AIMS/HYPOTHESIS: Recovery from diabetes requires restoration of beta cell mass. Igf1 expression in beta cells of transgenic mice regenerates the endocrine pancreas during type 1 diabetes. However, the IGF-I-mediated mechanism(s) restoring beta cell mass are not fully understood. Here, we examined the contribution of pre-existing beta cell proliferation and transdifferentiation of progenitor cells from bone marrow in IGF-I-induced islet regeneration. METHODS: Streptozotocin (STZ)-treated Igf1-expressing transgenic mice transplanted with green fluorescent protein (GFP)-expressing bone marrow cells were used. Bone marrow cell transdifferentiation and beta cell replication were measured by GFP/insulin and by the antigen identified by monoclonal antibody Ki67/insulin immunostaining of pancreatic sections respectively. Key cell cycle proteins were measured by western blot, quantitative RT-PCR and immunohistochemistry. RESULTS: Despite elevated IGF-I production, recruitment and differentiation of bone marrow cells to beta cells was not increased either in healthy or STZ-treated transgenic mice. In contrast, after STZ treatment, IGF-I overproduction decreased beta cell apoptosis and increased beta cell replication by modulating key cell cycle proteins. Decreased nuclear levels of cyclin-dependent kinase inhibitor 1B (p27) and increased nuclear localisation of cyclin-dependent kinase (CDK)-4 were consistent with increased beta cell proliferation. However, islet expression of cyclin D1 increased only after STZ treatment. In contrast, higher levels of cyclin-dependent kinase inhibitor 1A (p21) were detected in islets from non-STZ-treated transgenic mice. CONCLUSIONS/ INTERPRETATION: These findings indicate that IGF-I modulates cell cycle proteins and increases replication of pre-existing beta cells after damage. Therefore, our study suggests that local production of IGF-I may be a safe approach to regenerate endocrine pancreas to reverse diabetes.
AIMS/HYPOTHESIS: Recovery from diabetes requires restoration of beta cell mass. Igf1 expression in beta cells of transgenic mice regenerates the endocrine pancreas during type 1 diabetes. However, the IGF-I-mediated mechanism(s) restoring beta cell mass are not fully understood. Here, we examined the contribution of pre-existing beta cell proliferation and transdifferentiation of progenitor cells from bone marrow in IGF-I-induced islet regeneration. METHODS:Streptozotocin (STZ)-treated Igf1-expressing transgenic mice transplanted with green fluorescent protein (GFP)-expressing bone marrow cells were used. Bone marrow cell transdifferentiation and beta cell replication were measured by GFP/insulin and by the antigen identified by monoclonal antibody Ki67/insulin immunostaining of pancreatic sections respectively. Key cell cycle proteins were measured by western blot, quantitative RT-PCR and immunohistochemistry. RESULTS: Despite elevated IGF-I production, recruitment and differentiation of bone marrow cells to beta cells was not increased either in healthy or STZ-treated transgenic mice. In contrast, after STZ treatment, IGF-I overproduction decreased beta cell apoptosis and increased beta cell replication by modulating key cell cycle proteins. Decreased nuclear levels of cyclin-dependent kinase inhibitor 1B (p27) and increased nuclear localisation of cyclin-dependent kinase (CDK)-4 were consistent with increased beta cell proliferation. However, islet expression of cyclin D1 increased only after STZ treatment. In contrast, higher levels of cyclin-dependent kinase inhibitor 1A (p21) were detected in islets from non-STZ-treated transgenic mice. CONCLUSIONS/ INTERPRETATION: These findings indicate that IGF-I modulates cell cycle proteins and increases replication of pre-existing beta cells after damage. Therefore, our study suggests that local production of IGF-I may be a safe approach to regenerate endocrine pancreas to reverse diabetes.
Authors: Jake A Kushner; Maria A Ciemerych; Ewa Sicinska; Lynn M Wartschow; Monica Teta; Simon Y Long; Piotr Sicinski; Morris F White Journal: Mol Cell Biol Date: 2005-05 Impact factor: 4.272
Authors: R L Tuttle; N S Gill; W Pugh; J P Lee; B Koeberlein; E E Furth; K S Polonsky; A Naji; M J Birnbaum Journal: Nat Med Date: 2001-10 Impact factor: 53.440
Authors: Incheol Shin; F Michael Yakes; Federico Rojo; Nah-Young Shin; Andrei V Bakin; Jose Baselga; Carlos L Arteaga Journal: Nat Med Date: 2002-09-16 Impact factor: 53.440
Authors: Birgitte N Friedrichsen; Nicole Neubauer; Ying C Lee; Vivian K Gram; Niels Blume; Jacob S Petersen; Jens H Nielsen; Annette Møldrup Journal: J Endocrinol Date: 2006-03 Impact factor: 4.286
Authors: Randal May; Sripathi M Sureban; Stan A Lightfoot; Aimee B Hoskins; Daniel J Brackett; Russell G Postier; Rama Ramanujam; Chinthalapally V Rao; James H Wyche; Shrikant Anant; Courtney W Houchen Journal: Am J Physiol Gastrointest Liver Physiol Date: 2010-06-03 Impact factor: 4.052
Authors: John L Fowlkes; Jeffry S Nyman; R Clay Bunn; Chanhee Jo; Elizabeth C Wahl; Lichu Liu; Gael E Cockrell; Lindsey M Morris; Charles K Lumpkin; Kathryn M Thrailkill Journal: Bone Date: 2013-07-23 Impact factor: 4.398
Authors: K A Hlavaty; R F Gibly; X Zhang; C B Rives; J G Graham; W L Lowe; X Luo; L D Shea Journal: Am J Transplant Date: 2014-06-06 Impact factor: 8.086