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International Journal of Endocrinology
Volume 2012 (2012), Article ID 516718, 20 pages
http://dx.doi.org/10.1155/2012/516718
Review Article

A Simple Matter of Life and Death—The Trials of Postnatal Beta-Cell Mass Regulation

School of Life Sciences, Warwick University, Gibbet Hill Road, Coventry CV4 7AL, UK

Received 15 November 2011; Accepted 31 December 2011

Academic Editor: Velayutham Kumaravel

Copyright © 2012 Elena Tarabra et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. Y. Dor and D. A. Melton, “How important are adult stem cells for tissue maintenance?” Cell Cycle, vol. 3, no. 9, pp. 1104–1106, 2004. View at Scopus
  2. C. J. Rhodes, “Type 2 diabetes—a matter of β-cell life and death?” Science, vol. 307, no. 5708, pp. 380–384, 2005. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Bonner-Weir, “Islet growth and development in the adult,” Journal of Molecular Endocrinology, vol. 24, no. 3, pp. 297–302, 2000. View at Scopus
  4. B. Duvillié, C. Currie, T. Chrones et al., “Increased islet cell proliferation, decreased apoptosis, and greater vascularization leading to β-cell hyperplasia in mutant mice lacking insulin,” Endocrinology, vol. 143, no. 4, pp. 1530–1537, 2002. View at Publisher · View at Google Scholar · View at Scopus
  5. E. Bernal-Mizrachi, W. Wen, S. Stahlhut, C. M. Welling, and M. A. Permutt, “Islet β cell expression of constitutively active Akt1/PKBα induces striking hypertrophy, hyperplasia, and hyperinsulinemia,” Journal of Clinical Investigation, vol. 108, no. 11, pp. 1631–1638, 2001. View at Publisher · View at Google Scholar · View at Scopus
  6. A. E. Butler, J. Janson, S. Bonner-Weir, R. Ritzel, R. A. Rizza, and P. C. Butler, “β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes,” Diabetes, vol. 52, no. 1, pp. 102–110, 2003. View at Publisher · View at Google Scholar · View at Scopus
  7. S. Georgia and A. Bhushan, “β cell replication is the primary mechanism for maintaining postnatal β cell mass,” Journal of Clinical Investigation, vol. 114, no. 7, pp. 963–968, 2004. View at Publisher · View at Google Scholar · View at Scopus
  8. D. Mathis, L. Vence, and C. Benoist, “β-cell death during progression to diabetes,” Nature, vol. 414, no. 6865, pp. 792–798, 2001. View at Publisher · View at Google Scholar · View at Scopus
  9. A. R. Saltiel and C. R. Kahn, “Insulin signalling and the regulation of glucose and lipid metabolism,” Nature, vol. 414, no. 6865, pp. 799–806, 2001. View at Publisher · View at Google Scholar · View at Scopus
  10. I. Swenne and A. Andersson, “Effect of genetic background on the capacity for islet cell replication in mice,” Diabetologia, vol. 27, no. 4, pp. 464–467, 1984. View at Scopus
  11. A. M. Ackermann and M. Gannon, “Molecular regulation of pancreatic β-cell mass development, maintenance, and expansion,” Journal of Molecular Endocrinology, vol. 38, no. 1-2, pp. 193–206, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. T. Okada, W. L. Chong, J. Hu et al., “Insulin receptors in β-cells are critical for islet compensatory growth response to insulin resistance,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 21, pp. 8977–8982, 2007. View at Publisher · View at Google Scholar · View at Scopus
  13. Y. Terauchi, I. Takamoto, N. Kubota et al., “Glucokinase and IRS-2 are required for compensatory β cell hyperplasia in response to high-fat diet-induced insulin resistance,” Journal of Clinical Investigation, vol. 117, no. 1, pp. 246–257, 2007. View at Publisher · View at Google Scholar · View at Scopus
  14. S. L. Fernandez-Valverde, R. J. Taft, and J. S. Mattick, “MicroRNAs in β-cell biology, insulin resistance, diabetes and its complications,” Diabetes, vol. 60, no. 7, pp. 1825–1831, 2011. View at Publisher · View at Google Scholar
  15. M. N. Poy, J. Hausser, M. Trajkovski et al., “miR-375 maintains normal pancreatic α- and β-cell mass,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 14, pp. 5813–5818, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. Y. Li, X. Xu, Y. Liang et al., “miR-375 enhances palmitate-induced lipoapoptosis in insulin-secreting NIT-1 cells by repressing myotrophin (V1) protein expression,” International Journal of Clinical and Experimental Pathology, vol. 3, no. 3, pp. 254–264, 2010. View at Scopus
  17. A. E. Ouaamari, N. Baroukh, G. A. Martens, P. Lebrun, D. Pipeleers, and E. Van Obberghen, “MiR-375 targets 3′l-phosphoinositide-dependent protein Kinase-1 and regulates glucose-induced biological responses in pancreatic β-Cells,” Diabetes, vol. 57, no. 10, pp. 2708–2717, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. H. Q. Xia, Y. Pan, J. Peng, and G. X. Lu, “Over-expression of miR375 reduces glucose-induced insulin secretion in Nit-1 cells,” Molecular Biology Reports, vol. 38, no. 5, pp. 3061–3665, 2011. View at Publisher · View at Google Scholar · View at Scopus
  19. M. I. McCarthy, “Genomics, type 2 diabetes, and obesity,” The New England Journal of Medicine, vol. 363, no. 24, pp. 2339–2350, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. World Health Organization, “Diabetes Fact Sheet no. 312,” 2011, http://www.who.int/mediacentre/factsheets/fs312/en/index.html.
  21. J. E. Shaw, R. A. Sicree, and P. Z. Zimmet, “Global estimates of the prevalence of diabetes for 2010 and 2030,” Diabetes Research and Clinical Practice, vol. 87, no. 1, pp. 4–14, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. J. Levy, A. B. Atkinson, P. M. Bell, D. R. McCance, and D. R. Hadden, “Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the belfast diet study,” Diabetic Medicine, vol. 15, no. 4, pp. 290–296, 1998. View at Publisher · View at Google Scholar · View at Scopus
  23. R. Turner, “Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33),” The Lancet, vol. 352, no. 9131, pp. 837–853, 1998. View at Publisher · View at Google Scholar
  24. R. Turner, “Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34),” The Lancet, vol. 352, no. 9131, pp. 854–865, 1998. View at Publisher · View at Google Scholar
  25. H. Shamoon, H. Duffy, N. Fleischer et al., “The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus,” The New England Journal of Medicine, vol. 329, no. 14, pp. 977–986, 1993. View at Publisher · View at Google Scholar
  26. B. Richter, E. Bandeira-Echtler, K. Bergerhoff, C. Clar, and S. H. Ebrahim, “Rosiglitazone for type 2 diabetes mellitus,” Cochrane Database of Systematic Reviews (Online), no. 3, article CD006063, 2007. View at Scopus
  27. Y. Dor, J. Brown, O. I. Martinez, and D. A. Melton, “Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation,” Nature, vol. 429, no. 6987, pp. 41–46, 2004. View at Publisher · View at Google Scholar · View at Scopus
  28. E. Montanya, V. Nacher, M. Biarnes, and J. Soler, “Linear correlation between β-cell mass and body weight throughout the lifespan in Lewis rats. Role of β-cell hyperplasia and hypertrophy,” Diabetes, vol. 49, no. 8, pp. 1341–1346, 2000. View at Scopus
  29. J. H. Nielsen, E. D. Galsgaard, A. Møldrup et al., “Regulation of β-cell mass by hormones and growth factors,” Diabetes, vol. 50, no. 1, supplement, pp. S25–S29, 2001. View at Scopus
  30. A. E. Butler, J. Janson, W. C. Soeller, and P. C. Butler, “Increased β-cell apoptosis prevents adaptive increase in β-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid,” Diabetes, vol. 52, no. 9, pp. 2304–2314, 2003. View at Publisher · View at Google Scholar · View at Scopus
  31. J. J. Gagliardino, H. Del Zotto, L. Massa, L. E. Flores, and M. I. Borelli, “Pancreatic duodenal homeobox-1 and islet neogenesis-associated protein: a possible combined marker of activateable pancreatic cell precursors,” Journal of Endocrinology, vol. 177, no. 2, pp. 249–259, 2003. View at Publisher · View at Google Scholar · View at Scopus
  32. G. M. Steil, N. Trivedi, J. C. Jonas et al., “Adaptation of β-cell mass to substrate oversupply: enhanced function with normal gene expression,” American Journal of Physiology, vol. 280, no. 5, pp. E788–E796, 2001.
