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New Insights into the Roles of Insulin/IGF-I in the Development and Maintenance of β-Cell Mass

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Abbreviations

IRS:

insulin receptor substrates

IGF-I:

insulin-like-growth factor

PI 3-kinase:

Phosphatidyl inositol 3-kinase

References

  1. Cheatham B, Kahn CR. Insulin action and the insulin signaling network. Endocr Rev 1995;16:117–142.

    Article  PubMed  Google Scholar 

  2. Blakesley VA, Butler AA, Koval AP, Okubo Y, LeRoith D. The IGF System. Humana, New Jersey 1999;143–164.

  3. De Meyts P, Wallach B, Christoffersen CT, Urso B, Gronskov K, Latus LJ, Yakushiji F, Ilondo MM, Shymko RM. The insulin-like growth factor-I receptor. Structure, ligand-binding mechanism and signal transduction. Horm Res 1994.;42:152–169.

    PubMed  Google Scholar 

  4. Kahn CR. Diabetogenes and the cause of type II diabetes (Banting Lecture). Diabetes 1994;1066–1084.

  5. DeFronzo RA. Lilly Lecture 1987. The triumvirate: β-cell, muscle, liver: A collusion responsible for NIDDM. Diabetes 1988;37:667–687.

    PubMed  Google Scholar 

  6. White MF. IRS proteins and the common path to Diabetes. Am J Physiol Endocrinol Metab 2002;283:E413–E422.

    PubMed  Google Scholar 

  7. Virkamaki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 1999;103:931–943.

    PubMed  Google Scholar 

  8. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001;414:799–806.

    PubMed  Google Scholar 

  9. White MF, Yenush L. The IRS-signaling system: A network of docking proteins that mediate insulin and cytokine action. Curr Top Microbiol Immunol 1998;228:179–208.

    PubMed  Google Scholar 

  10. Kulkarni RN. Receptors for insulin and insulin-like growth factor-1 and insulin receptor substrate-1 mediate pathways that regulate islet function. Biochem Soc Trans 2002;30:317–322.

    Article  PubMed  Google Scholar 

  11. Leibowitz G, Oprescu AI, Uckaya G, Gross DJ, Cerasi E, Kaiser N. Insulin does not mediate glucose stimulation of proinsulin biosynthesis. Diabetes 2002;52:998–1003.

    Google Scholar 

  12. Wicksteed B, Alarcon C, Briaud I, Lingohr MK, Rhodes CJ. Glucose-induced translational control of proinsulin biosynthesis is proportional to preproinsulin mRNA levels in islet beta-cells but not regulated via a positive feedback of secreted insulin. J Biol Chem 2003;278:42080–42090.

    Article  PubMed  Google Scholar 

  13. Irminger JC, Vollenweider FM, Neerman-Arbez M, Halban PA. Human proinsulin conversion in the regulated and the constitutive pathways of transfected AtT20 cells. J Biol Chem 1994;269:1756–1762.

    PubMed  Google Scholar 

  14. Halban PA. Proinsulin processing in the regulated and the constitutive secretory pathway. Diabetologia 37 Suppl 1994;2:S65–S72.

    Article  Google Scholar 

  15. Pictet R, Rutter WJ. Development of the embryonic endocrine pancreas. In: Steiner, D.F. and Freinkel, M, eds. Handbook of Physiology. American Physiological Society, Washington, D.C. 1972;25–66.

    Google Scholar 

  16. Herrera PL. Defining the cell lineages of the islets of Langerhans using transgenic mice. Int J Dev Biol 2002;46:97–103.

    PubMed  Google Scholar 

  17. Murtaugh LC, Melton DA. Genes, signals, and lineages in pancreas development. Annu Rev Cell Dev Biol 2003;19:71–89.

    Article  PubMed  Google Scholar 

  18. Sander M, German MS. The beta cell transcription factors and development of the pancreas. J Mol Med 1997;75:327–340.

    Article  PubMed  Google Scholar 

  19. Habener JF, Kemp DM, Thomas MK. Minireview: Transcriptional regulation in pancreatic development. Endocrinology 2005;146:1025–1034.

