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

Autologous pancreatic islet transplantation is an established therapy for patients with 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. To this end, 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 a 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 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. ### Competing Interest Statement The authors have declared no competing interest. * ACRglu : Acute C-peptide response to glucose ACRpot : Glucose-potentiated acute C-peptide response to arginine AUC : Area under the curve GLP-1 : Glucagon-like peptide 1 HOMA : Homeostasis model assessment IEQ : Islet equivalent IPGTT : Intraperitoneal glucose tolerance test MMTT : Mixed meal tolerance test NSG : NOD-scid IL2Rgnull PC1/3 : Prohormone convertase 1/3 PI/C ratio : Proinsulin-to-C-peptide ratio proIAPP/IAPP ratio : proIAPP-to-total IAPP ratio STZ : Streptozotocin T1D : Type 1 diabetes TPIAT : Total pancreatic islet autologous transplant