  33. C. Bernard, M. F. Berthault, C. Saulnier, and A. Ktorza, “Neogenesis vs. apoptosis as main components of pancreatic β cell mass changes in glucose-infused normal and mildly diabetic adult rats,” FASEB Journal, vol. 13, no. 10, pp. 1195–1205, 1999. View at Scopus
  34. C. Bernard, C. Thibault, M. F. Berthault et al., “Pancreatic β-cell regeneration after 48-h glucose infusion in mildly diabetic rats is not correlated with functional improvement,” Diabetes, vol. 47, no. 7, pp. 1058–1065, 1998. View at Publisher · View at Google Scholar · View at Scopus
  35. S. Bonner-Weir, D. Deery, J. L. Leahy, and G. C. Weir, “Compensatory growth of pancreatic β-cells in adult rats after short-term glucose infusion,” Diabetes, vol. 38, no. 1, pp. 49–53, 1989. View at Scopus
  36. M. Paris, C. Bernard-Kargar, M. F. Berthault, L. Bouwens, and A. Ktorza, “Specific and combined effects of insulin and glucose on functional pancreatic β-cell mass in vivo in adult rats,” Endocrinology, vol. 144, no. 6, pp. 2717–2727, 2003. View at Publisher · View at Google Scholar · View at Scopus
  37. D. R. Laybutt, M. Glandt, G. Xu et al., “Critical reduction β-cell mass results in two distinct outcomes over time. Adaptation with impaired glucose tolerance or decompensated diabetes,” The Journal of Biological Chemistry, vol. 278, no. 5, pp. 2997–3005, 2003. View at Publisher · View at Google Scholar · View at Scopus
  38. I. Swenne, “The role of glucose on the in vitro regulation of cell cycle kinetics and proliferation of fetal pancreatic B-cells,” Diabetes, vol. 31, no. 9, pp. 754–760, 1982. View at Scopus
  39. B. G. Topp, M. D. McArthur, and D. T. Finegood, “Metabolic adaptations to chronic glucose infusion in rats,” Diabetologia, vol. 47, no. 9, pp. 1602–1610, 2004. View at Publisher · View at Google Scholar · View at Scopus
  40. S. Porat, N. Weinberg-Corem, S. Tornovsky-Babaey et al., “Control of pancreatic β cell regeneration by glucose metabolism,” Cell Metabolism, vol. 13, no. 4, pp. 440–449, 2011. View at Publisher · View at Google Scholar
  41. A. Hoorens, M. van de Casteele, G. Klöppel, and D. Pipeleers, “Glucose promotes survival of rat pancreatic β cells by activating synthesis of proteins which suppress a constitutive apoptotic program,” Journal of Clinical Investigation, vol. 98, no. 7, pp. 1568–1574, 1996. View at Scopus
  42. J. C. Jonas, A. Sharma, W. Hasenkamp et al., “Chronic hyperglycemia triggers loss of pancreatic β cell differentiation in an animal model of diabetes,” The Journal of Biological Chemistry, vol. 274, no. 20, pp. 14112–14121, 1999. View at Publisher · View at Google Scholar · View at Scopus
  43. V. Grill and A. Björklund, “Overstimulation and β-cell function,” Diabetes, vol. 50, supplement 1, pp. S122–S124, 2001.
  44. K. Maedler, P. Sergeev, F. Ris et al., “Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets,” Journal of Clinical Investigation, vol. 110, no. 6, pp. 851–860, 2002. View at Publisher · View at Google Scholar · View at Scopus
  45. Y. Tanaka, P. O. T. Tran, J. Harmon, and R. P. Robertson, “A role for glutathione peroxidase in protecting pancreatic β cells against oxidative stress in a model of glucose toxicity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 19, pp. 12363–12368, 2002. View at Publisher · View at Google Scholar · View at Scopus
  46. S. Pelengaris, M. Khan, and G. I. Evan, “Suppression of Myc-induced apoptosis in β cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression,” Cell, vol. 109, no. 3, pp. 321–334, 2002. View at Publisher · View at Google Scholar · View at Scopus
  47. D. R. Laybutt, G. C. Weir, H. Kaneto et al., “Overexpression of c-Myc in β-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes,” Diabetes, vol. 51, no. 6, pp. 1793–1804, 2002. View at Scopus
  48. S. Pelengaris and M. Khan, “The many faces of c-MYC,” Archives of Biochemistry and Biophysics, vol. 416, no. 2, pp. 129–136, 2003. View at Publisher · View at Google Scholar · View at Scopus
  49. N. Kaiser, G. Leibowitz, and R. Nesher, “Glucotoxicity and β-cell failure in type 2 diabetes mellitus,” Journal of Pediatric Endocrinology and Metabolism, vol. 16, no. 1, pp. 5–22, 2003.
  50. A. Clark, C. A. Wells, I. D. Buley et al., “Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes,” Diabetes Research, vol. 9, no. 4, pp. 151–159, 1988. View at Scopus
  51. G. Klöppel, M. Löhr, K. Habich, M. Oberholzer, and P. U. Heitz, “Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited,” Survey and Synthesis of Pathology Research, vol. 4, no. 2, pp. 110–125, 1985.
  52. H. Sakuraba, H. Mizukami, N. Yagihashi, R. Wada, C. Hanyu, and S. Yagihashi, “Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients,” Diabetologia, vol. 45, no. 1, pp. 85–96, 2002. View at Publisher · View at Google Scholar · View at Scopus
  53. K. H. Yoon, S. H. Ko, J. H. Cho et al., “Selective β-cell loss and α-cell expansion in patients with type 2 diabetes mellitus in Korea,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 5, pp. 2300–2308, 2003. View at Publisher · View at Google Scholar
  54. A. Andersson, “The influence of hyperglycaemia, hyperinsulinaemia and genetic background on the fate of intrasplenically implanted mouse islets,” Diabetologia, vol. 25, no. 3, pp. 269–272, 1983. View at Scopus
  55. C. Guillen, P. Navarro, M. Robledo, A. M. Valverde, and M. Benito, “Differential mitogenic signaling in insulin receptor-deficient fetal pancreatic β-cells,” Endocrinology, vol. 147, no. 4, pp. 1959–1968, 2006. View at Publisher · View at Google Scholar · View at Scopus
  56. T. R. Koiter, S. Wijkstra, G. C. J. van der Schaaf-Verdonk, H. Moes, and G. A. Schuiling, “Pancreatic beta-cell function and islet-cell proliferation: effect of hyperinsulinaemia,” Physiology and Behavior, vol. 57, no. 4, pp. 717–721, 1995. View at Publisher · View at Google Scholar · View at Scopus
  57. J. Movassat, C. Saulnier, and B. Portha, “β-cell mass depletion precedes the onset of hyperglycaemia in the GK rat, a genetic model of non-insulin-dependent diabetes mellitus,” Diabete et Metabolisme, vol. 21, no. 5, pp. 365–370, 1995. View at Scopus
  58. Y. Guz, I. Nasir, and G. Teitelman, “Regeneration of pancreatic β cells from intra-islet precursor cells in an experimental model of diabetes,” Endocrinology, vol. 142, no. 11, pp. 4956–4968, 2001. View at Publisher · View at Google Scholar · View at Scopus
  59. K. Otani, R. N. Kulkarni, A. C. Baldwin et al., “Reduced β-cell mass and altered glucose sensing impair insulin-secretory function in βIRKO mice,” American Journal of Physiology, vol. 286, no. 1, pp. E41–E49, 2004.
