{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T05:47:39Z","timestamp":1772257659731,"version":"3.50.1"},"reference-count":45,"publisher":"American Diabetes Association","issue":"12","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,12,1]]},"abstract":"<jats:p>Type 1 diabetic patients are diagnosed when \u03b2-cell destruction is almost complete. Reversal of type 1 diabetes will require \u03b2-cell regeneration from islet cell precursors and prevention of recurring autoimmunity. IGF-I expression in \u03b2-cells of streptozotocin (STZ)-treated transgenic mice regenerates the endocrine pancreas by increasing \u03b2-cell replication and neogenesis. Here, we examined whether IGF-I also protects islets from autoimmune destruction. Expression of interferon (IFN)-\u03b2 in \u03b2-cells of transgenic mice led to islet \u03b22-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-\u03b2\u2013expressing \u03b2-cells of double-transgenic mice reduced \u03b22-microglobulin, blocked Fas expression, and counteracted islet infiltration. This was parallel to a decrease in \u03b2-cell death by apoptosis in islets of STZ-treated IGF-I+IFN-\u03b2\u2013expressing mice. These mice were normoglycemic, normoinsulinemic, and showed normal glucose tolerance. They also presented similar pancreatic insulin content and \u03b2-cell mass to healthy mice. Thus, local expression of IGF-I prevented islet infiltration and \u03b2-cell death in mice with increased susceptibility to diabetes. These results indicate that pancreatic expression of IGF-I may regenerate and protect \u03b2-cell mass in type 1 diabetes.<\/jats:p>","DOI":"10.2337\/db06-0328","type":"journal-article","created":{"date-parts":[[2006,11,28]],"date-time":"2006-11-28T02:41:20Z","timestamp":1164681680000},"page":"3246-3255","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":39,"title":["Expression of IGF-I in Pancreatic Islets Prevents Lymphocytic Infiltration and Protects Mice From Type 1 Diabetes"],"prefix":"10.2337","volume":"55","author":[{"given":"Alba","family":"Casellas","sequence":"first","affiliation":[{"name":"From the Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Auto\u0300noma de Barcelona, Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariana","family":"Salavert","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Auto\u0300noma de Barcelona, Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Agudo","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Auto\u0300noma de Barcelona, Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduard","family":"Ayuso","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Auto\u0300noma de Barcelona, Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica","family":"Jimenez","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Auto\u0300noma de Barcelona, Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Moya","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Auto\u0300noma de Barcelona, Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio","family":"Mun\u0303oz","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Auto\u0300noma de Barcelona, Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvie","family":"Franckhauser","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Auto\u0300noma de Barcelona, Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatima","family":"Bosch","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Auto\u0300noma de Barcelona, Bellaterra, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","reference":[{"key":"2022031208045122800_R1","doi-asserted-by":"crossref","unstructured":"Tisch