title: Metabolic Complications Precede Alloreactivity and Are Characterized by Changes in Suppression of Tumorigenicity 2 Signaling.
abstract: New-onset post-transplantation diabetes mellitus (PTDM) occurs commonly after allogeneic hematopoietic cell transplantation (HCT) and is associated with inferior survival. We hypothesize that PTDM and nonrelapse mortality (NRM) are related to IL-33/suppression of tumorigenicity 2 (ST2) signaling and that soluble ST2 (sST2) levels will predict PTDM diagnosis. sST2 was measured at engraftment and day +30 in 36 euglycemic HCT recipients followed prospectively for PTDM (cohort 1). Results were confirmed in a validation cohort of 26 patients without pre-existing diabetes analyzed retrospectively for PTDM (cohort 2). Twelve patients with established diabetes before HCT were analyzed in cohort 3. When compared with recipients without PTDM, patients developing PTDM (n = 24) from cohort 1 had elevated sST2 levels at engraftment (P = .02) and at day +30 (P < .01). Cohort 2 confirmed this finding at engraftment (P = .01). Cohort 3 patients with pretransplantation diabetes had higher sST2 at engraftment than patients maintaining euglycemia after HCT from cohort 2 (P = .03). Multivariate analysis of cohorts 1 and 2 showed high engraftment sST2 predicted increased PTDM and NRM risk, independent of conditioning and grades 3 to 4 acute graft-versus-host-disease. sST2 was elevated in PTDM, indicating a relationship between glucose homeostasis and the IL-33/ST2 axis after transplantation. Correction of metabolic complications may decrease sST2 and improve NRM.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Romany A N
authors.initials: RA
authors.lastname: Johnpulle
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Sophie
authors.initials: S
authors.lastname: Paczesny
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Dae Kwang
authors.initials: DK
authors.lastname: Jung
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Etienne
authors.initials: E
authors.lastname: Daguindau
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Madan H
authors.initials: MH
authors.lastname: Jagasia
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Bipin N
authors.initials: BN
authors.lastname: Savani
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Wichai
authors.initials: W
authors.lastname: Chinratanalab
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Cornell
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Stacey
authors.initials: S
authors.lastname: Goodman
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: John P
authors.initials: JP
authors.lastname: Greer
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Adetola A
authors.initials: AA
authors.lastname: Kassim
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Salyka
authors.initials: S
authors.lastname: Sengsayadeth
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Byrne
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: brian.engelhardt@vanderbilt.edu.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Engelhardt
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000209:etiology*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000097:blood / Q000378:metabolism*; D000067596:Interleukin-33 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D015398:Signal Transduction; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D001786:Blood Glucose; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33
keywords: Allogeneic; IL-33; Metabolic complications; Post-transplantation diabetes mellitus; Soluble suppression of tumorigenicity 2; Treatment-related mortality; sST2