Beta-cell death and dysfunction drives hyperglycaemia in organ donors

Area of Science:

• Endocrinology
• Transplantation Immunology
• Cell Biology

Background:

• Donor hyperglycemia post-brain death is often attributed to insulin resistance.
• However, data from islet and pancreas transplantation suggest alternative mechanisms may be more significant.

Purpose of the Study:

• To investigate the relationship between donor insulin use and markers of beta-cell death and function in brain-dead pancreas donors.
• To evaluate how these markers correlate with islet isolation success and post-transplant graft function.

Main Methods:

• Compared clinical and biochemical data of insulin-treated (IT) versus non-insulin-treated (not-IT) brain-dead pancreas donors.
• Measured plasma glucose, C-peptide, cell-free DNA from the insulin gene promoter (INS-cfDNA), and microRNA-375 (miR-375) as indicators of beta-cell death.
• Assessed the predictive value of these markers for islet graft outcomes.

Main Results:

• 43% of 92 pancreas donors required insulin therapy.
• Insulin-treated donors exhibited poorer glycemic control and beta-cell function (higher peak glucose, lower C-peptide) compared to non-insulin-treated donors.
• Insulin-treated donors had significantly higher levels of INS-cfDNA and miR-375, indicating increased beta-cell death.
• Circulating donor miR-375 levels strongly predicted islet graft failure in recipients at 3 months.

Conclusions:

• Hyperglycemia in pancreas donors necessitating insulin treatment is strongly associated with beta-cell death.
• This beta-cell death is a key factor explaining the reduced post-transplant function observed in grafts from insulin-treated donors.