    Article  PubMed  Google Scholar 

  20. Gu G, Dubauskaite J, Melton DA. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 2002;129:2447–2457.

    PubMed  Google Scholar 

  21. Fowden AL, Hill DJ. Intra-uterine programming of the endocrine pancreas. Brit Med Bull 2001;123–142.

  22. Dupont J, Holzenberger M. Biology of insulin-like growth factors in development. Birth Defects Res C Embryo Today 2003;69:257–271.

    Article  PubMed  Google Scholar 

  23. Hill DJ, Milner RD. Insulin as a growth factor. Pediatr Res 1985;19:879–886.

    PubMed  Google Scholar 

  24. Milner RDG, Hill DJ. Fetal growth control: The role of insulin and related peptides. Clin Endocrinol 1984;21:415–433.

    Google Scholar 

  25. Hogg J, Han VKM, Clemmons DR, Hill DJ. Interactions of glucose, insulin-like growth factors (IGFs) and IGF binding proteins in the regulation of DNA synthesis by isolated fetal rat islets of langerhans. J Endocrinol 1993;401–412.

  26. Fehmann HC, Jehle P, Goke B. IGF-I and IGF-II: Expression and function in the endocrine pancreas. Exp Clin Endocrinol Diabetes 103 Suppl 1995;2:37–41.

    Google Scholar 

  27. Hill DJ, Hogg J. Growth factor control of pancreatic B cell hyperplasia. Baillieres Clin Endocrinol Metab 1991;5:689–698.

    PubMed  Google Scholar 

  28. Hill DJ, Petrik J, Arany E. Growth factors and the regulation of fetal growth. Diabetes Care Suppl 1998;2:B60–B69.

    Google Scholar 

  29. Orban PC, Chui D, Marth JD. Tissue- and site-specific DNA recombination in transgenic mice. Proc Natl Acad Sci USA 1992;89:6861–6865.

    PubMed  Google Scholar 

  30. Ryding AD, Sharp MG, Mullins JJ. Conditional transgenic technologies. J Endocrinol 2001;171:1–14.

    Article  PubMed  Google Scholar 

  31. Duvillie B, Currie C, Chrones T, Bucchini D, Jami J, Joshi RL, Hill DJ. Increased islet cell proliferation, decreased apoptosis, and greater vascularization leading to beta-cell hyperplasia in mutant mice lacking insulin. Endocrinology 2002;143:1530–1537.

    Article  PubMed  Google Scholar 

  32. Duvillie B, Cordonnier N, Deltour L, Dandoy-Dron F, Itier JM, Monthioux E, Jami J, Joshi RL, Bucchini D. Phenotypic alterations in insulin-deficient mutant mice. Proc Natl Acad Sci USA 1997;94:5137–5140.

    Article  PubMed  Google Scholar 

  33. Lammert E, Cleaver O, Melton D. Induction of pancreatic differentiation by siganls from blood vessels. Science 2001;1–10.

  34. Lammert E, Cleaver O, Melton D. Role of endothelial cells in early pancreas and liver development. Mech Dev 2003;120:59–64.

    Article  PubMed  Google Scholar 

  35. Cleaver O, Melton DA. Endothelial signaling during development. Nat Med 2003;9:661–668.

    Article  PubMed  Google Scholar 

  36. Lu Y, Herrera PL, Guo Y, Sun D, Tang Z, LeRoith D, Liu JL. Pancreatic-specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes. Diabetes 2004;53:3131–3141.

    PubMed  Google Scholar 

  37. Petrik J, Pell JM, Arany E, McDonald TJ, Dean WL, Reik W, Hill DJ. Overexpression of insulin-like growth factor-II in transgenic mice is associated with pancreatic islet cell hyperplasia. Endocrinology 1999;140:2353–2363.

    Article  PubMed  Google Scholar 

  38. Devedjian JC, George M, Casellas A, Pujol A, Visa J, Pelegrin M, Gros L, Bosch F. Transgenic mice overexpressing insulin-like growth factor-II in beta cells develop type 2 diabetes. The Journal of Clinical Investigation 2000;105:731–740.

    PubMed  Google Scholar 

  39. Nakae J, Kido Y, Accili D. Distinct and overlapping functions of insulin and IGF-1 receptors. Endo Reviews 2001;22:818–835.

