Beta-cell Death and Dysfunction Drives Hyperglycaemia in Organ Donors

Overview

Journal Diabetes Obes Metab

Specialty Endocrinology

Date 2023 Aug 30

PMID 37646197

Authors

Iestyn M Shapey

Angela Summers

James OSullivan

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Absent in Melanoma (AIM)2 Promotes the Outcome of Islet Transplantation by Repressing Ischemia-Induced Interferon (IFN) Signaling.

Wrublewsky S, Wilden C, Bickelmann C, Menger M, Laschke M, Ampofo E Cells. 2024; 13(1).

PMID: 38201220 PMC: 10778091. DOI: 10.3390/cells13010016.

Beta-cell death and dysfunction drives hyperglycaemia in organ donors.

Shapey I, Summers A, OSullivan J, Fullwood C, Hanley N, Casey J Diabetes Obes Metab. 2023; 25(12):3529-3537.

PMID: 37646197 PMC: 10947469. DOI: 10.1111/dom.15248.

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