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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1992-2005
Number of pages14
JournalAmerican Journal of Transplantation
Volume22
Issue number8
DOIs
StatePublished - Aug 2022

Bibliographical note

Funding Information:
We acknowledge the patients and organ donors who contributed to this study. This work is supported by JDRF (1‐INO‐2019‐794‐S‐B) and CIHR (PJT‐153156) to C.B.V., JDRF postdoctoral fellowship (3‐PDF‐2017‐373‐A‐N) to Y.C.C., NIH (5R03DK102469) to M.B.D., and NIH CTSI (UL1TR002494) to UMN.

Publisher Copyright:
© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.

Keywords

  • biomarkers
  • islet autotransplant

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Fingerprint

Dive into the research topics of 'Elevated islet prohormone ratios as indicators of insulin dependency in auto-islet transplant recipients'. Together they form a unique fingerprint.

Cite this