  60. N. Blume, J. Skouv, L. I. Larsson, J. J. Hoist, and O. D. Madsen, “Potent inhibitory effects of transplantable rat glucagonomas and insulinomas on the respective endogenous islet cells are associated with pancreatic apoptosis,” Journal of Clinical Investigation, vol. 96, no. 5, pp. 2227–2235, 1995. View at Scopus
  61. P. R. Flatt, K. S. Tan, and C. J. Bailey, “Effects of transplantation and resection of a radiation-induced rat insulinoma on glucose homeostasis and the endocrine pancreas,” British Journal of Cancer, vol. 54, no. 4, pp. 685–692, 1986. View at Scopus
  62. S. N. Flier, R. N. Kulkarni, and C. R. Kahn, “Evidence for a circulating islet cell growth factor in insulin-resistant states,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 13, pp. 7475–7480, 2001. View at Publisher · View at Google Scholar · View at Scopus
  63. C. Miyaura, L. Chen, M. Appel et al., “Expression of reg/PSP, a pancreatic exocrine gene: relationship to changes in islet β-cell mass,” Molecular Endocrinology, vol. 5, no. 2, pp. 226–234, 1991. View at Scopus
  64. A. Giacca, C. Xiao, A. I. Oprescu, A. C. Carpentier, and G. F. Lewis, “Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies,” American Journal of Physiology, vol. 300, no. 2, pp. E255–E262, 2011. View at Publisher · View at Google Scholar
  65. V. Poitout, “Glucolipotoxicity of the pancreatic β-cell: myth or reality?” Biochemical Society Transactions, vol. 36, no. 5, pp. 901–904, 2008. View at Publisher · View at Google Scholar · View at Scopus
  66. Y. P. Zhou and V. E. Grill, “Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle,” Journal of Clinical Investigation, vol. 93, no. 2, pp. 870–876, 1994. View at Scopus
  67. Y. P. Zhou and V. Grill, “Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans,” Journal of Clinical Endocrinology and Metabolism, vol. 80, no. 5, pp. 1584–1590, 1995. View at Scopus
  68. A. I. Oprescu, G. Bikopoulos, A. Naassan et al., “Free fatty acid-induced reduction in glucose-stimulated insulin secretion: evidence for a role of oxidative stress in vitro and in vivo,” Diabetes, vol. 56, no. 12, pp. 2927–2937, 2007. View at Publisher · View at Google Scholar · View at Scopus
  69. A. Carpentier, S. D. Mittelman, R. N. Bergman, A. Giacca, and G. F. Lewis, “Prolonged elevation of plasma free fatty acids impairs pancreatic β- cell function in obese nondiabetic humans but not in individuals with type 2,” Diabetes, vol. 49, no. 3, pp. 399–408, 2000. View at Scopus
  70. A. Carpentier, S. D. Mittelman, B. Lamarche, R. N. Bergman, A. Giacca, and G. F. Lewis, “Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation,” American Journal of Physiology, vol. 276, no. 6, pp. E1055–E1066, 1999. View at Scopus
  71. S. Kashyap, R. Belfort, A. Gastaldelli et al., “A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes,” Diabetes, vol. 52, no. 10, pp. 2461–2474, 2003. View at Publisher · View at Google Scholar · View at Scopus
  72. C. Xiao, A. Giacca, A. Carpentier, and G. F. Lewis, “Differential effects of monounsaturated, polyunsaturated and saturated fat ingestion on glucose-stimulated insulin secretion, sensitivity and clearance in overweight and obese, non-diabetic humans,” Diabetologia, vol. 49, no. 6, pp. 1371–1379, 2006. View at Publisher · View at Google Scholar · View at Scopus
  73. Y. Sako and V. E. Grill, “A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation,” Endocrinology, vol. 127, no. 4, pp. 1580–1589, 1990. View at Scopus
  74. M. L. Elks, “Chronic perifusion of rat islets with palmitate suppresses glucose- stimulated insulin release,” Endocrinology, vol. 133, no. 1, pp. 208–214, 1993. View at Publisher · View at Google Scholar · View at Scopus
  75. S. Gremlich, C. Bonny, G. Waeber, and B. Thorens, “Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels,” The Journal of Biological Chemistry, vol. 272, no. 48, pp. 30261–30269, 1997. View at Publisher · View at Google Scholar · View at Scopus
  76. I. Briaud, J. S. Harmon, C. L. Kelpe, V. B. G. Segu, and V. Poitout, “Lipotoxicity of the pancreatic β-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids,” Diabetes, vol. 50, no. 2, pp. 315–321, 2001. View at Scopus
  77. C. L. Kelpe, P. C. Moore, S. D. Parazzoli, B. Wicksteed, C. J. Rhodes, and V. Poitout, “Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis,” The Journal of Biological Chemistry, vol. 278, no. 32, pp. 30015–30021, 2003. View at Publisher · View at Google Scholar · View at Scopus
  78. D. K. Hagman, L. B. Hays, S. D. Parazzoli, and V. Poitout, “Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of Langerhans,” The Journal of Biological Chemistry, vol. 280, no. 37, pp. 32413–32418, 2005. View at Publisher · View at Google Scholar · View at Scopus
  79. A. Pick, J. Clark, C. Kubstrup et al., “Role of apoptosis in failure of β-cell mass compensation for insulin resistance and β-cell defects in the male Zucker diabetic fatty rat,” Diabetes, vol. 47, no. 3, pp. 358–364, 1998. View at Publisher · View at Google Scholar · View at Scopus
  80. M. Shimabukuro, Y. T. Zhou, M. Levi, and R. H. Unger, “Fatty acid-induced β cell apoptosis: a link between obesity and diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 5, pp. 2498–2502, 1998. View at Publisher · View at Google Scholar · View at Scopus
  81. M. Cnop, J. C. Hannaert, A. Hoorens, D. L. Eizirik, and D. G. Pipeleers, “Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation,” Diabetes, vol. 50, no. 8, pp. 1771–1777, 2001. View at Scopus
  82. K. Maedler, G. A. Spinas, D. Dyntar, W. Moritz, N. Kaiser, and M. Y. Donath, “Distinct effects of saturated and monounsaturated fatty acids on β-cell turnover and function,” Diabetes, vol. 50, no. 1, pp. 69–76, 2001. View at Scopus
  83. R. Lupi, F. Dotta, L. Marselli et al., “Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that β-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated,” Diabetes, vol. 51, no. 5, pp. 1437–1442, 2002. View at Scopus
  84. C. E. Wrede, L. M. Dickson, M. K. Lingohr, I. Briaud, and C. J. Rhodes, “Protein kinase B/Akt prevents fatty acid-induced apoptosis in pancreatic β-cells (INS-1),” The Journal of Biological Chemistry, vol. 277, no. 51, pp. 49676–49684, 2002. View at Publisher · View at Google Scholar · View at Scopus
  85. S. Piro, M. Anello, C. Di Pietro et al., “Chronic exposure to free fatty acids or high glucose induces apoptosis in rat pancreatic islets: possible role of oxidative stress,” Metabolism, vol. 51, no. 10, pp. 1340–1347, 2002. View at Publisher · View at Google Scholar · View at Scopus
  86. K. Maedler, J. Oberholzer, P. Bucher, G. A. Spinas, and M. Y. Donath, “Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic β-cell turnover and function,” Diabetes, vol. 52, no. 3, pp. 726–733, 2003. View at Publisher · View at Google Scholar · View at Scopus
  87. I. Maestre, J. Jordán, S. Calvo et al., “Mitochondrial dysfunction is involved in apoptosis induced by serum withdrawal and fatty acids in the β-cell line INS-1,” Endocrinology, vol. 144, no. 1, pp. 335–345, 2003. View at Publisher · View at Google Scholar · View at Scopus
  88. W. El-Assaad, J. Buteau, M. L. Peyot et al., “Saturated fatty acids synergize with elevated glucose to cause pancreatic β-cell death,” Endocrinology, vol. 144, no. 9, pp. 4154–4163, 2003. View at Publisher · View at Google Scholar · View at Scopus
  89. S. Jacqueminet, I. Briaud, C. Rouault, G. Reach, and V. Poitout, “Inhibition of insulin gene expression by long-term exposure of pancreatic β cells to palmitate is dependent on the presence of a stimulatory glucose concentration,” Metabolism, vol. 49, no. 4, pp. 532–536, 2000. View at Scopus
