title: Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy.
abstract: The role of circulating factors in regulating colonic stem cells (CoSCs) and colonic epithelial homeostasis is unclear. Individuals with long-standing type 1 diabetes (T1D) frequently have intestinal symptoms, termed diabetic enteropathy (DE), though its etiology is unknown. Here, we report that T1D patients with DE exhibit abnormalities in their intestinal mucosa and CoSCs, which fail to generate in vitro mini-guts. Proteomic profiling of T1D+DE patient serum revealed altered levels of insulin-like growth factor 1 (IGF-I) and its binding protein 3 (IGFBP3). IGFBP3 prevented in vitro growth of patient-derived organoids via binding its receptor TMEM219, in an IGF-I-independent manner, and disrupted in vivo CoSC function in a preclinical DE model. Restoration of normoglycemia in patients with long-standing T1D via kidney-pancreas transplantation or in diabetic mice by treatment with an ecto-TMEM219 recombinant protein normalized circulating IGF-I/IGFBP3 levels and reestablished CoSC homeostasis. These findings demonstrate that peripheral IGF-I/IGFBP3 controls CoSCs and their dysfunction in DE.
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA.|Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Addio
authors.affiliation: Department of Pathology, Ospedale di Circolo, Varese 21100, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: La Rosa
authors.affiliation: Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Maestroni
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Peter
authors.initials: P
authors.lastname: Jung
authors.affiliation: Surgery, Protein Microsequencing Facility, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Orsenigo
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA.|Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Moufida
authors.initials: M
authors.lastname: Ben Nasr
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA.|Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Tezza
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA.|Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bassi
authors.affiliation: Department of Pathology, Ospedale di Circolo, Varese 21100, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Finzi
authors.affiliation: Department of Pathology, Ospedale di Circolo, Varese 21100, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marando
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA.|Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vergani
authors.affiliation: Gastroenterology, Protein Microsequencing Facility, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Frego
authors.affiliation: Pathology Unit, Protein Microsequencing Facility, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Albarello
authors.affiliation: ProMiFa, Protein Microsequencing Facility, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Annapaola
authors.initials: A
authors.lastname: Andolfo
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma 43121, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Manuguerra
authors.affiliation: Gastroenterology, Protein Microsequencing Facility, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Edi
authors.initials: E
authors.lastname: Viale
authors.affiliation: Surgery, Protein Microsequencing Facility, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Staudacher
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma 43121, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Corradi
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08028, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Batlle
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Breault
authors.affiliation: Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy.|Vita Salute San Raffaele University, Milano 20132, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Secchi
authors.affiliation: Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio 78229, Texas, USA.|Department of Internal Medicine, Obesity and Comorbidities Research Center (O.C.R.C.), State University of Campinas, São Paulo 13100, Brazil.
authors.forename: Franco
authors.initials: F
authors.lastname: Folli
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, USA.|Transplant Medicine, IRCCS Ospedale San Raffaele, Milan 20132, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
mesh_terms: D000818:Animals; D003106:Colon / Q000166:cytology* / Q000502:physiology; D048909:Diabetes Complications / Q000378:metabolism / Q000473:pathology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D040901:Proteomics; D013234:Stem Cells / Q000502:physiology*
chemical_list: C583557:IGF1 protein, human; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D008565:Membrane Proteins; D007334:Insulin-Like Growth Factor I
keywords: IGF-I; IGFBP3; colonic stem cells; diabetic enteropathy; diabetic nephropathy; hyperglycemia; kidney transplantation; pancreas transplantation; type 1 diabetes; type 2 diabetes; uremia