    Article  Google Scholar 

  40. Efstratiadis A. Genetics of mouse growth. Int J Dev Biol 1998;955–976.

  41. Liu JP, Baker J, Perkins JA, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (lgf-1) and type 1 IGF receptor (lgf1r). Cell 1993;75:59–72.

    Article  PubMed  Google Scholar 

  42. Powell-Braxton L, Hollingshead P, Warburton C, Dowd M, Pitts-Meek S, Calton C, Gillet N, Stewart TA. IGF-I is required for normal embryonic growth in mice. Genes & Development 1993;7:2609–2617.

    Google Scholar 

  43. Woods KA, Camacho-Hubner C, Savage MO, Clark AJL. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 1996;335:1363–1367.

    Article  PubMed  Google Scholar 

  44. Accili D, Drago J, Lee EJ, Johnson MD, Cool MH, Salvatore P, Asico LD, Jose PA, Taylor SI, Westphal H. Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat Genet 1996;12:106–109.

    Article  PubMed  Google Scholar 

  45. Joshi RL, Lamothe B, Cordonnier N, Mesbah K, Monthioux E, Jami J, Bucchini C. Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality. EMBO J 1996;15:1542–1547.

    PubMed  Google Scholar 

  46. Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner-Weir S, White MF. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998;391(6670):900–904.

    Article  PubMed  Google Scholar 

  47. Kido Y, Nakae J, Xuan S, Efstratiadis A, Accili D. Beta Cell Development in Mice Lacking Insulin and Type I IGF Receptors. Diabetes 2000;49 (Suppl 1)

  48. Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic β cells creates an insulin secretory defect similar to that in Type 2 diabetes. Cell 1999;96:329–339.

    Article  PubMed  Google Scholar 

  49. Kulkarni RN, Holzenberger M, Shih DQ, Ozcan U, Stoffel M, Magnuson MA, Kahn CR. beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat Genet 2002;31:111–115.

    PubMed  Google Scholar 

  50. Xuan S, Kitamura T, Nakae J, Politi K, Kido Y, Fisher PE, Morroni M, Cinti S, White MF, Herrera PL, et al. Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor. J Clin Invest 2002;110:1011–1019.

    Article  PubMed  Google Scholar 

  51. Otani K, Kulkarni RN, Baldwin AC, Krutzfeldt J, Ueki K, Stoffel M, Kahn CR, Polonsky KS. Reduced beta-cell mass and altered glucose sensing impair insulin-secretory function in betaIRKO mice. Am J Physiol Endocrinol Metab 2004;286:E41–E49.

    Article  PubMed  Google Scholar 

  52. Kulkarni RN, Kahn CR. Genetic models of insulin resistance: Alterations in β-cell biology. In: Molecular Basis of Pancreas Development and Function. Habener, J.F. and Hussain, M., eds. Kluwer Academic Publishers, New York City. 2001;299–323.

    Google Scholar 

  53. Elders MJ, Schedewie HK, Olefsky J, Givens B, Char F, Bier DM, Baldwin D, Fiser RH, Seyedabadi S, Rubenstein A. Endocrine-metabolic relationships in patients with leprechaunism. J Natl Med Assoc 1982;74:1195–1210.

    PubMed  Google Scholar 

  54. Taylor SI. Lilly Lecture: Molecular mechanisms of insulin resistance-Lessons from patients with mutations in the insulin receptor gene. Diabetes 1992;41:1473–1490.

    PubMed  Google Scholar 

  55. Araki E, Lipes MA, Patti ME, Brüning JC, Haag BL, III, Johnson RS, Kahn CR. Alternative pathway of insulin signaling in mice with targeted disruption of the IRS-1 gene. Nature 1994;372:186–190.

    Article  PubMed  Google Scholar 

  56. Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S, et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 1994;372:182–186.

    Google Scholar 

  57. Kulkarni RN, Winnay JN, Daniels M, Bruning JC, Flier SN, Hanahan D, Kahn CR. Altered function of insulin receptor substrate-1-deficient mouse islets and cultured beta-cell lines. J Clin Invest 1999;104:R69–R75.