  90. J. S. Harmon, C. E. Gleason, Y. Tanaka, V. Poitout, and R. P. Robertson, “Antecedent hyperglycemia, not hyperlipidemia, is associated with increased islet triacylglycerol content and decreased insulin gene mRNA level in Zucker diabetic fatty rats,” Diabetes, vol. 50, no. 7–12, pp. 2481–2486, 2001. View at Scopus
  91. I. Briaud, C. L. Kelpe, L. M. Johnson, P. O. T. Tran, and V. Poitout, “Differential effects of hyperlipidemia on insulin secretion in islets of langerhans from hyperglycemic versus normoglycemic rats,” Diabetes, vol. 51, no. 3, pp. 662–668, 2002. View at Scopus
  92. V. Koshkin, X. Wang, P. E. Scherer, C. B. Chan, and M. B. Wheeler, “Mitochondrial functional state in clonal pancreatic β-cells exposed to free fatty acids,” The Journal of Biological Chemistry, vol. 278, no. 22, pp. 19709–19715, 2003. View at Publisher · View at Google Scholar · View at Scopus
  93. J. Buteau, S. Foisy, E. Joly, and M. Prentki, “Glucagon-like peptide 1 induces pancreatic β-cell proliferation via transactivation of the epidermal growth factor receptor,” Diabetes, vol. 52, no. 1, pp. 124–132, 2003. View at Publisher · View at Google Scholar · View at Scopus
  94. L. Farilla, H. Hongxiang, C. Bertolotto et al., “Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats,” Endocrinology, vol. 143, no. 11, pp. 4397–4408, 2002. View at Publisher · View at Google Scholar · View at Scopus
  95. Y. Li, T. Hansotia, B. Yusta, F. Ris, P. A. Halban, and D. J. Drueker, “Glucagon-like peptide-1 receptor signaling modulates β cell apoptosis,” The Journal of Biological Chemistry, vol. 278, no. 1, pp. 471–478, 2003. View at Publisher · View at Google Scholar · View at Scopus
  96. H. Hui, A. Nourparvar, X. Zhao, and R. Perfetti, “Glucagon-like peptide-1 inhibits apoptosis of insulin-secreting cells via a cyclic 5′-adenosine monophosphate-dependent protein kinase A- and a phosphatidylinositol 3-kinase-dependent pathway,” Endocrinology, vol. 144, no. 4, pp. 1444–1455, 2003. View at Publisher · View at Google Scholar · View at Scopus
  97. L. Farilla, A. Bulotta, B. Hirshberg et al., “Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets,” Endocrinology, vol. 144, no. 12, pp. 5149–5158, 2003. View at Publisher · View at Google Scholar · View at Scopus
  98. G. Xu, D. A. Stoffers, J. F. Habener, and S. Bonner-Weir, “Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats,” Diabetes, vol. 48, no. 12, pp. 2270–2276, 1999. View at Scopus
  99. J. Buteau, S. Foisy, C. J. Rhodes, L. Carpenter, T. J. Biden, and M. Prentki, “Protein kinase Cζ activation mediates glucagon-like peptide-1—induced pancreatic β-cell proliferation,” Diabetes, vol. 50, no. 10, pp. 2237–2243, 2001. View at Scopus
  100. R. Perfetti, J. I. E. Zhou, M. E. Doyle, and J. M. Egan, “Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats,” Endocrinology, vol. 141, no. 12, pp. 4600–4605, 2000. View at Publisher · View at Google Scholar · View at Scopus
  101. J. Buteau, M. L. Spatz, and D. Accili, “Transcription factor FoxO1 mediates glucagon-like peptide-1 effects on pancreatic β-cell mass,” Diabetes, vol. 55, no. 5, pp. 1190–1196, 2006. View at Publisher · View at Google Scholar · View at Scopus
  102. Y. Li, X. Cao, L. X. Li, P. L. Brubaker, H. Edlund, and D. J. Drucker, “β-Cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1,” Diabetes, vol. 54, no. 2, pp. 482–491, 2005. View at Publisher · View at Google Scholar · View at Scopus
  103. S. Park, X. Dong, T. L. Fisher et al., “Exendin-4 uses Irs2 signaling to mediate pancreatic β cell growth and function,” The Journal of Biological Chemistry, vol. 281, no. 2, pp. 1159–1168, 2006. View at Publisher · View at Google Scholar · View at Scopus
  104. W. J. Song, W. E. Schreiber, E. Zhong et al., “Exendin-4 stimulation of cyclin A2 in β-cell proliferation,” Diabetes, vol. 57, no. 9, pp. 2371–2381, 2008. View at Publisher · View at Google Scholar · View at Scopus
  105. S. I. Tschen, S. Dhawan, T. Gurlo, and A. Bhushan, “Age-dependent decline in β-cell proliferation restricts the capacity of β-cell regeneration in mice,” Diabetes, vol. 58, no. 6, pp. 1312–1320, 2009. View at Publisher · View at Google Scholar · View at Scopus
  106. C. Tourrel, D. Bailbé, M. J. Meile, M. Kergoat, and B. Portha, “Glucagon-like peptide-1 and exendin-4 stimulate β-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age,” Diabetes, vol. 50, no. 7, pp. 1562–1570, 2001. View at Scopus
  107. E. J. Abraham, C. A. Leech, J. C. Lin, H. Zulewski, and J. F. Habener, “Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells,” Endocrinology, vol. 143, no. 8, pp. 3152–3161, 2002. View at Publisher · View at Google Scholar · View at Scopus
  108. G. Xu, H. Kaneto, M. D. Lopez-Avalos, G. C. Weir, and S. Bonner-Weir, “GLP-1/exendin-4 facilitates β-cell neogenesis in rat and human pancreatic ducts,” Diabetes Research and Clinical Practice, vol. 73, no. 1, pp. 107–110, 2006. View at Publisher · View at Google Scholar
  109. J. A. Pospisilik, J. Martin, T. Doty et al., “Dipeptidyl peptidase IV inhibitor treatment stimulates β-cell survival and islet neogenesis in streptozotocin-induced diabetic rats,” Diabetes, vol. 52, no. 3, pp. 741–750, 2003. View at Publisher · View at Google Scholar · View at Scopus
  110. T. Carpenter, M. E. Trautmann, A. D. Baron et al., “Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery,” The New England Journal of Medicine, vol. 353, no. 20, pp. 2192–2194, 2005. View at Publisher · View at Google Scholar
  111. D. E. Cummings, “Gastric bypass and nesidioblastosis—too much of a good thing for islets?” The New England Journal of Medicine, vol. 353, no. 3, pp. 300–302, 2005. View at Publisher · View at Google Scholar · View at Scopus
  112. G. J. Service, G. B. Thompson, F. J. Service, J. C. Andrews, M. L. Collazo-Clavell, and R. V. Lloyd, “Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery,” The New England Journal of Medicine, vol. 353, no. 3, pp. 249–254, 2005. View at Publisher · View at Google Scholar · View at Scopus
  113. S. Takiguchi, Y. Takata, A. Funakoshi et al., “Disrupted cholecystokinin type-A receptor (CCKAR) gene in OLETF rats,” Gene, vol. 197, no. 1-2, pp. 169–175, 1997. View at Publisher · View at Google Scholar · View at Scopus
  114. Y. Wang and X. H. Guo, “Effects of GLP-1 treatment on protection of B cells in Otsuka Long-Evans Tokushima fatty rats,” Beijing da Xue Xue Bao, vol. 38, no. 4, pp. 375–380, 2006. View at Scopus
  115. Q. Wang and P. Brubaker, “Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice,” Diabetologia, vol. 45, no. 9, pp. 1263–1273, 2002. View at Publisher · View at Google Scholar · View at Scopus
  116. B. D. Green, K. S. Lavery, N. Irwin et al., “Novel glucagon-like peptide-1 (GLP-1) analog (Val8)GLP-1 results in significant improvements of glucose tolerance and pancreatic β-cell function after 3-week daily administration in obese diabetic (ob/ob) mice,” Journal of Pharmacology and Experimental Therapeutics, vol. 318, no. 2, pp. 914–921, 2006. View at Publisher · View at Google Scholar
  117. J. G. Kim, L. L. Baggio, D. P. Bridon et al., “Development and characterization of a glucagon-like peptide 1-albumin conjugate the ability to activate the glucagon-like peptide 1 receptor in vivo,” Diabetes, vol. 52, no. 3, pp. 751–759, 2003. View at Publisher · View at Google Scholar · View at Scopus
  118. Y. Li, C. Shi, Q. Lv et al., “GLP-1 C-terminal structures affect its blood glucose lowering-function,” Journal of Peptide Science, vol. 14, no. 7, pp. 777–785, 2008. View at Publisher · View at Google Scholar · View at Scopus
