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Beta-cell death and dysfunction drives hyperglycaemia in organ donors

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posted on 2023-09-13, 15:24 authored by Pratik Choudhary, Iestyn Shapey, Angela Summers, James O'Sullivan, Catherine Fullwood, Neil A Hanley, John Casey, Shareen Forbes, Miranda Rosenthal, Paul RV Johnson, James Bushnell, James AM Shaw, Daniel Neiman, Ruth Shemer, Benjamin Glaser, Yuval Dor, Titus Augustine, Martin K Rutter, David van Dellen

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.

Funding

Diabetes UK

Medical Research Council

Royal College of Surgeons of Edinburgh

NIHR Manchester Biomedical Research Centre. Grant Number: NIHR203308

History

Author affiliation

Diabetes Research Centre, University of Leicester

Version

  • VoR (Version of Record)

Published in

Diabetes, Obesity and Metabolism

Publisher

Wiley

issn

1463-1326

Copyright date

2023

Available date

2023-09-13

Language

en

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