R, McDevitt H: Insulin-dependent diabetes mellitus. Cell\u200885:291\u2013297,1996","DOI":"10.1016\/S0092-8674(00)81106-X"},{"key":"2022031208045122800_R2","doi-asserted-by":"crossref","unstructured":"Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y: Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu\u200829:1\u201313,1980","DOI":"10.1538\/expanim1978.29.1_1"},{"key":"2022031208045122800_R3","doi-asserted-by":"crossref","unstructured":"Atkinson MA, Eisenbarth GS: Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet\u2008358:221\u2013229,2001","DOI":"10.1016\/S0140-6736(01)05415-0"},{"key":"2022031208045122800_R4","unstructured":"Pickup JC, Williams G: Chronic Complications of Diabetes. Oxford, U.K., Blackwell Scientific Publications,1994"},{"key":"2022031208045122800_R5","doi-asserted-by":"crossref","unstructured":"Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med\u2008343:230\u2013238,2000","DOI":"10.1056\/NEJM200007273430401"},{"key":"2022031208045122800_R6","doi-asserted-by":"crossref","unstructured":"Bach JF, Chatenoud L: Tolerance to islet autoantigens in type 1 diabetes. Annu Rev Immunol\u200819:131\u2013161,2001","DOI":"10.1146\/annurev.immunol.19.1.131"},{"key":"2022031208045122800_R7","doi-asserted-by":"crossref","unstructured":"Horwitz MS, Fine C, Ilic A, Sarvetnick N: Requirements for viral-mediated autoimmune diabetes: beta-cell damage and immune infiltration. J Autoimmun\u200816:211\u2013217,2001","DOI":"10.1006\/jaut.2000.0486"},{"key":"2022031208045122800_R8","doi-asserted-by":"crossref","unstructured":"Horwitz MS, Ilic A, Fine C, Rodriguez E, Sarvetnick N: Presented antigen from damaged pancreatic beta cells activates autoreactive T cells in virus-mediated autoimmune diabetes. J Clin Invest\u2008109:79\u201387,2002","DOI":"10.1172\/JCI0211198"},{"key":"2022031208045122800_R9","doi-asserted-by":"crossref","unstructured":"Vassileva G, Chen SC, Zeng M, Abbondanzo S, Jensen K, Gorman D, Baroudy BM, Jiang Y, Murgolo N, Lira SA: Expression of a novel murine type I IFN in the pancreatic islets induces diabetes in mice. J Immunol\u2008170:5748\u20135755,2003","DOI":"10.4049\/jimmunol.170.11.5748"},{"key":"2022031208045122800_R10","doi-asserted-by":"crossref","unstructured":"Stewart TA, Hultgren B, Huang X, Pitts-Meek S, Hully J, MacLachlan NJ: Induction of type I diabetes by interferon-alpha in transgenic mice. Science\u2008260:1942\u20131946,1993","DOI":"10.1126\/science.8100367"},{"key":"2022031208045122800_R11","unstructured":"Somoza N, Vargas F, Roura-Mir C, Vives-Pi M, Fernandez-Figueras MT, Ariza A, Gomis R, Bragado R, Marti M, Jaraquemada D, et al.: Pancreas in recent onset insulin-dependent diabetes mellitus: changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V beta usage, and cytokine profile. J Immunol\u2008153:1360\u20131377,1994"},{"key":"2022031208045122800_R12","doi-asserted-by":"crossref","unstructured":"Pelegrin M, Devedjian JC, Costa C, Visa J, Solanes G, Pujol A, Asins G, Valera A, Bosch F: Evidence from transgenic mice that interferon-beta may be involved in the onset of diabetes mellitus. J Biol Chem\u2008273:12332\u201312340,1998","DOI":"10.1074\/jbc.273.20.12332"},{"key":"2022031208045122800_R13","doi-asserted-by":"crossref","unstructured":"Alba A, Puertas MC, Carrillo J, Planas R, Ampudia R, Pastor X, Bosch F, Pujol-Borrell R, Verdaguer J, Vives-Pi M: IFN beta accelerates autoimmune type 1 diabetes in nonobese diabetic mice and breaks the tolerance to beta cells in nondiabetes-prone mice. J