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Expression of IGF-I in Pancreatic Islets Prevents Lymphocytic Infiltration and Protects Mice From Type 1 Diabetes

From the Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain

Address correspondence and reprint requests to Fatima Bosch, 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. E-mail: fatima.bosch{at}uab.es

Abbreviations: IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; STZ, streptozotocin; TUNEL, transferase-mediated dUTP nick-end labeling

Type 1 diabetic patients are diagnosed when ß-cell destruction is almost complete. Reversal of type 1 diabetes will require ß-cell regeneration from islet cell precursors and prevention of recurring autoimmunity. IGF-I expression in ß-cells of streptozotocin (STZ)-treated transgenic mice regenerates the endocrine pancreas by increasing ß-cell replication and neogenesis. Here, we examined whether IGF-I also protects islets from autoimmune destruction. Expression of interferon (IFN)-ß in ß-cells of transgenic mice led to islet ß₂-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-ß–expressing ß-cells of double-transgenic mice reduced ß₂-microglobulin, blocked Fas expression, and counteracted islet infiltration. This was parallel to a decrease in ß-cell death by apoptosis in islets of STZ-treated IGF-I+IFN-ß–expressing mice. These mice were normoglycemic, normoinsulinemic, and showed normal glucose tolerance. They also presented similar pancreatic insulin content and ß-cell mass to healthy mice. Thus, local expression of IGF-I prevented islet infiltration and ß-cell death in mice with increased susceptibility to diabetes. These results indicate that pancreatic expression of IGF-I may regenerate and protect ß-cell mass in type 1 diabetes.

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