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Perspective: Postnatal pancreatic beta cell growth
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Meier JJ, Bhushan A, Butler AE, et al. Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 2005; 48:2221-2228. This paper describes the persistence of β-cells in the pancreas of individuals with type 1 diabetes despite ongong auto-immunity and accelerated β-cell death, providing indirect evidence of ongoing new β-cell production.
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Meier JJ, Bhushan A, Butler AE, et al. Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 2005; 48:2221-2228. This paper describes the persistence of β-cells in the pancreas of individuals with type 1 diabetes despite ongong auto-immunity and accelerated β-cell death, providing indirect evidence of ongoing new β-cell production.
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3
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33745788583
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Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes
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This is a case report describing accelerated β-cell proliferation in the setting of new onset autoimmune diabetes in an elderly man, demonstrating that human β-cells may retain proliferative potential throughout adulthood
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Meier JJ, Lin JC, Butler AE, et al. Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia 2006; 49:1838-1844. This is a case report describing accelerated β-cell proliferation in the setting of new onset autoimmune diabetes in an elderly man, demonstrating that human β-cells may retain proliferative potential throughout adulthood.
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Diabetologia
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Meier, J.J.1
Lin, J.C.2
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•]) demonstrating that immune modulation with Freund's complete adjuvant and euglycemia achieved through islet transplantation resulted in recovery of endogenous insulin production in a minority of NOD mice. These studies demonstrated that immune modulation and euglycemia may provide a permissive environment for β-cell regeneration.
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•]) demonstrating that immune modulation with Freund's complete adjuvant and euglycemia achieved through islet transplantation resulted in recovery of endogenous insulin production in a minority of NOD mice. These studies demonstrated that immune modulation and euglycemia may provide a permissive environment for β-cell regeneration.
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33645223082
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Suri A, Calderon B, Esparza TJ, et al. Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells. Science 2006; 311:1778-1780. These studies demonstrated that immune modulation and euglycemia may provide a permissive environment for β-cell regeneration.
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Suri A, Calderon B, Esparza TJ, et al. Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells. Science 2006; 311:1778-1780. These studies demonstrated that immune modulation and euglycemia may provide a permissive environment for β-cell regeneration.
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Chong AS, Shen J, Tao J, et al. Reversal of diabetes in nonobese diabetic mice without spleen cell-derived beta cell regeneration. Science 2006; 311:1774-1775. These studies demonstrated that immune modulation and euglycemia may provide a permissive environment for β-cell regeneration.
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Chong AS, Shen J, Tao J, et al. Reversal of diabetes in nonobese diabetic mice without spleen cell-derived beta cell regeneration. Science 2006; 311:1774-1775. These studies demonstrated that immune modulation and euglycemia may provide a permissive environment for β-cell regeneration.
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24944591025
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New sources of pancreatic beta-cells
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Bonner-Weir S, Weir GC. New sources of pancreatic beta-cells. Nat Biotechnol 2005; 23:857-861.
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Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation
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Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 2004; 429:41-46.
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Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass
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Georgia S, Bhushan A. Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J Clin Invest 2004; 114:963-968.
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Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth
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Kushner JA, Ciemerych MA, Sicinska E, et al. Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. Mol Cell Biol 2005; 25:3752-3762.
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Kushner, J.A.1
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Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia
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Rane SG, Dubus P, Mettus RV, et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 1999; 22:44-52.
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Cozar-Castellano I, Weinstock M, Haught M, et al. Evaluation of beta-cell replication in mice transgenic for hepatocyte growth factor and placental lactogen: comprehensive characterization of the G1/S regulatory proteins reveals unique involvement of p21cip. Diabetes 2006; 55:70-77. This study demonstrated β-cell p21 upregulation in the setting of trophic stimulation and enhanced β-cell response to mitogenic stimulation in the absence of p21, suggesting that CKI upregulation may be an inherent brake on proliferation.