  119. J. Mu, A. Petrov, G. J. Eiermann et al., “Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes,” European Journal of Pharmacology, vol. 623, no. 1–3, pp. 148–154, 2009. View at Publisher · View at Google Scholar · View at Scopus
  120. A. Maida, T. Hansotia, C. Longuet, Y. Seino, and D. J. Drucker, “Differential importance of glucose-dependent insulinotropic polypeptide vs glucagon-like peptide 1 receptor signaling for beta cell survival in mice,” Gastroenterology, vol. 137, no. 6, pp. 2146–2157, 2009. View at Publisher · View at Google Scholar · View at Scopus
  121. V. A. Gault, N. Irwin, B. D. Green et al., “Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro3)GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-related diabetes,” Diabetes, vol. 54, no. 8, pp. 2436–2446, 2005. View at Publisher · View at Google Scholar · View at Scopus
  122. Q. Cheng, P. K. Law, M. De Gasparo, and P. S. Leung, “Combination of the dipeptidyl peptidase IV inhibitor LAF237 [(S)-1-[(3-hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] with the angiotensin II type 1 receptor antagonist valsartan [N-(1-oxopentyl)-N- [[2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl]methyl]-L-valine] enhances pancreatic islet morphology and function in a mouse model of type 2 diabetes,” Journal of Pharmacology and Experimental Therapeutics, vol. 327, no. 3, pp. 683–691, 2008. View at Publisher · View at Google Scholar · View at Scopus
  123. N. Irwin, G. C. Clarke, B. D. Green et al., “Evaluation of the antidiabetic activity of DPP IV resistant N-terminally modified versus mid-chain acylated analogues of glucose-dependent insulinotropic polypeptide,” Biochemical Pharmacology, vol. 72, no. 6, pp. 719–728, 2006. View at Publisher · View at Google Scholar · View at Scopus
  124. G. S. Kidd, M. Donowitz, T. O'Dorisio, S. Cataland, and F. Newman, “Mild chronic watery diarrhea-hypokalemia syndrome associated with pancreatic islet cell hyperplasia. Elevated plasma and tissue levels of gastric inhibitory polypeptide and successful management with nicotinic acid,” The American Journal of Medicine, vol. 66, no. 5, pp. 883–888, 1979. View at Scopus
  125. B. N. Friedrichsen, N. Neubauer, Y. C. Lee et al., “Stimulation of pancreatic β-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways,” Journal of Endocrinology, vol. 188, no. 3, pp. 481–492, 2006. View at Publisher · View at Google Scholar
  126. J. A. Ehses, V. R. Casilla, T. Doty et al., “Glucose-dependent insulinotropic polypeptide promotes β-(INS-1) cell survival via cyclic adenosine monophosphate-mediated caspase-3 inhibition and regulation of p38 mitogen-activated protein kinase,” Endocrinology, vol. 144, no. 10, pp. 4433–4445, 2003. View at Publisher · View at Google Scholar · View at Scopus
  127. A. Trümper, K. Trümper, and D. Hörsch, “Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in β(INS-1)-cells,” Journal of Endocrinology, vol. 174, no. 2, pp. 233–246, 2002. View at Publisher · View at Google Scholar
  128. A. Trümper, K. Trümper, H. Trusheim, R. Arnold, B. Göke, and D. Hörsch, “Glucose-dependent insulinotropic polypeptide is a growth factor for β (INS-1) cells by pleiotropic signaling,” Molecular Endocrinology, vol. 15, no. 9, pp. 1559–1570, 2001. View at Publisher · View at Google Scholar
  129. S. B. Widenmaier, S. J. Kim, G. K. Yang et al., “A GIP receptor agonist exhibits β-cell anti-apoptotic actions in rat models of diabetes resulting in improved β-cell function and glycemic control,” PLoS ONE, vol. 5, no. 3, article e9590, 2010. View at Publisher · View at Google Scholar
  130. J. Hogg, V. K. M. han, D. R. Clemmons, and D. J. Hill, “Interactions of nutrients, insulin-like growth factors (IGFs) and IGF-binding proteins in the regulation of DNA synthesis by isolated fetal rat islets of Langerhans,” Journal of Endocrinology, vol. 138, no. 3, pp. 401–412, 1993. View at Scopus
  131. J. Sieradzki, H. Fleck, A. K. Chatterjee, and H. Schatz, “Stimulatory effect of insulin-like growth factor-I on [3H]thymidine incorporation, DNA content and insulin biosynthesis and secretion of isolated pancreatic rat islets,” Journal of Endocrinology, vol. 117, no. 1, pp. 59–62, 1988. View at Scopus
  132. I. Swenne, D. J. Hill, A. J. Strain, and R. D. G. Milner, “Growth hormone regulation of somatomedin C/insulin-like growth factor I production and DNA replication in fetal rat islets in tissue culture,” Diabetes, vol. 36, no. 3, pp. 288–294, 1987. View at Scopus
  133. I. Swenne, “Pancreatic beta-cell growth and diabetes mellitus,” Diabetologia, vol. 35, no. 3, pp. 193–201, 1992. View at Scopus
  134. J. H. Nielsen, S. Linde, B. S. Welinder, N. Billestrup, and O. D. Madsen, “Growth hormone is a growth factor for the differentiated pancreatic β-cell,” Molecular Endocrinology, vol. 3, no. 1, pp. 165–173, 1989.
  135. N. Billestrup, A. Moldrup, P. Serup, L. S. Mathews, G. Norstedt, and J. H. Nielsen, “Introduction of exogenous growth hormone receptors augments growth hormone-responsive insulin biosynthesis in rat insulinoma cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 18, pp. 7210–7214, 1990. View at Scopus
  136. S. R. Hügl, M. F. White, and C. J. Rhodes, “Insulin-like growth factor I (IGF-I)-stimulated pancreatic β-cell growth is glucose-dependent synergistic activation of insulin receptor substrate-mediated signal transduction pathways by glucose and IGF-I in INS- 1 cells,” The Journal of Biological Chemistry, vol. 273, no. 28, pp. 17771–17779, 1998. View at Publisher · View at Google Scholar · View at Scopus
  137. M. George, E. Ayuso, A. Casellas, C. Costa, J. C. Devedjian, and F. Bosch, “β cell expression of IGF-I leads to recovery from type 1 diabetes,” Journal of Clinical Investigation, vol. 109, no. 9, pp. 1153–1163, 2002. View at Publisher · View at Google Scholar · View at Scopus
  138. J. Petrik, J. M. Pell, E. Arany et al., “Overexpression of insulin-like growth factor-II in transgenic mice is associated with pancreatic islet cell hyperplasia,” Endocrinology, vol. 140, no. 5, pp. 2353–2363, 1999. View at Scopus
  139. Y. Lu, P. L. Herrera, Y. Guo et al., “Pancreatic-specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes,” Diabetes, vol. 53, no. 12, pp. 3131–3141, 2004. View at Publisher · View at Google Scholar · View at Scopus
  140. J. C. Devedjian, M. George, A. Casellas et al., “Transgenic mice overexpressing insulin-like growth factor-II in β cells develop type 2 diabetes,” Journal of Clinical Investigation, vol. 105, no. 6, pp. 731–740, 2000. View at Scopus
  141. E. Kuntz, M. Pinget, and C. Damgé, “Cholecystokinin octapeptide: a potential growth factor for pancreatic beta cells in diabetic rats,” Journal of the Pancreas, vol. 5, no. 6, pp. 464–475, 2004. View at Scopus
  142. T. C. Brelje and R. L. Sorenson, “Role of prolactin versus growth hormone on islet B-cell proliferation in vitro: implications for pregnancy,” Endocrinology, vol. 128, no. 1, pp. 45–57, 1991. View at Scopus
  143. J. A. Lavine, P. W. Raess, D. B. Davis et al., “Contamination with E1A-positive wild-type adenovirus accounts for species-specific stimulation of islet cell proliferation by CCK: a cautionary note,” Molecular Endocrinology, vol. 24, no. 2, pp. 464–467, 2010. View at Publisher · View at Google Scholar · View at Scopus
  144. K. Williams, D. Abanquah, S. Joshi-Gokhale et al., “Systemic and acute administration of parathyroid hormone-related peptide(1–36) stimulates endogenous beta cell proliferation while preserving function in adult mice,” Diabetologia, vol. 54, no. 11, pp. 2867–2877, 2011. View at Publisher · View at Google Scholar
