and beta-cell function were significantly poorer in IT donors versus not-IT donors [median (IQR) peak glucose: 8 (7-11) vs. 6 (6-8) mmol/L, p = .016; C-peptide: 3280 (3159-3386) vs. 3195 (2868-3386) pmol/L, p = .046]. IT donors had significantly higher levels of INS-cfDNA [35 (18-52) vs. 30 (8-51) copies/ml, p = .035] and miR-375 [1.050 (0.19-1.95) vs. 0.73 (0.32-1.10) copies/nl, p = .05]. Circulating donor miR-375 was highly predictive of recipient islet graft failure at 3 months [adjusted receiver operator curve (SE) = 0.813 (0.149)].ConclusionsIn pancreas donors, hyperglycaemia requiring IT is strongly associated with beta-cell death. This provides an explanation for the relationship of donor IT with post-transplant beta-cell dysfunction in transplant recipients. |
| Keywords: | beta-cell death glycaemic control hyperglycaemia insulin islet organ donor pancreas transplant |