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Cozar-Castellano I, Weinstock M, Haught M, et al. Evaluation of beta-cell replication in mice transgenic for hepatocyte growth factor and placental lactogen: comprehensive characterization of the G1/S regulatory proteins reveals unique involvement of p21cip. Diabetes 2006; 55:70-77. This study demonstrated β-cell p21 upregulation in the setting of trophic stimulation and enhanced β-cell response to mitogenic stimulation in the absence of p21, suggesting that CKI upregulation may be an inherent brake on proliferation.
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Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice
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Uchida T, Nakamura T, Hashimoto N, et al. Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. Nat Med 2005; 11:175-182.
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Uchida, T.1
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33646351055
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Hashimoto N, Kido Y, Uchida T, et al. Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass. Nat Genet 2006; 38:589-593. This study demonstrated postnatal β-cell failure resulting from PDK-1 deletion. Beta-cell failure was associated with diminished signaling downstream of PDK-1 and largely reversed by FOXO-1 haplo-insufficiency. These findings suggest a critical role for PDK-1 in the β-cell and that FOXO-1 mediates β-cell failure in this setting.
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Hashimoto N, Kido Y, Uchida T, et al. Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass. Nat Genet 2006; 38:589-593. This study demonstrated postnatal β-cell failure resulting from PDK-1 deletion. Beta-cell failure was associated with diminished signaling downstream of PDK-1 and largely reversed by FOXO-1 haplo-insufficiency. These findings suggest a critical role for PDK-1 in the β-cell and that FOXO-1 mediates β-cell failure in this setting.
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Fatrai S, Elghazi L, Balcazar N, et al. Akt induces beta-cell proliferation by regulating cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity. Diabetes 2006; 55:318-325. This study demonstrated downstream events in the setting of constitutive β-cell AKT activation including GSK-3β and FOXO-1 phosphorylation, increased D-cyclin expression and increased CDK-4 activity. Further, p21 expression was increased, supporting its role as a molecular brake on proliferation.
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Fatrai S, Elghazi L, Balcazar N, et al. Akt induces beta-cell proliferation by regulating cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity. Diabetes 2006; 55:318-325. This study demonstrated downstream events in the setting of constitutive β-cell AKT activation including GSK-3β and FOXO-1 phosphorylation, increased D-cyclin expression and increased CDK-4 activity. Further, p21 expression was increased, supporting its role as a molecular brake on proliferation.
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26844548626
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Karnik SK, Hughes CM, Gu X, et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci U S A 2005; 102:14659-14664. MEN1 haplo-insufficiency results in increased β-cell proliferation in association with decreased expression of the CKIs, p18 and p27, associated with decreased menin-mediated methylation of critical promoter elements. This study demonstrated a role for menin in the regulation of β-cell proliferation, and suggested an underlying epigenetic mechanism.
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Karnik SK, Hughes CM, Gu X, et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci U S A 2005; 102:14659-14664. MEN1 haplo-insufficiency results in increased β-cell proliferation in association with decreased expression of the CKIs, p18 and p27, associated with decreased menin-mediated methylation of critical promoter elements. This study demonstrated a role for menin in the regulation of β-cell proliferation, and suggested an underlying epigenetic mechanism.
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33745238921
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Schnepp RW, Chen YX, Wang H, et al. Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells. Cancer Res 2006; 66:5707-5715. This study demonstrated that conditional MEN1 deletion acutely increases islet cell proliferation in association with p18 and p27 loss, indicating its role in islet cell cycle regulation.
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Schnepp RW, Chen YX, Wang H, et al. Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells. Cancer Res 2006; 66:5707-5715. This study demonstrated that conditional MEN1 deletion acutely increases islet cell proliferation in association with p18 and p27 loss, indicating its role in islet cell cycle regulation.