    PubMed  Google Scholar 

  58. Kubota N, Tobe K, Terauchi Y, Eto K, Yamauchi T, Suzuki R, Tsubamoto Y, Komeda K, Nakano R, Miki H, et al. Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory β-cell hyperplasia. Diabetes 2000;49:1880–1889.

    PubMed  Google Scholar 

  59. Aspinwall CA, Qian WJ, Roper MG, Kulkarni RN, Kahn CR, Kennedy RT. Roles of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release of intracellular Ca2+ stores in insulin-stimulated insulin secretion in beta-cells. J Biol Chem 2000;275:22331–22338.

    Article  PubMed  Google Scholar 

  60. Kulkarni RN, Roper M, Dahlgren GM, et. al. Insulin secretory defect in IRS-1 null mice is linked with reduced calcium signaling and altered expression of SERCA-2b and-3. Diabetes 2004;53:1517–1525.

    PubMed  Google Scholar 

  61. Hennige AM, Ozcan U, Okada T, Jhala US, Schubert M, White MF, Kulkarni RN. Alterations in growth and apoptosis of insulin receptor substrate-1 deficient beta-cells. Am J Physiol Endocrinol Metab. In press, 2005.

  62. Lin X, Taguchi A, Park S, Kushner JA, Li F, Li Y, White MF. Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes. J Clin Invest 2004;114:908–916.

    Article  PubMed  Google Scholar 

  63. Kubota N, Terauchi Y, Tobe K, Yano W, Suzuki R, Ueki K, Takamoto I, Satoh H, Maki T, Kubota T, et al. Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus. J Clin Invest 2004;114:917–927.

    Article  PubMed  Google Scholar 

  64. Choudhury AI, et. al. The role of insulin receptor substrate 2 in hypothalamic and beta-cell function. Journal of Clinical Investigation. In press, 2005.

  65. Burks DJ, de Mora JF, Schubert M, Withers DJ, Myers MG, Towery HH, Altamuro SL, Flint CL, White MF. IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 2000;407:377–382.

    Article  PubMed  Google Scholar 

  66. Liu SC, Wang Q, Lienhard GE, Keller SR. Insulin receptor substrate 3 is not essential for growth or glucose homeostasis. J Biol Chem 1999;274:18093–18099.

    Article  PubMed  Google Scholar 

  67. Fantin VR, Wang GE, Lienhard GE, Keller SR. Mice lacking insulin receptor substrate 4 exhibit mild defects in growth, reproduction, and glucose homostasis. Am J Physiol 2000;278:E127–133.

    PubMed  Google Scholar 

  68. Ueki K, Yballe CM, Brachmann SM, Vicent D, Watt JM, Kahn CR, Cantley LC. Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 2002;99:419–424.

    Article  PubMed  Google Scholar 

  69. Terauchi Y, Tsuji T, Satoh S, Minoura H, Murakami K, Okuno A, Inukai K, Asano T, Kaburagi Y, Ueki K, et al. Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nat Genet 1999;21:230–235.

    Article  PubMed  Google Scholar 

  70. Mauvais-Jarvis F, Ueki K, Fruman DA, Hirshman MF, Sakamoto K, Goodyear LJ, Iannacone M, Accili D, Cantley LC, Kahn CR. Reduced expression of the murine p85a subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J Clin Invest 2002;109:141–149.

    Article  PubMed  Google Scholar 

  71. Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EBI, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBb). Science 2001;292:1728–1731.

    Article  PubMed  Google Scholar 

  72. Pende M, Kozma SC, Jaquet M, Oorschot V, Burcelin R, Marchand-Brustel Y, Klumperman J, Thorens B, Thomas G. Hypoinsulinaemia,glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature 2000;408:994–997.

    Google Scholar 

  73. Bonner-Weir S, Smith FE. Islet cell growth and the growth factors involved. TEM 1994;5:60–64.

    Google Scholar 

  74. Bonner-Weir S. Regulation of pancreatic β-cell mass in vivo. Recent Prog Horm Res 1994;49:91–104.

    PubMed  Google Scholar 

  75. Vasavada RC, Garcia-Ocana A, Zawalich WS, Sorenson RL, Dann P, Syed M, Ogren L, Talamantes F, Stewart AF. Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation, and hypoglycemia. J Biol Chem 2000;275:15399–15406.

