title: Insulin-like Growth Factor 2 Overexpression Induces β-Cell Dysfunction and Increases Beta-cell Susceptibility to Damage.
abstract: The human insulin-like growth factor 2 (IGF2) and insulin genes are located within the same genomic region. Although human genomic studies have demonstrated associations between diabetes and the insulin/IGF2 locus or the IGF2 mRNA-binding protein 2 (IGF2BP2), the role of IGF2 in diabetes pathogenesis is not fully understood. We previously described that transgenic mice overexpressing IGF2 specifically in β-cells (Tg-IGF2) develop a pre-diabetic state. Here, we characterized the effects of IGF2 on β-cell functionality. Overexpression of IGF2 led to β-cell dedifferentiation and endoplasmic reticulum stress causing islet dysfunction in vivo. Both adenovirus-mediated overexpression of IGF2 and treatment of adult wild-type islets with recombinant IGF2 in vitro further confirmed the direct implication of IGF2 on β-cell dysfunction. Treatment of Tg-IGF2 mice with subdiabetogenic doses of streptozotocin or crossing these mice with a transgenic model of islet lymphocytic infiltration promoted the development of overt diabetes, suggesting that IGF2 makes islets more susceptible to β-cell damage and immune attack. These results indicate that increased local levels of IGF2 in pancreatic islets may predispose to the onset of diabetes. This study unravels an unprecedented role of IGF2 on β-cells function.
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Departments of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Casellas
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Departments of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mallol
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy.
authors.forename: Ariana
authors.initials: A
authors.lastname: Salavert
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Departments of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain.
authors.forename: Veronica
authors.initials: V
authors.lastname: Jimenez
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Departments of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Garcia
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Departments of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Agudo
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Obach
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Departments of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Haurigot
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Departments of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Vilà
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Departments of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Molas
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Departments of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lage
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Departments of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Morró
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Departments of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain.
authors.forename: Estefania
authors.initials: E
authors.lastname: Casana
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma Barcelona, 08193-Bellaterra and.
authors.forename: Jesús
authors.initials: J
authors.lastname: Ruberte
authors.affiliation: From the Center of Animal Biotechnology and Gene Therapy, Departments of Biochemistry and Molecular Biology and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036-Barcelona, Spain fatima.bosch@uab.es.
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051381:Rats
chemical_list: C035170:IGF2 protein, human; D007328:Insulin; D007335:Insulin-Like Growth Factor II
keywords: beta cell (B-cell); diabetes; endoplasmic reticulum stress (ER stress); insulin-like growth factor (IGF); islet