Elevated islet prohormone ratios as indicators of insulin dependency in islet transplant recipients

Yi-Chun Chen (University of British Columbia)

Yi-Chun Chen, Agnieszka Klimek-Abercrombie, Kathryn Potter, Lindsay Pallo, Galina Soukhatcheva, Dai Lei, Melena Bellin, C. Bruce Verchere

Pancreatic islet transplantation has therapeutic potential in T1D and is also an established therapy for patients with chronic pancreatitis; however, long-term transplant outcomes are modest. Identifying indicators and predictors of graft function could aid in the improvement of transplant outcomes and glycemic control.

We analyzed plasma beta-cell (pro)hormones including proinsulin, C-peptide, amidated islet amyloid polypeptide (IAPP), and proIAPP1-48 levels in a retrospective cohort of autologous total pancreatic islet transplant patients (n = 28), as well as in a mouse model of optimal versus sub-optimal human islet transplantation. We also performed histological analysis of islet grafts retrieved from mice to evaluate islet prohormone processing machinery in situ.

Summary of Results
Proinsulin-to-C-peptide (PI/C) and proIAPP-to-total IAPP (proIAPP/IAPP) ratios measured at 3 months post-autologous islet transplant were significantly higher in patients who remained insulin dependent at 1 year follow-up (PI/C: 8.83 ± 1.03 vs. 5.76 ± 0.93, p < 0.05; proIAPP/IAPP: 0.62 ± 0.10 vs. 0.30 ± 0.02, p < 0.05). In a mouse model of sub-optimal human islet transplantation, we found that mice that later became hyperglycemic displayed significantly higher PI/C ratios than mice that remained normoglycemic (1.08 ± 0.10 vs. 0.25 ± 0.41, n = 8 and 41, respectively; p < 0.05). Histological analysis of islet grafts retrieved from mice showed reduced insulin- and proinsulin-positive area, but elevated glucagon-positive area in grafts that experienced greater secretory demand. Increased prohormone convertase 1/3 (PC1/3) immunoreactivity was detected in glucagon-positive cells, and glucagon-like peptide 1 (GLP-1) immunoreactive area was elevated in grafts from mice that displayed hyperglycemia or elevated plasma PI/C ratios, demonstrating intra-islet incretin production in metabolically challenged human islet grafts.

In failing islet transplants, incomplete beta cell prohormone processing may be an early indicator of graft dysfunction and future insulin dependency. Alpha cell prohormone processing is also likely altered, leading to intra-islet GLP-1 production.