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Park S, Dong X, Fisher TL, et al. Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function. J Biol Chem 2006; 281:1159-1168. This study demonstrated that exendin-4 treatment increases IRS-2 expression and signaling downstream of IRS-2 in rodent and human β-cells and that exendin-4 does not preserve β-cell mass in IRS-2 null mice, suggesting that the trophic actions of exendin-4 are IRS-2 dependent.
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Park S, Dong X, Fisher TL, et al. Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function. J Biol Chem 2006; 281:1159-1168. This study demonstrated that exendin-4 treatment increases IRS-2 expression and signaling downstream of IRS-2 in rodent and human β-cells and that exendin-4 does not preserve β-cell mass in IRS-2 null mice, suggesting that the trophic actions of exendin-4 are IRS-2 dependent.
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The development of beta-cell mass: Recent progress and potential role of GLP-1
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Stoffers DA. The development of beta-cell mass: recent progress and potential role of GLP-1. Horm Metab Res 2004; 36 (11-12):811-821.
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Emerging role of protein kinase B/Akt signaling in pancreatic beta-cell mass and function
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Elghazi L, Balcazar N, Bernal-Mizrachi E. Emerging role of protein kinase B/Akt signaling in pancreatic beta-cell mass and function. Int J Biochem Cell Biol 2006; 38:157-163.
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Ueki K, Okada T, Hu J, et al. Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes. Nat Genet 2006; 38:583-588. This study demonstrated postnatal β-cell failure and diabetes in mice with combined selective β-cell deletion of both the insulin and insulin-like growth factor-1 receptors, confirming the importance of their shared signaling pathway in the β-cell.
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Ueki K, Okada T, Hu J, et al. Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes. Nat Genet 2006; 38:583-588. This study demonstrated postnatal β-cell failure and diabetes in mice with combined selective β-cell deletion of both the insulin and insulin-like growth factor-1 receptors, confirming the importance of their shared signaling pathway in the β-cell.
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Lingohr MK, Briaud I, Dickson LM, et al. Specific regulation of IRS-2 expression by glucose in rat primary pancreatic islet beta-cells. J Biol Chem 2006; 281:15884-15892. This study demonstrated that glucose regulates IRS-2 expression at the transcriptional level in a calcium dependent process. This suggests that changes in IRS-2 expression may be important for β-cell adaptation to metabolic cues.
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Kushner JA, Simpson L, Wartschow LM, et al. Phosphatase and tensin homolog regulation of islet growth and glucose homeostasis. J Biol Chem 2005; 280:39388-39393. This study demonstrated the suppressive role of Pten downstream of IRS-2 in β-cells by showing that Pten haplo-insufficiency preserves islet growth and functionin IRS-2 null mice and promotes signaling in the insulin receptor/insulin-like growth factor receptor pathway.
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Selective deletion of Pten in pancreatic beta cells leads to increased islet mass and resistance to STZ-induced diabetes
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Stiles BL, Kuralwalla-Martinez C, Guo W, et al. Selective deletion of Pten in pancreatic beta cells leads to increased islet mass and resistance to STZ-induced diabetes. Mol Cell Biol 2006; 26:2772-2781. This study demonstrated that β-cell specific Pten deletion resulted in decreased β-cell death and increased proliferation, indicating a suppressive role for Pten in β-cell growth and viability.
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Buteau J, Spatz ML, Accili D. Transcription factor FOXO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass. Diabetes 2006; 55:1190-1196. Using in-vitro and murine models, this study demonstrated that GLP-1 stimulation increases FOXO-1 phosphorylation/inactivation, and that constitutively active FOXO-1 blocks the beneficial effects of exendin-4 on β-cell growth and viability.
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Buteau J, Spatz ML, Accili D. Transcription factor FOXO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass. Diabetes 2006; 55:1190-1196. Using in-vitro and murine models, this study demonstrated that GLP-1 stimulation increases FOXO-1 phosphorylation/inactivation, and that constitutively active FOXO-1 blocks the beneficial effects of exendin-4 on β-cell growth and viability.
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