Immunol\u2008173:6667\u20136675,2004","DOI":"10.4049\/jimmunol.173.11.6667"},{"key":"2022031208045122800_R14","doi-asserted-by":"crossref","unstructured":"Hellerstrom C, Swenne I: Functional maturation and proliferation of fetal pancreatic \u03b2-cells. Diabetes\u200840:89\u201393,1991","DOI":"10.2337\/diab.40.2.S89"},{"key":"2022031208045122800_R15","doi-asserted-by":"crossref","unstructured":"Lefebvre VH, Otonkoski T, Ustinov J, Huotari MA, Pipeleers DG, Bouwens L: Culture of adult human islet preparations with hepatocyte growth factor and 804G matrix is mitogenic for duct cells but not for \u03b2-cells. Diabetes\u200847:134\u2013137,1998","DOI":"10.2337\/diab.47.1.134"},{"key":"2022031208045122800_R16","doi-asserted-by":"crossref","unstructured":"Rafaeloff R, Pittenger GL, Barlow SW, Qin XF, Yan B, Rosenberg L, Duguid WP, Vinik AI: Cloning and sequencing of the pancreatic islet neogenesis associated protein (INGAP) gene and its expression in islet neogenesis in hamsters. J Clin Invest\u200899:2100\u20132109,1997","DOI":"10.1172\/JCI119383"},{"key":"2022031208045122800_R17","unstructured":"Rooman I, Schuit F, Bouwens L: Effect of vascular endothelial growth factor on growth and differentiation of pancreatic ductal epithelium. Lab Invest\u200876:225\u2013232,1997"},{"key":"2022031208045122800_R18","doi-asserted-by":"crossref","unstructured":"Watanabe T, Yonemura Y, Yonekura H, Suzuki Y, Miyashita H, Sugiyama K, Moriizumi S, Unno M, Tanaka O, Kondo H, et al.: Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein. Proc Natl Acad Sci U S A\u200891:3589\u20133592,1994","DOI":"10.1073\/pnas.91.9.3589"},{"key":"2022031208045122800_R19","doi-asserted-by":"crossref","unstructured":"Le Roith D: Seminars in medicine of the Beth Israel Deaconess Medical Center: insulin-like growth factors. N Engl J Med\u2008336:633\u2013640,1997","DOI":"10.1056\/NEJM199702273360907"},{"key":"2022031208045122800_R20","doi-asserted-by":"crossref","unstructured":"George M, Ayuso E, Casellas A, Costa C, Devedjian JC, Bosch F: Beta cell expression of IGF-I leads to recovery from type 1 diabetes. J Clin Invest\u2008109:1153\u20131163,2002","DOI":"10.1172\/JCI0212969"},{"key":"2022031208045122800_R21","doi-asserted-by":"crossref","unstructured":"Mabley JG, Belin V, John N, Green IC: Insulin-like growth factor I reverses interleukin-1beta inhibition of insulin secretion, induction of nitric oxide synthase and cytokine-mediated apoptosis in rat islets of Langerhans. FEBS Lett\u2008417:235\u2013238,1997","DOI":"10.1016\/S0014-5793(97)01291-X"},{"key":"2022031208045122800_R22","doi-asserted-by":"crossref","unstructured":"Castrillo A, Bodelon OG, Bosca L: Inhibitory effect of IGF-I on type 2 nitric oxide synthase expression in Ins-1 cells and protection against activation-dependent apoptosis: involvement of phosphatidylinositol 3-kinase. Diabetes\u200849:209\u2013217,2000","DOI":"10.2337\/diabetes.49.2.209"},{"key":"2022031208045122800_R23","doi-asserted-by":"crossref","unstructured":"Storling J, Binzer J, Andersson AK, Zullig RA, Tonnesen M, Lehmann R, Spinas GA, Sandler S, Billestrup N, Mandrup-Poulsen T: Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt. Diabetologia\u200848:2039\u20132050,2005","DOI":"10.1007\/s00125-005-1912-2"},{"key":"2022031208045122800_R24","doi-asserted-by":"crossref","unstructured":"Giannoukakis N, Mi Z, Rudert WA, Gambotto A, Trucco M, Robbins P: Prevention of beta cell dysfunction and apoptosis activation in human islets by adenoviral gene transfer of the insulin-like growth factor I. Gene