  145. Y. Fujinaka, D. Sipula, A. Garcia-Ocaña, and R. C. Vasavada, “Characterization of mice doubly transgenic for parathyroid hormone-related protein and murine placental lactogen: a novel role for placental lactogen in pancreatic β-cell survival,” Diabetes, vol. 53, no. 12, pp. 3120–3130, 2004. View at Publisher · View at Google Scholar · View at Scopus
  146. R. C. Vasavada, C. Cavaliere, A. J. D'Ercole et al., “Overexpression of parathyroid hormone-related protein in the pancreatic islets of transgenic mice causes islet hyperplasia, hyperinsulinemia, and hypoglycemia,” The Journal of Biological Chemistry, vol. 271, no. 2, pp. 1200–1208, 1996. View at Publisher · View at Google Scholar · View at Scopus
  147. S. E. Porter, R. L. Sorenson, P. Dann, A. Garcia-Ocana, A. F. Stewart, and R. C. Vasavada, “Progressive pancreatic islet hyperplasia in the islet-targeted, parathyroid hormone-related protein-overexpressing mouse,” Endocrinology, vol. 139, no. 9, pp. 3743–3751, 1998. View at Publisher · View at Google Scholar · View at Scopus
  148. N. G. Kondegowda, S. Joshi-Gokhale, G. Harb et al., “Parathyroid hormone-related protein enhances human β-cell proliferation and function with associated induction of cyclin-dependent kinase 2 and cyclin E expression,” Diabetes, vol. 59, no. 12, pp. 3131–3138, 2010. View at Publisher · View at Google Scholar · View at Scopus
  149. M. L. Villanueva-Peñacarrillo, J. Cancelas, F. De Miguel et al., “Parathyroid hormone-related peptide stimulates DNA synthesis and insulin secretion in pancreatic islets,” Journal of Endocrinology, vol. 163, no. 3, pp. 403–408, 1999. View at Scopus
  150. B. Zhang, M. Hosaka, Y. Sawada et al., “Parathyroid hormone-related protein induces insulin expression through activation of MAP kinase-specific phosphatase-1 that dephosphorylates c-Jun NH2-terminal kinase in pancreatic beta-cells,” Diabetes, vol. 52, no. 11, pp. 2720–2730, 2003. View at Publisher · View at Google Scholar · View at Scopus
  151. N. Vandegraaff, et al., “Growth factors and beta cell replication,” The International Journal of Biochemistry & Cell Biology, vol. 38, no. 5-6, pp. 931–950, 2006.
  152. T. Irako, T. Akamizu, H. Hosoda et al., “Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats,” Diabetologia, vol. 49, no. 6, pp. 1264–1273, 2006. View at Publisher · View at Google Scholar · View at Scopus
  153. R. Granata, F. Settanni, L. Trovato et al., “Unacylated as well s acylated ghrelin promotes cell survival and inhibit apoptosis in HIT-T15 pancretic β-cells,” Journal of Endocrinological Investigation, vol. 29, no. 9, pp. RC19–RC22, 2006.
  154. R. Granata, F. Settanni, L. Biancone et al., “Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic β-cells and human islets: involvement of 3′,5′-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-kinase/Akt signaling,” Endocrinology, vol. 148, no. 2, pp. 512–529, 2007. View at Publisher · View at Google Scholar · View at Scopus
  155. Y. Sayo, K. Murao, H. Imachi et al., “The multiple endocrine neoplasia type 1 gene product, menin, inhibits insulin production in rat insulinoma cells,” Endocrinology, vol. 143, no. 6, pp. 2437–2440, 2002. View at Publisher · View at Google Scholar · View at Scopus
  156. J. S. Crabtree, P. C. Scacheri, J. M. Ward et al., “Of mice and MEN1: insulinomas in a conditional mouse knockout,” Molecular and Cellular Biology, vol. 23, no. 17, pp. 6075–6085, 2003. View at Publisher · View at Google Scholar · View at Scopus
  157. S. K. Karnik, C. M. Hughes, X. Gu et al., “Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 41, pp. 14659–14664, 2005. View at Publisher · View at Google Scholar · View at Scopus
  158. J. J. Heit, S. K. Karnik, and S. K. Kim, “Intrinsic regulators of pancreatic β-cell proliferation,” Annual Review of Cell and Developmental Biology, vol. 22, pp. 311–338, 2006. View at Publisher · View at Google Scholar · View at Scopus
  159. J. J. Heit, A. Apelqvist, X. Gu et al., “Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function,” Nature, vol. 443, no. 7109, pp. 345–349, 2006. View at Publisher · View at Google Scholar · View at Scopus
  160. R. W. Schnepp, Y. X. Chen, H. Wang et al., “Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells,” Cancer Research, vol. 66, no. 11, pp. 5707–5715, 2006. View at Publisher · View at Google Scholar · View at Scopus
  161. P. La, Y. Yang, S. K. Karnik et al., “Menin-mediated caspase 8 expression in suppressing multiple endocrine neoplasia type 1,” The Journal of Biological Chemistry, vol. 282, no. 43, pp. 31332–31340, 2007. View at Publisher · View at Google Scholar · View at Scopus
  162. N. Liadis, L. Salmena, E. Kwan et al., “Distinct in vivo roles of Caspase-8 in β-cells in physiological and diabetes models,” Diabetes, vol. 56, no. 9, pp. 2302–2311, 2007. View at Publisher · View at Google Scholar · View at Scopus
  163. M. S. Islam, N. M. Morton, A. Hansson, and V. Emilsson, “Rat insulinoma-derived pancreatic β-cells express a functional leptin receptor that mediates a proliferative response,” Biochemical and Biophysical Research Communications, vol. 238, no. 3, pp. 851–855, 1997. View at Publisher · View at Google Scholar
  164. S. Okuya, K. Tanabe, Y. Tanizawa, and Y. Oka, “Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis,” Endocrinology, vol. 142, no. 11, pp. 4827–4830, 2001. View at Publisher · View at Google Scholar · View at Scopus
  165. M. Shimabukuro, M. Y. Wang, Y. T. Zhou, C. B. Newgard, and R. H. Unger, “Protection against lipoapoptosis of β cells through leptin-dependent maintenance of Bcl-2 expression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 16, pp. 9558–9561, 1998. View at Publisher · View at Google Scholar · View at Scopus
  166. J. E. P. Brown and S. J. Dunmore, “Leptin decreases apoptosis and alters BCL-2: bax ratio in clonal rodent pancreatic beta-cells,” Diabetes/Metabolism Research and Reviews, vol. 23, no. 6, pp. 497–502, 2007. View at Publisher · View at Google Scholar · View at Scopus
  167. M. S. Islam, A. Sjöholm, and V. Emilsson, “Fetal pancreatic islets express functional leptin receptors and leptin stimulates proliferation of fetal islet cells,” International Journal of Obesity, vol. 24, no. 10, pp. 1246–1253, 2000.
  168. K. Tanabe, S. Okuya, Y. Tanizawa, A. Matsutani, and Y. Oka, “Leptin induces proliferation of pancreatic β cell line MIN6 through activation of mitogen-activated protein kinase,” Biochemical and Biophysical Research Communications, vol. 241, no. 3, pp. 765–768, 1997. View at Publisher · View at Google Scholar
  169. C. M. Taniguchi, B. Emanuelli, and C. R. Kahn, “Critical nodes in signalling pathways: insights into insulin action,” Nature Reviews Molecular Cell Biology, vol. 7, no. 2, pp. 85–96, 2006. View at Publisher · View at Google Scholar · View at Scopus
  170. N. Kubota, Y. Terauchi, K. Tobe et al., “Insulin receptor substrate 2 plays a crucial role in β cells and the hypothalamus,” Journal of Clinical Investigation, vol. 114, no. 7, pp. 917–927, 2004. View at Publisher · View at Google Scholar · View at Scopus
  171. P. R. Huypens, “Leptin and adiponectin regulate compensatory beta cell growth in accordance to overweight,” Medical Hypotheses, vol. 68, no. 5, pp. 1134–1137, 2007. View at Publisher · View at Google Scholar · View at Scopus
  172. K. Maedler, P. Sergeev, J. A. Ehses et al., “Leptin modulates β cell expression of IL-1 receptor antagonist and release of IL-1β in human islets,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 21, pp. 8138–8143, 2004. View at Publisher · View at Google Scholar · View at Scopus
  173. M. Guldstrand, B. Ahrén, and U. Adamson, “Improved β-cell function after standardized weight reduction in severely obese subjects,” American Journal of Physiology, vol. 284, no. 3, pp. E557–E565, 2003.
