Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy

Francesca D'Addio, Stefano La Rosa, Anna Maestroni, Peter Jung, Elena Orsenigo, Moufida Ben Nasr, Sara Tezza, Roberto Bassi, Giovanna Finzi, Alessandro Marando, Andrea Vergani, Roberto Frego, Luca Albarello, Annapaola Andolfo, Roberta Manuguerra, Edi Viale, Carlo Staudacher, Domenico Corradi, Eduard Batlle, David BreaultAntonio Secchi, Franco Folli, Paolo Fiorina

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)486-498
Number of pages13
JournalCell Stem Cell
Volume17
Issue number4
DOIs
StatePublished - 2015

Keywords

  • IGF-I
  • IGFBP3
  • colonic stem cells
  • diabetic enteropathy
  • diabetic nephropathy
  • hyperglycemia
  • kidney transplantation
  • pancreas transplantation
  • type 1 diabetes
  • type 2 diabetes
  • uremia

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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