    Article  PubMed  Google Scholar 

  76. Vasavada RC, Cavaliere C, D’Ercole AJ, Dann P, Burtis WJ, Madlener AL, Zawalich K, Zawalich W, Philbrick W, Stewart AF. Overexpression of parathyroid hormone-related protein in the pancreatic islets of transgenic mice causes islet hyperplasia, hyperinsulinemia, and hypoglycemia. J Biol Chem 1996;271:1200–1208.

    Article  PubMed  Google Scholar 

  77. Garcia-Ocana A, Takane KK, Syed MA, Philbrick WM, Vasavada RC, Stewart AF. Hepatocyte growth factor overexpression in the islet of transgenic mice increases beta cell proliferation, enhances islet mass, and induces mild hypoglycemia. J Biol Chem 2000;275:1226–1232.

    Article  PubMed  Google Scholar 

  78. Bonner-Weir S, Taneja M, Weir GC, Tatarkiewiez K, Song K, Sharma A, O’Neil JJ. In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 2000;97:7999–8004.

    Article  PubMed  Google Scholar 

  79. Suarez-Pinzon WL, Lakey JR, Brand SJ, Rabinovitch A. Combination Therapy with Epidermal Growth Factor and Gastrin Induces Neogenesis of Human Islet beta-Cells from Pancreatic Duct Cells and an Increase in Functional beta-Cell Mass*. J Clin Endocrinol Metab 2005.

  80. Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH, Yoo SJ, Kang MI, Cha BY, Lee KW, et al. Selective beta-Cell Loss and alpha-Cell Expansion in Patients with Type 2 Diabetes Mellitus in Korea. J Clin Endocrinol Metab 2003;88:2300–2308.

    Article  PubMed  Google Scholar 

  81. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–110.

    PubMed  Google Scholar 

  82. 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.

    Google Scholar 

  83. Gershengorn MC, Hardikar AA, Wei C, Geras-Raaka E, Marcus-Samuels B, Raaka BM. Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells. Science 2004;306:2261–2264.

    Google Scholar 

  84. Lechner A, Nolan AL, Blacken RA, Habener JF. Redifferentiation of insulin-secreting cells after in vitro expansion of adult human pancreatic islet tissue. Biochem Biophys Res Commun 2005;327:581–588.

    Article  PubMed  Google Scholar 

  85. Georgia S, Bhushan A. Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J Clin Invest 2004;114:963–968.

    Article  PubMed  Google Scholar 

  86. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003;15:740–746.

    Article  PubMed  Google Scholar 

  87. Potter E, Bergwitz C, Brabant G. The cadherin-catenin system: Implications for growth and differentiation of endocrine tissues. Endocr Rev 1999;20:207–239.

    Article  PubMed  Google Scholar 

  88. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002;2:442–454.

    Article  PubMed  Google Scholar 

  89. Savagner P. Leaving the neighborhood: Molecular mechanisms involved during epithelial-mesenchymal transition. Bio Essays 2001;23:912–923.

    Google Scholar 

  90. Morali OG, Delmas V, Moore R, Jeanney C, Thiery JP, Larue L. IGF-II induces rapid beta-catenin relocation to the nucleus during epithelium to mesenchyme transition. Oncogene 2001;20:4942–4950.

    Article  PubMed  Google Scholar 

  91. Kang Y, Massague J. Epithelial-mesenchymal transitions: Twist in development and metastasis. Cell 2004;118:277–279.

    Article  PubMed  Google Scholar 

  92. El Bahrawy MA, Pignatelli M. E-cadherin and catenins: Molecules with versatile roles in normal and neoplastic epithelial cell biology. Microsc Res Tech 1998;43:224–232.

    Article  PubMed  Google Scholar 

  93. Dahl U, Sjodin A, Semb H. Cadherins regulate aggregation of pancreatic beta-cells in vivo. Development 1996;122:2895–2902.

    PubMed  Google Scholar 

  94. Kulkarni RN, Jhala US, Winnay JN, Krajewski S, Montminy M, Kahn CR. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest 2004;114:828–836.

    Article  PubMed  Google Scholar 

  95. Bonner-Weir S, Scaglia L, Montana E, Juang JH, Weir GC. β-cell reserve: Compensatory mechanisms of the β-cell. In Diabetes 1994. Baba S, Kaneko T, eds. Excerta Medica International Congress 1995;179–228.

