title: Unmethylated Insulin DNA Is Elevated After Total Pancreatectomy With Islet Autotransplantation: Assessment of a Novel Beta Cell Marker.
abstract: Beta cell death may occur both after islet isolation and during infusion back into recipients undergoing total pancreatectomy with islet autotransplantation (TPIAT) for chronic pancreatitis. We measured the novel beta cell death marker unmethylated insulin (INS) DNA in TPIAT recipients before and immediately after islet infusion (n = 21) and again 90 days after TPIAT, concurrent with metabolic functional assessments (n = 25). As expected, INS DNA decreased after pancreatectomy (p = 0.0002). All TPIAT recipients had an elevated unmethylated INS DNA ratio in the first hours following islet infusion. In four samples (three patients), INS DNA was also assessed immediately after islet isolation and again before islet infusion to assess the impact of the isolation process: Unmethylated and methylated INS DNA fractions both increased over this interval, suggesting death of beta cells and exocrine tissue before islet infusion. Higher glucose excursion with mixed-meal tolerance testing was associated with persistently elevated INS DNA at day 90. In conclusion, we observed universal early elevations in the beta cell death marker INS DNA after TPIAT, with pronounced elevations in the islet supernatant before infusion, likely reflecting beta cell death induced by islet isolation. Persistent posttransplant elevation of INS DNA predicted greater hyperglycemia at 90 days.
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN.|Department of Surgery, University of Minnesota, Minneapolis, MN.
authors.forename: M D
authors.initials: MD
authors.lastname: Bellin
authors.affiliation: Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, CT.
authors.forename: P
authors.initials: P
authors.lastname: Clark
authors.affiliation: L2 Diagnostics, New Haven, CT.
authors.forename: S
authors.initials: S
authors.lastname: Usmani-Brown
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN.
authors.forename: T B
authors.identifier: 0000-0002-5941-0659
authors.initials: TB
authors.lastname: Dunn
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN.
authors.forename: G J
authors.initials: GJ
authors.lastname: Beilman
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN.
authors.forename: S
authors.initials: S
authors.lastname: Chinnakotla
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN.
authors.forename: T L
authors.initials: TL
authors.lastname: Pruett
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN.
authors.forename: P
authors.initials: P
authors.lastname: Ptacek
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN.
authors.forename: B J
authors.initials: BJ
authors.lastname: Hering
authors.affiliation: School of Public Health, Yale University, New Haven, CT.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN.
authors.forename: T
authors.initials: T
authors.lastname: Gilmore
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN.
authors.forename: J J
authors.initials: JJ
authors.lastname: Wilhelm
authors.affiliation: Department of Biostatistics, University of Minnesota, Minneapolis, MN.
authors.forename: J S
authors.initials: JS
authors.lastname: Hodges
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN.
authors.forename: A
authors.initials: A
authors.lastname: Moran
authors.affiliation: Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, CT.
authors.forename: K C
authors.initials: KC
authors.lastname: Herold
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D019175:DNA Methylation; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007328:Insulin / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D010180:Pancreatectomy / Q000009:adverse effects*; D050500:Pancreatitis, Chronic / Q000601:surgery*; D011183:Postoperative Complications; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D014182:Transplantation, Autologous; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007328:Insulin; D004247:DNA
keywords: biomarker; cell death; clinical research/practice; diabetes: type 1; endocrinology/diabetology; islet isolation; islet transplantation; islets of Langerhans; translational research/science