Relationship between IGF-1 and body weight in inflammatory bowel diseases: Cellular and molecular mechanisms involved.

Abstract

Inflammatory bowel diseases (IBD), represented by ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic inflammation of the gastrointestinal tract, what leads to diarrhea, malnutrition, and weight loss. Depression of the growth hormone-insulin-like growth factor-1 axis (GH-IGF-1 axis) could be responsible of these symptoms. We demonstrate that long-term treatment (54 weeks) of adult CD patients with adalimumab (ADA) results in a decrease in serum IGF-1 without changes in serum IGF-1 binding protein (IGF1BP4). These results prompted us to conduct a preclinical study to test the efficiency of IGF-1 in the medication for experimental colitis. IGF-1 treatment of rats with DSS-induced colitis has a beneficial effect on the following circulating biochemical parameters: glucose, albumin, and total protein levels. In this experimental group we also observed healthy maintenance of colon size, body weight, and lean mass in comparison with the DSS-only group. Histological analysis revealed restoration of the mucosal barrier with the IGF-1 treatment, which was characterized by healthy quantities of mucin production, structural maintenance of adherers junctions (AJs), recuperation of E-cadherin and β-catenin levels and decrease in infiltrating immune cells and in metalloproteinase-2 levels. The experimentally induced colitis caused activation of apoptosis markers, including cleaved caspase 3, caspase 8, and PARP and decreases cell-cycle checkpoint activators including phosphorylated Rb, cyclin E, and E2F1. The IGF-1 treatment inhibited cyclin E depletion and partially protects PARP levels. The beneficial effects of IGF-1 in experimental colitis could be explained by a re-sensitization of the IGF-1/IRS-1/AKT cascade to exogenous IGF-1. Given these results, we postulate that IGF-1 treatment of IBD patients could prove to be successful in reducing disease pathology.

• Authors: Luis G Guijarro, David Cano-Martínez, M Val Toledo-Lobo, Patricia Sanmartín Salinas, María Chaparro, Ana M Gómez-Lahoz, Sofía Zoullas, Rosa Rodríguez-Torres, Irene D Román, Laura Sebastián Monasor, Lidia Ruiz-Llorente, María Del Carmen Boyano-Adánez, Iván Guerra, Marisa Iborra, José Luis Cabriada, Luis Bujanda, Carlos Taxonera, Valle García-Sánchez, Ignacio Marín-Jiménez, Manuel Barreiro-de Acosta, Isabel Vera, María Dolores Martín-Arranz, Francisco Mesonero, Laura Sempere, Fernando Gomollón, Joaquín Hinojosa, Melchor Alvarez-Mon, Javier P Gisbert, Miguel A Ortega, Borja Hernández-Breijo, On Behalf Of The Predicrohn Study Group From Geteccu
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 144 Pg. 112239 (Dec 2021) ISSN: 1950-6007 [Electronic] France
• PMID: 34601192 (Publication Type: Journal Article, Multicenter Study)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Biomarkers
• IGF1 protein, human
• Insulin Receptor Substrate Proteins
• Irs1 protein, rat
• Tumor Necrosis Factor Inhibitors
• Insulin-Like Growth Factor I
• Proto-Oncogene Proteins c-akt
• Adalimumab

Topics

• Adalimumab (therapeutic use)
• Adult
• Animals
• Biomarkers (blood)
• Body Weight (drug effects)
• Colitis (metabolism, pathology, prevention & control)
• Colitis, Ulcerative (blood, diagnosis, drug therapy)
• Colon (drug effects, metabolism, pathology)
• Crohn Disease (blood, diagnosis, drug therapy)
• Disease Models, Animal
• Female
• Humans
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin-Like Growth Factor I (metabolism, pharmacology)
• Intestinal Mucosa (drug effects, metabolism, pathology)
• Longitudinal Studies
• Male
• Middle Aged
• Prospective Studies
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats, Wistar
• Signal Transduction
• Spain
• Time Factors
• Treatment Outcome
• Tumor Necrosis Factor Inhibitors (therapeutic use)
• Rats