Ther\u20087:2015\u20132022,2000","DOI":"10.1038\/sj.gt.3301333"},{"key":"2022031208045122800_R25","doi-asserted-by":"crossref","unstructured":"Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res\u200829:e45,2001","DOI":"10.1093\/nar\/29.9.e45"},{"key":"2022031208045122800_R26","doi-asserted-by":"crossref","unstructured":"Yoon JW, Jun HS: Cellular and molecular pathogenic mechanisms of insulin-dependent diabetes mellitus. Ann N Y Acad Sci\u2008928:200\u2013211,2001","DOI":"10.1111\/j.1749-6632.2001.tb05650.x"},{"key":"2022031208045122800_R27","doi-asserted-by":"crossref","unstructured":"Santamaria P, Nakhleh RE, Sutherland DE, Barbosa JJ: Characterization of T lymphocytes infiltrating human pancreas allograft affected by isletitis and recurrent diabetes. Diabetes\u200841:53\u201361,1992","DOI":"10.2337\/diabetes.41.1.53"},{"key":"2022031208045122800_R28","doi-asserted-by":"crossref","unstructured":"Moriwaki M, Itoh N, Miyagawa J, Yamamoto K, Imagawa A, Yamagata K, Iwahashi H, Nakajima H, Namba M, Nagata S, Hanafusa T, Matsuzawa Y: Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with recent-onset type I diabetes mellitus. Diabetologia\u200842:1332\u20131340,1999","DOI":"10.1007\/s001250051446"},{"key":"2022031208045122800_R29","doi-asserted-by":"crossref","unstructured":"Chandra J, Zhivotovsky B, Zaitsev S, Juntti-Berggren L, Berggren PO, Orrenius S: Role of apoptosis in pancreatic \u03b2-cell death in diabetes. Diabetes\u200850 (Suppl. 1):S44\u2013S47,2001","DOI":"10.2337\/diabetes.50.2007.S44"},{"key":"2022031208045122800_R30","doi-asserted-by":"crossref","unstructured":"Kikutani H, Makino S: The murine autoimmune diabetes model: NOD and related strains. Adv Immunol\u200851:285\u2013322,1992","DOI":"10.1016\/S0065-2776(08)60490-3"},{"key":"2022031208045122800_R31","doi-asserted-by":"crossref","unstructured":"Bach JF: Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev\u200815:516\u2013542,1994","DOI":"10.1210\/edrv-15-4-516"},{"key":"2022031208045122800_R32","doi-asserted-by":"crossref","unstructured":"Serreze DV, Leiter EH, Christianson GJ, Greiner D, Roopenian DC: Major histocompatibility complex class I\u2013deficient NOD-B2m\u2013null mice are diabetes and insulitis resistant. Diabetes\u200843:505\u2013509,1994","DOI":"10.2337\/diab.43.3.505"},{"key":"2022031208045122800_R33","doi-asserted-by":"crossref","unstructured":"Singh B, Rabinovitch A: Influence of microbial agents on the development and prevention of autoimmune diabetes. Autoimmunity\u200815:209\u2013213,1993","DOI":"10.3109\/08916939309019929"},{"key":"2022031208045122800_R34","doi-asserted-by":"crossref","unstructured":"Bowman MA, Leiter EH, Atkinson MA: Prevention of diabetes in the NOD mouse: implications for therapeutic intervention in human disease. Immunol Today\u200815:115\u2013120,1994","DOI":"10.1016\/0167-5699(94)90154-6"},{"key":"2022031208045122800_R35","doi-asserted-by":"crossref","unstructured":"Sumida T, Furukawa M, Sakamoto A, Namekawa T, Maeda T, Zijlstra M, Iwamoto I, Koike T, Yoshida S, Tomioka H, et al.: Prevention of insulitis and diabetes in beta 2-microglobulin-deficient non-obese diabetic mice. Int Immunol\u20086:1445\u20131449,1994","DOI":"10.1093\/intimm\/6.9.1445"},{"key":"2022031208045122800_R36","doi-asserted-by":"crossref","unstructured":"Wicker LS, Leiter EH, Todd JA, Renjilian RJ, Peterson E, Fischer PA, Podolin PL, Zijlstra M, Jaenisch R, Peterson LB: \u03b22-Microglobulin\u2013deficient NOD mice do not develop insulitis or diabetes. Diabetes\u200843:500\u2013504,1994","DOI":"10.2337\/diab.43.3.500"},{"key":"2022031208045122800_R37","doi-asserted-by":"crossref","unstructured":"Harlan