title: Expression of IGF-I in pancreatic islets prevents lymphocytic infiltration and protects mice from type 1 diabetes.
abstract: Type 1 diabetic patients are diagnosed when beta-cell destruction is almost complete. Reversal of type 1 diabetes will require beta-cell regeneration from islet cell precursors and prevention of recurring autoimmunity. IGF-I expression in beta-cells of streptozotocin (STZ)-treated transgenic mice regenerates the endocrine pancreas by increasing beta-cell replication and neogenesis. Here, we examined whether IGF-I also protects islets from autoimmune destruction. Expression of interferon (IFN)-beta in beta-cells of transgenic mice led to islet beta(2)-microglobulin and Fas hyperexpression and increased lymphocytic infiltration. Pancreatic islets showed high insulitis, and these mice developed overt diabetes when treated with very-low doses of STZ, which did not affect control mice. IGF-I expression in IFN-beta-expressing beta-cells of double-transgenic mice reduced beta(2)-microglobulin, blocked Fas expression, and counteracted islet infiltration. This was parallel to a decrease in beta-cell death by apoptosis in islets of STZ-treated IGF-I+IFN-beta-expressing mice. These mice were normoglycemic, normoinsulinemic, and showed normal glucose tolerance. They also presented similar pancreatic insulin content and beta-cell mass to healthy mice. Thus, local expression of IGF-I prevented islet infiltration and beta-cell death in mice with increased susceptibility to diabetes. These results indicate that pancreatic expression of IGF-I may regenerate and protect beta-cell mass in type 1 diabetes.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Casellas
authors.forename: Ariana
authors.initials: A
authors.lastname: Salavert
authors.forename: Judith
authors.initials: J
authors.lastname: Agudo
authors.forename: Eduard
authors.initials: E
authors.lastname: Ayuso
authors.forename: Veronica
authors.initials: V
authors.lastname: Jimenez
authors.forename: Marta
authors.initials: M
authors.lastname: Moya
authors.forename: Sergio
authors.initials: S
authors.lastname: Muñoz
authors.forename: Sylvie
authors.initials: S
authors.lastname: Franckhauser
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000473:pathology; D016899:Interferon-beta / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration
chemical_list: D001786:Blood Glucose; D007334:Insulin-Like Growth Factor I; D016899:Interferon-beta