Beta‐cell death and dysfunction drives hyperglycaemia in organ donors

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.

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

“…Therefore, numerous strategies have been developed under preclinical and clinical conditions to protect transplanted islets from ischemia-induced graft failure [ 8 , 9 , 10 , 11 , 12 ]. Particularly, approaches that prevent the deleterious events associated with apoptosis and necrosis are the focus of many studies [ 11 , 13 , 14 ]. Nonetheless, the underlying complex signaling pathways for islet cell death are still not fully understood [ 15 ].…”