  96. Accili D. A kinase in the life of the beta cell. J Clin Invest 2001;108:1575–1576.

    Article  PubMed  Google Scholar 

  97. Rabinovitch A, Quigley C, Russell T, Patel Y, Mintz DH. Insulin and multiplication stimulating activity (and insulin-like growth factor) stimulate islet beta-cell replication in neonatal rat pancreatic monolayer cultures. Diabetes 1982;160–164.

  98. McEvoy RC, Schmitt RV, Hegre OD. Syngeneic transplantation of fetal rat pancreas. I. Effect of insulin treatment of the reversal of alloxan diabetes. Diabetes 1978;27:982–987.

    PubMed  Google Scholar 

  99. Movassat J, Saulnier C, Portha B. Insulin administration enhances growth of the beta-cell mass in streptozotocin-treated newborn rats. Diabetes 1997;46:1445–1452.

    PubMed  Google Scholar 

  100. Ohsugi M, Cras-Meneur C, Zhou Y, Bernal-Mizrachi E, Johnson JD, Luciani DS, Polonsky KS, Permutt MA. Reduced expression of the insulin receptor in mouse insulinoma (MIN6) cells reveals multiple roles of insulin signaling in gene expression, proliferation, insulin content, and secretion. J Biol Chem 2005;280:4992–5003.

    Article  PubMed  Google Scholar 

  101. Bonner-Weir S, Deery D, Leahy JL, Weir GC. Compensatory growth of pancreatic β-cells in adult rats after short-term glucose infusion. Diabetes 1989;38:49–53.

    PubMed  Google Scholar 

  102. Stoffers DA. The development of beta-cell mass: Recent progress and potential role of GLP-1. Horm Metab Res 2004;36:811–821.

    Article  PubMed  Google Scholar 

  103. Song KH, Ko SH, Ahn YB, Yoo SJ, Chin HM, Kaneto H, Yoon KH, Cha BY, Lee KW, Son HY. In vitro transdifferentiation of adult pancreatic acinar cells into insulin-expressing cells. Biochem Biophys Res Commun 2004;316:1094–1100.

    Article  PubMed  Google Scholar 

  104. Paris M, Tourrel-Cuzin C, Plachot C, Ktorza A. Review: Pancreatic beta-cell neogenesis revisited. Exp Diabesity Res 2004;5:111–121.

    Article  PubMed  Google Scholar 

  105. Ferber S, Halkin A, Cohen H, Ber I, Einav Y, Goldberg I, Barshack I, Seijffers R, Kopolovic J, Kaiser N, et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nature Medicine 2000;6:568–572.

    Article  PubMed  Google Scholar 

  106. Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, Maeda M, Chan L. NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med 2003;9:596–603.

    Article  PubMed  Google Scholar 

  107. Duncan SA, Navas MA, Dufort D, Rossant J, Stoffel M. Regulation of a transcription factor network required for differentiation and metabolism. Science 1998;281:692–695.

    Article  PubMed  Google Scholar 

  108. Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, Volkert TL, Schreiber J, Rolfe PA, Gifford DK, et al. Control of pancreas and liver gene expression by HNF transcription factors. Science 2004;303:1378–1381.

    Google Scholar 

  109. Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM, Shelton KD, Lindner J, Cherrington AD, Magnuson MA. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatc b cell-specific gene knock-outs using Cre recombinase. J Biol Chem 1999;274:305–315.

    Article  PubMed  Google Scholar 

  110. Scharf JG, Ramadori G, Braulke T, Hartmann H. Cellular localization and hormonal regulation of biosynthesis of insulin-like growth factor binding proteins and of the acid-labile subunit within rat liver. Prog Growth Factor Res 1995;6:175–180.

    Article  PubMed  Google Scholar 

  111. Funakoshi H, Nakamura T. Hepatocyte growth factor: From diagnosis to clinical applications. Clin Chim.Acta 2003;327:1–23.

    Article  PubMed  Google Scholar 

  112. Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 2000;6:87–97.

