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

Pancreatic islet transplantation has therapeutic potential in type 1 diabetes and is also an established therapy in chronic pancreatitis. However, the long‐term transplant outcomes are modest. Identifying indicators of graft function will aid the preservation of transplanted islets and glycemic control. We analyzed beta cell prohormone peptide levels in a retrospective cohort of total pancreatectomy autologous islet transplant patients (n = 28). Proinsulin‐to‐C‐peptide (PI/C) and proIAPP‐to‐total IAPP (proIAPP/IAPP) ratios measured at 3 months post‐transplant were significantly higher in patients who remained insulin dependent at 1 year follow‐up. In an immuno‐deficient mouse model of human islet transplantation, recipient mice that later became hyperglycemic displayed significantly higher PI/C ratios than mice that remained normoglycemic. Histological analysis of islet grafts showed reduced proportional insulin‐ and proinsulin‐positive area, but elevated glucagon‐positive area in grafts that experienced greater secretory demand. Increased prohormone convertase 1/3 was detected in glucagon‐positive cells, and glucagon‐like peptide 1 (GLP‐1) 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. These data indicate that in failing grafts, alpha cell prohormone processing is likely altered, and incomplete beta cell prohormone processing may be an early indicator of insulin dependency. Elevated proinsulin‐to‐C‐peptide ratios precedes insulin dependency in human recipients of auto‐islet transplants and in islet graft failure in murine recipients of optimal or sub‐optimal doses of human islets.