| Literature DB >> 26431183 |
Francesca D'Addio1,2, Stefano La Rosa3, Anna Maestroni2, Peter Jung4, Elena Orsenigo5, Moufida Ben Nasr1,2, Sara Tezza1,2, Roberto Bassi1,2, Giovanna Finzi3, Alessandro Marando3, Andrea Vergani1,2, Roberto Frego6, Luca Albarello7, Annapaola Andolfo8, Roberta Manuguerra9, Edi Viale6, Carlo Staudacher5, Domenico Corradi9, Eduard Batlle4,10, David Breault11, Antonio Secchi2,12, Franco Folli13,14, Paolo Fiorina1,2.
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.Entities:
Keywords: IGF-I; IGFBP3; colonic stem cells; diabetic enteropathy; diabetic nephropathy; hyperglycemia; kidney transplantation; pancreas transplantation; type 1 diabetes; type 2 diabetes; uremia
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Year: 2015 PMID： 26431183 PMCID： PMC4826279 DOI： 10.1016/j.stem.2015.07.010
Source DB: PubMed Journal: Cell Stem Cell ISSN： 1875-9777 Impact factor: 24.633