  174. K. Maedler, F. T. Schulthess, C. Bielman et al., “Glucose and leptin induce apoptosis in human β-cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases,” FASEB Journal, vol. 22, no. 6, pp. 1905–1913, 2008. View at Publisher · View at Google Scholar
  175. A. Fukuhara, M. Matsuda, M. Nishizawa et al., “Visfatin: a protein secreted by visceral fat that Mimics the effects of insulin,” Science, vol. 307, no. 5708, pp. 426–430, 2005. View at Publisher · View at Google Scholar · View at Scopus
  176. M. P. Chen, F. M. Chung, D. M. Chang et al., “Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 1, pp. 295–299, 2006. View at Publisher · View at Google Scholar
  177. J. H. Nielsen, C. Svensson, E. D. Galsgaard, A. Møldrup, and N. Billestrup, “Beta cell proliferation and growth factors,” Journal of Molecular Medicine, vol. 77, no. 1, pp. 62–66, 1999. View at Scopus
  178. R. L. Sorenson and T. C. Brelje, “Adaptation of islets of Langerhans to pregnancy: β-cell growth, enhanced insulin secretion and the role of lactogenic hormones,” Hormone and Metabolic Research, vol. 29, no. 6, pp. 301–307, 1997.
  179. L. Elghazi, C. Cras-Méneur, P. Czernichow, and R. Scharfmann, “Role for FGFR2IIIb-mediated signals in controlling pancreatic endocrine progenitor cell proliferation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 6, pp. 3884–3889, 2002. View at Publisher · View at Google Scholar · View at Scopus
  180. M. Freidin, S. Asche, T. A. Bargiello, M. V. L. Bennett, and C. K. Abrams, “Connexin 32 increases the proliferative response of Schwann cells to neuregulin-1 (Nrg1),” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 9, pp. 3567–3572, 2009. View at Publisher · View at Google Scholar · View at Scopus
  181. M. C. C. Lim, G. Maubach, and L. Zhuo, “TGF-β1 down-regulates connexin 43 expression and gap junction intercellular communication in rat hepatic stellate cells,” European Journal of Cell Biology, vol. 88, no. 12, pp. 719–730, 2009. View at Publisher · View at Google Scholar · View at Scopus
  182. C. C. G. Naus, J. F. Bechberger, Y. Zhang et al., “Altered gap junctional communication, intercellular signaling, and growth in cultured astrocytes deficient in connexin43,” Journal of Neuroscience Research, vol. 49, no. 5, pp. 528–540, 1997. View at Publisher · View at Google Scholar · View at Scopus
  183. V. Serre-Beinier, S. Le Gurun, N. Belluardo et al., “Cx36 preferentially connects β-cells within pancreatic islets,” Diabetes, vol. 49, no. 5, pp. 727–734, 2000. View at Scopus
  184. P. Klee, S. Lamprianou, A. Charollais et al., “Connexin implication in the control of the murine beta-cell mass,” Pediatric Research, vol. 70, no. 2, pp. 142–147, 2011. View at Publisher · View at Google Scholar
  185. G. Winnier, M. Blessing, P. A. Labosky, and B. L. M. Hogan, “Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse,” Genes and Development, vol. 9, no. 17, pp. 2105–2116, 1995. View at Scopus
  186. H. Hua, Y. Q. Zhang, S. Dabernat et al., “BMP4 regulates pancreatic progenitor cell expansion through Id2,” The Journal of Biological Chemistry, vol. 281, no. 19, pp. 13574–13580, 2006. View at Publisher · View at Google Scholar · View at Scopus
  187. L. Fajas, J. S. Annicotte, S. Miard, D. Sarruf, M. Watanabe, and J. Auwerx, “Impaired pancreatic growth, β cell mass, and β cell function in E2F1-7(/) mice,” Journal of Clinical Investigation, vol. 113, no. 9, pp. 1288–1295, 2004. View at Publisher · View at Google Scholar · View at Scopus
  188. A. Iglesias, M. Murga, U. Laresgoiti et al., “Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice,” Journal of Clinical Investigation, vol. 113, no. 10, pp. 1398–1407, 2004. View at Publisher · View at Google Scholar · View at Scopus
  189. J. A. Kushner, M. A. Ciemerych, E. Sicinska et al., “Cyclins D2 and D1 are essential for postnatal pancreatic β-cell growth,” Molecular and Cellular Biology, vol. 25, no. 9, pp. 3752–3762, 2005. View at Publisher · View at Google Scholar · View at Scopus
  190. X. Zhang, J. P. Gaspard, Y. Mizukami, J. Li, F. Graeme-Cook, and D. C. Chung, “Overexpression of cyclin D1 in pancreatic β-cells in vivo results in islet hyperplasia without hypoglycemia,” Diabetes, vol. 54, no. 3, pp. 712–719, 2005. View at Publisher · View at Google Scholar · View at Scopus
  191. S. G. Rane, P. Dubus, R. V. Mettus et al., “Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia,” Nature Genetics, vol. 22, no. 1, pp. 44–54, 1999. View at Publisher · View at Google Scholar · View at Scopus
  192. N. Marzo, C. Mora, M. E. Fabregat et al., “Pancreatic islets from cyclin-dependent kinase 4/R24C (Cdk4) knockin mice have significantly increased beta cell mass and are physiologically functional, indicating that Cdk4 is a potential target for pancreatic beta cell mass regeneration in Type 1 diabetes,” Diabetologia, vol. 47, no. 4, pp. 686–694, 2004. View at Publisher · View at Google Scholar · View at Scopus
  193. I. Cozar-Castellano, K. K. Takane, R. Bottino, A. N. Balamurugan, and A. F. Stewart, “Induction of beta-cell proliferation and retinoblastoma protein phosphorylation in rat and human islets using adenovirus-mediated transfer of cyclin-dependent kinase-4 and cyclin D1,” Diabetes, vol. 53, no. 1, pp. 149–159, 2004. View at Publisher · View at Google Scholar · View at Scopus
  194. T. Tsutsui, B. Hesabi, D. S. Moons et al., “Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity,” Molecular and Cellular Biology, vol. 19, no. 10, pp. 7011–7019, 1999. View at Scopus
  195. T. Uchida, T. Nakamura, N. Hashimoto et al., “Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice,” Nature Medicine, vol. 11, no. 2, pp. 175–182, 2005. View at Publisher · View at Google Scholar · View at Scopus
  196. T. L. Jetton, J. Lausier, K. LaRock et al., “Mechanisms of compensatory β-cell growth in insulin-resistant rats: roles of Akt kinase,” Diabetes, vol. 54, no. 8, pp. 2294–2304, 2005. View at Publisher · View at Google Scholar · View at Scopus
  197. A. Kauffmann-Zeh, P. Rodriguez-Viciana, E. Ulrich et al., “Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB,” Nature, vol. 385, no. 6616, pp. 544–548, 1997. View at Publisher · View at Google Scholar · View at Scopus
  198. M. K. Lingohr, L. M. Dickson, C. E. Wrede, J. F. McCuaig, M. G. Myers Jr., and C. J. Rhodes, “IRS-3 inhibits IRS-2-mediated signaling in pancreatic β-cells,” Molecular and Cellular Endocrinology, vol. 204, no. 1-2, pp. 85–99, 2003. View at Publisher · View at Google Scholar
  199. Q. Wang, L. Li, E. Xu, V. Wong, C. Rhodes, and P. L. Brubaker, “Glucagon-like peptitle-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells,” Diabetologia, vol. 47, no. 3, pp. 478–487, 2004. View at Publisher · View at Google Scholar · View at Scopus
  200. P. Cohen, “The Croonian Lecture 1998. Identification of a protein kinase cascade of major importance in insulin signal transduction,” Philosophical Transactions of the Royal Society B, vol. 354, no. 1382, pp. 485–495, 1999. View at Scopus