    Article  PubMed  Google Scholar 

  113. Wolfrum C, Besser D, Luca E, Stoffel M. Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization. Proc Natl Acad Sci USA 2003;100:11624–11629.

    Article  PubMed  Google Scholar 

  114. Kulkarni RN, Kahn CR. Molecular biology. HNFs–linking the liver and pancreatic islets in diabetes. Science 2004;303:1311–1312.

    Article  PubMed  Google Scholar 

  115. Kaneko K, Shirotani T, Araki E, Matsumoto K, Taguchi T, Motoshima H, Yoshizato K, Kishikawa H, Shichiri M. Insulin inhibits glucagon secretion by the activation of PI3-kinase in In-R1-G9 cells. Diabetes Res Clin Pract 1999;44:83–92.

    Article  PubMed  Google Scholar 

  116. Van Schravendijk CF, Foriers A, Van den Brande JL, Pipeleers DG. Evidence for the presence of type I insulin-like growth factor receptors on rat pancreatic A and B cells. Endocrinology 1987;121:1784–1788.

    PubMed  Google Scholar 

  117. Unger RH. Glucagon physiology and pathophysiology in the light of new advances. Diabetologia 1985;28:574–578.

    Article  PubMed  Google Scholar 

  118. Harvel PJ, Taborsky GJ, The contribution of the autonomic nervous system to changes of glucagon and insulin secretion durning hypoglycemic stress. Endocr Rev 1989;10:332–350 (Abstr.

    Google Scholar 

  119. Cryer PE Banting Lecture. Hypoglycemia: The limiting factor in the management of IDDM. Diabetes 1994;43:1378–1389.

  120. Sloop KW, Cao JX, Siesky AM, Zhang HY, Bodenmiller DM, Cox AL, Jacobs SJ, Moyers JS, Owens RA, Showalter AD, et al. Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors. J Clin Invest 2004;113:1571–1581.

    Article  PubMed  Google Scholar 

  121. Duvillie B, Cordonnier N, Deltour L, Dandoy-Dron F, Itier JM, Monthioux E, Jami J, Joshi RL, Bucchini D. Phenotypic alterations in insulin-deficient mutant mice. Proc Natl Acad Sci USA 1997;94:5137–5140.

    Article  PubMed  Google Scholar 

  122. Accili D, Drago J, Lee EJ, Johnson MD, Cool MH, Salvatore P, Asico LD, Jose PA, Taylor SI, Westphal H. Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat Genet 1996;12:106–109.

    Article  PubMed  Google Scholar 

  123. Joshi RL, Lamothe B, Cordonnier N, Mesbah K, Monthioux E, Jami J, Bucchini D. Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality. EMBO J 1996;15:1542–1547.

    PubMed  Google Scholar 

  124. Liu JL, Yakar S, LeRoith D. Mice deficient in liver production of insulin-like growth factor I display sexual dimorphism in growth hormone-stimulated postnatal growth. Endocrinology 2000;141:4436–4441.

    Article  PubMed  Google Scholar 

  125. Chen D, Mauvais-Jarvis F, Ueki K, Fisher SJ, Kahn CR. P50a/p55a PI-3 kinase knockout mice display elevated insulin sensitivity and resistance to obesity. Journal of Clinical Investigation In press, 2003.

  126. Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T, Roninson I, Weng W, Suzuki R, Tobe K, et al. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev 2001;15:2203–2208.

    Article  PubMed  Google Scholar 

  127. Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ. Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 2001;276:38349–38352.

    Google Scholar 

  128. Kitamura T, Kido Y, Nef S, Merenmies J, Parada LF, Accili D. Preserved pancreatic beta-cell development and function in mice lacking the insulin receptor-related receptor. Mol Cell Biol 2001;21:5624–5630.

    Article  PubMed  Google Scholar 

  129. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith D. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci USA 1999;96:7324–7329.

    Article  PubMed  Google Scholar 

  130. Yakar S, Liu JL, Fernandez AM, Wu Y, Schally AV, Frystyk J, Chernausek SD, Mejia W, Le Roith D. Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity. Diabetes 2001;50:1110–1118.

    PubMed  Google Scholar 

  131. Moller DE, Chang PY, Yaspelkis BB, III, Flier JS, Wallberg-Henriksson H, Ivy JL. Transgenic mice with muscle-specific insulin resistance develop increased adiposity, impaired glucose tolerance, and dyslipidemia. Endocrinology 1996;137:2397–2405.