DM, Barnett MA, Abe R, Pechhold K, Patterson NB, Gray GS, June CH: Very-low-dose streptozotocin induces diabetes in insulin promoter mB7\u20131 transgenic mice. Diabetes\u200844:816\u2013823,1995","DOI":"10.2337\/diab.44.7.816"},{"key":"2022031208045122800_R38","doi-asserted-by":"crossref","unstructured":"Saji M, Moriarty J, Ban T, Singer DS, Kohn LD: Major histocompatibility complex class I gene expression in rat thyroid cells is regulated by hormones, methimazole, and iodide as well as interferon. J Clin Endocrinol Metab\u200875:871\u2013878,1992","DOI":"10.1210\/jcem.75.3.1381373"},{"key":"2022031208045122800_R39","doi-asserted-by":"crossref","unstructured":"Ly A, Duc HT, Kalamarides M, Trojan LA, Pan Y, Shevelev A, Francois JC, Noel T, Kane A, Henin D, Anthony DD, Trojan J: Human glioma cells transformed by IGF-I triple helix technology show immune and apoptotic characteristics determining cell selection for gene therapy of glioblastoma. Mol Pathol\u200854:230\u2013239,2001","DOI":"10.1136\/mp.54.4.230"},{"key":"2022031208045122800_R40","doi-asserted-by":"crossref","unstructured":"Trojan J, Duc HT, Upegui-Gonzalez LC, Hor F, Guo Y, Anthony D, Ilan J: Presence of MHC-I and B-7 molecules in rat and human glioma cells expressing antisense IGF-I mRNA. Neurosci Lett\u2008212:9\u201312,1996","DOI":"10.1016\/0304-3940(96)12770-1"},{"key":"2022031208045122800_R41","doi-asserted-by":"crossref","unstructured":"Trojan J, Johnson TR, Rudin SD, Ilan J, Tykocinski ML: Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA. Science\u2008259:94\u201397,1993","DOI":"10.1126\/science.8418502"},{"key":"2022031208045122800_R42","doi-asserted-by":"crossref","unstructured":"Withers DJ, Burks DJ, Towery HH, Altamuro SL, Flint CL, White MF: Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet\u200823:32\u201340,1999","DOI":"10.1038\/12631"},{"key":"2022031208045122800_R43","doi-asserted-by":"crossref","unstructured":"Ayuso E, Chillon M, Agudo J, Haurigot V, Bosch A, Carretero A, Otaegui PJ, Bosch F: In vivo gene transfer to pancreatic beta cells by systemic delivery of adenoviral vectors. Human Gene Ther\u200815:805\u2013812,2004","DOI":"10.1089\/1043034041648426"},{"key":"2022031208045122800_R44","doi-asserted-by":"crossref","unstructured":"Wang Z, Zhu T, Rehman KK, Bertera S, Zhang J, Chen C, Papworth G, Watkins S, Trucco M, Robbins PD, Li J, Xiao X: Widespread and stable pancreatic gene transfer by adeno-associated virus vectors via different routes. Diabetes\u200855:875\u2013884,2006","DOI":"10.2337\/diabetes.55.04.06.db05-0927"},{"key":"2022031208045122800_R45","doi-asserted-by":"crossref","unstructured":"Ayuso E, Chillon M, Garcia F, Agudo J, Andaluz A, Carretero A, Monfar M, Moya M, Montane J, Otaegui PJ, Bosch F: In vivo gene transfer to healthy and diabetic canine pancreas. Mol Ther\u200813:747\u2013755,2006","DOI":"10.1016\/j.ymthe.2005.10.017"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/55\/12\/3246\/383732\/zdb01206003246.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/55\/12\/3246\/383732\/zdb01206003246.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:07:23Z","timestamp":1667405243000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/55\/12\/3246\/13243\/Expression-of-IGF-I-in-Pancreatic-Islets-Prevents"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,12,1]]},"references-count":45,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2006,12,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db06-0328","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,12,1]]}}}