Beta-cell death and dysfunction drives hyperglycaemia in organ donors

Iestyn M. Shapey*, Angela Summers, James O'Sullivan, Catherine Fullwood, Neil A. Hanley, John Casey, Shareen Forbes, Miranda Rosenthal, Paul R.V. Johnson, Pratik Choudhary, James Bushnell, James A.M. Shaw, Daniel Neiman, Ruth Shemer, Benjamin Glaser, Yuval Dor, Titus Augustine, Martin K. Rutter, David van Dellen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: Donor 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. Methods: In 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. Results: Of 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)]. Conclusions: In 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.

Original languageAmerican English
Pages (from-to)3529-3537
Number of pages9
JournalDiabetes, Obesity and Metabolism
Volume25
Issue number12
DOIs
StatePublished - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Keywords

  • beta-cell death
  • glycaemic control
  • hyperglycaemia
  • insulin
  • islet
  • organ donor
  • pancreas
  • transplant

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