    Article  PubMed  Google Scholar 

  132. Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, Goodyear LJ, Kahn CR. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 1998;2:559–569.

    Article  PubMed  Google Scholar 

  133. Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller-Wieland D, Kahn CR. Role of brain insulin receptor in control of body weight and reproduction. Science 2000;289:2122–2125.

    Google Scholar 

  134. Bluher M, Michael MD, Peroni OD, Ueki K, Carter N, Kahn BB, Kahn CR. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell 2002;3:25–38.

    Article  PubMed  Google Scholar 

  135. Lauro D, Kido Y, Hayashi H, Ebina Y, Accili D. Transgenic knock-out mice with a targeted impairment of insulin action in skeletal muscle and adipose tissue. Diabetes 1998;47:A45 (Abstr.

    Google Scholar 

  136. Fernandez AM, Kim JK, Yakar S, Dupont J, Hernandez-Sanchez C, Castle AL, Filmore J, Shulman GI, Le Roith D. Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes. Genes Dev 2001;15:1926–1934.

    Article  PubMed  Google Scholar 

  137. Bernal-Mizrachi E, Wen W, Stahlhut S, Welling CM, Permutt MA. Islet beta cell expression of constitutively active Akt1/PKB alpha induces striking hypertrophy, hyperplasia, and hyperinsulinemia. J Clin Invest 2001;108:1631–1638.

    Article  PubMed  Google Scholar 

  138. Bernal-Mizrachi E, Fatrai S, Johnson JD, Ohsugi M, Otani K, Han Z, Polonsky KS, Permutt MA. Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet beta cells. J Clin Invest 2004;114:928–936.

    Article  PubMed  Google Scholar 

  139. Kitamura T, Nakae J, Kitamura Y, Kido Y, Biggs WH 3rd, Wright CV, White MF, Arden KC, Accili D. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest 2002;110:1839–1847.

    Article  PubMed  Google Scholar 

  140. Bouche C, Kulkarni RN, Kahn CR, Goldfine AB. Exogenous insulin enhances glucose-stimulated insulin secretion in healty humans. Diabetes 2005;54(suppl 1):A45.

    Google Scholar 

  141. Leibiger B, Leibiger IB, Moede T, Kemper S, Kulkarni RN, Kahn CR, de Vargas LM, Berggren PO. Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. Mol Cell. 2001;7(3):559–570.

    Article  PubMed  Google Scholar 

  142. Da Silva Xavier, Qian Q, Cullen PJ, Rutter GA. Distinct roles for insulin and insulin-like growth factor-1 receptors in pancreatic beta-cell glucose sensing revealed by RNA silencing. Biochem J. 2004;377:149–158.

    Article  PubMed  Google Scholar 

  143. Sorenson RL, Brelje TC. Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones. Horm Metab Res. 1997;29(6):301–307.

    PubMed  Google Scholar 

  144. Nielsen JH, Galsgaard ED, Moldrup A, Friedrichsen BN, Billestrup N, Hansen JA, Lee YC, Carlsson C. Regulation of beta-cell mass by hormones and growth factors. Diabetes 2001;50(Suppl 1):S25–29.

    Google Scholar 

  145. Kushner JA, Ciemerych MA, Sicinska E, Wartschow LM, Teta M, Long SY, Sicinski P, White MF. Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. Mol Cell Biol 2005;25(9):3752–3762.

    Article  Google Scholar 

  146. Persaud S, Asare-Anane H, Jones PM. Insulin receptor activation inhibits insulin secretion from human islets of Langerhans. FEBS Lett 2002;16;510(3):225–228.

    Google Scholar 

  147. Sesti G. Apoptosis in the beta cells: cause or consequence of insulin secretion defect in diabetes? Ann Med. 2002;34(6):444–450.

    Article  PubMed  Google Scholar 

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Kulkarni, R.N. New Insights into the Roles of Insulin/IGF-I in the Development and Maintenance of β-Cell Mass. Rev Endocr Metab Disord 6, 199–210 (2005). https://doi.org/10.1007/s11154-005-3051-y

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