  201. C. Belham, S. Wu, and J. Avruch, “Intracellular signalling: PDK1—a kinase at the hub of things,” Current Biology, vol. 9, no. 3, pp. R93–R96, 1999. View at Publisher · View at Google Scholar · View at Scopus
  202. M. A. Lawlor and D. R. Alessi, “PKB/Akt: a key mediator of cell proliferation, survival and insulin responses?” Journal of Cell Science, vol. 114, no. 16, pp. 2903–2910, 2001. View at Scopus
  203. Y. I. Kitamura, T. Kitamura, J. P. Kruse et al., “FoxO1 protects against pancreatic β cell failure through NeuroD and MafA induction,” Cell Metabolism, vol. 2, no. 3, pp. 153–163, 2005. View at Publisher · View at Google Scholar · View at Scopus
  204. T. Kitamura, J. Nakae, Y. Kitamura et al., “The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic β cell growth,” Journal of Clinical Investigation, vol. 110, no. 12, pp. 1839–1847, 2002. View at Publisher · View at Google Scholar · View at Scopus
  205. C. S. Lee, N. J. Sund, M. Z. Vatamaniuk, F. M. Matschinsky, D. A. Stoffers, and K. H. Kaestner, “Foxa2 controls Pdx1 gene expression in pancreatic β-cells in vivo,” Diabetes, vol. 51, no. 8, pp. 2546–2551, 2002. View at Scopus
  206. D. Kawamori, H. Kaneto, Y. Nakatani et al., “The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation,” The Journal of Biological Chemistry, vol. 281, no. 2, pp. 1091–1098, 2006. View at Publisher · View at Google Scholar · View at Scopus
  207. H. Okamoto, M. L. Hribal, H. V. Lin, W. R. Bennett, A. Ward, and D. Accili, “Role of the forkhead protein FoxO1 in β cell compensation to insulin resistance,” Journal of Clinical Investigation, vol. 116, no. 3, pp. 775–782, 2006. View at Publisher · View at Google Scholar · View at Scopus
  208. J. Ai, J. Duan, X. Lv et al., “Overexpression of FoxO1 causes proliferation of cultured pancreatic β cells exposed to low nutrition,” Biochemistry, vol. 49, no. 1, pp. 218–225, 2010. View at Publisher · View at Google Scholar · View at Scopus
  209. D. J. Withers, J. S. Gutierrez, H. Towery et al., “Disruption of IRS-2 causes type 2 diabetes in mice,” Nature, vol. 391, no. 6670, pp. 900–904, 1998. View at Publisher · View at Google Scholar · View at Scopus
  210. E. Araki, M. A. Lipes, M. E. Patti et al., “Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene,” Nature, vol. 372, no. 6502, pp. 186–190, 1994. View at Publisher · View at Google Scholar · View at Scopus
  211. A. M. Hennige, U. Ozcan, T. Okada et al., “Alterations in growth and apoptosis of insulin receptor substrate-1-deficient β-cells,” American Journal of Physiology, vol. 289, no. 2, pp. E337–E346, 2005. View at Publisher · View at Google Scholar
  212. H. Cho, J. L. Thorvaldsen, Q. Chu, F. Feng, and M. J. Birnbaum, “Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice,” The Journal of Biological Chemistry, vol. 276, no. 42, pp. 38349–38352, 2001. View at Publisher · View at Google Scholar · View at Scopus
  213. R. L. Tuttle, N. S. Gill, W. Pugh et al., “Regulation of pancreatic β-cell growth and survival by the serine/threonine protein kinase Akt1/PKBα,” Nature Medicine, vol. 7, no. 10, pp. 1133–1137, 2001. View at Publisher · View at Google Scholar · View at Scopus
  214. L. M. Dickson and C. J. Rhodes, “Pancreatic β-cell growth and survival in the onset of type 2 diabetes: a role for protein kinase B in the Akt?” American Journal of Physiology, vol. 287, no. 2, pp. E192–E198, 2004. View at Publisher · View at Google Scholar
  215. R. N. Kulkarni, U. S. Jhala, J. N. Winnay, S. Krajewski, M. Montminy, and C. R. Kahn, “PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance,” Journal of Clinical Investigation, vol. 114, no. 6, pp. 828–836, 2004. View at Publisher · View at Google Scholar · View at Scopus
  216. M. Brissova, M. Blaha, C. Spear et al., “Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis,” American Journal of Physiology, vol. 288, no. 4, pp. E707–E714, 2005. View at Publisher · View at Google Scholar
  217. Z. Liu, K. Tanabe, E. Bernal-Mizrachi, and M. A. Permutt, “Mice with beta cell overexpression of glycogen synthase kinase-3β have reduced beta cell mass and proliferation,” Diabetologia, vol. 51, no. 4, pp. 623–631, 2008. View at Publisher · View at Google Scholar · View at Scopus
  218. M. Surjit and S. K. Lal, “Glycogen synthase kinase-3 phosphorylates and regulates the stability of p27kip1 protein,” Cell Cycle, vol. 6, no. 5, pp. 580–588, 2007. View at Scopus
  219. J. A. Diehl, M. Cheng, M. F. Roussel, and C. J. Sherr, “Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization,” Genes and Development, vol. 12, no. 22, pp. 3499–3511, 1998. View at Scopus
  220. M. J. Boucher, L. Selander, L. Carlsson, and H. Edlund, “Phosphorylation marks IPF1/PDX1 protein for degradation by glycogen synthase kinase 3-dependent mechanisms,” The Journal of Biological Chemistry, vol. 281, no. 10, pp. 6395–6403, 2006. View at Publisher · View at Google Scholar · View at Scopus
  221. J. Downward, “Ras signalling and apoptosis,” Current Opinion in Genetics and Development, vol. 8, no. 1, pp. 49–54, 1998. View at Publisher · View at Google Scholar · View at Scopus
  222. M. Benito, A. M. Valverde, and M. Lorenzo, “IGF-I: a mitogen also involved in differentiation processes in mammalian cells,” International Journal of Biochemistry and Cell Biology, vol. 28, no. 5, pp. 499–510, 1996. View at Publisher · View at Google Scholar · View at Scopus
  223. T. Kadowaki, et al., “Signal transduction mechanism of insulin and insulin-like growth factor-1,” Endocrine Journal, vol. 43, supplement, pp. S33–S41, 1996.
  224. J. Avruch, X. F. Zhang, and J. M. Kyriakis, “Raf meets ras: completing the framework of a signal transduction pathway,” Trends in Biochemical Sciences, vol. 19, no. 7, pp. 279–283, 1994. View at Publisher · View at Google Scholar · View at Scopus
  225. S. Khoo and M. H. Cobb, “Activation of mitogen-activating protein kinase by glucose is not required for insulin secretion,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 11, pp. 5599–5604, 1997. View at Publisher · View at Google Scholar · View at Scopus
  226. L. S. Smit, D. J. Meyer, N. Billestrup, G. Norstedt, J. Schwartz, and C. Carter-Su, “The role of the growth hormone (GH) receptor and JAK1 and JAK2 kinases in the activation of Stats 1, 3, and 5 by GH,” Molecular Endocrinology, vol. 10, no. 5, pp. 519–533, 1996. View at Publisher · View at Google Scholar · View at Scopus
  227. J. C. Chow, P. R. Ling, Z. Qu et al., “Growth hormone stimulates tyrosine phosphorylation of JAK2 and STAT5, but not insulin receptor substrate-1 or SHC proteins in liver and skeletal muscle of normal rats in vivo,” Endocrinology, vol. 137, no. 7, pp. 2880–2886, 1996. View at Publisher · View at Google Scholar · View at Scopus
  228. E. D. Galsgaard, B. N. Friedrichsen, J. H. Nielsen, and A. Møldrup, “Expression of dominant-negative STAT5 inhibits growth hormone- and prolactin-induced proliferation of insulin-producing cells,” Diabetes, vol. 50, no. 1, supplement, pp. S40–S41, 2001. View at Scopus
  229. J. Jensen, E. D. Galsgaard, A. E. Karlsen, Y. C. Lee, and J. H. Nielsen, “STAT5 activation by human GH protects insulin-producing cells against interleukin-1β, interferon-γ and tumour necrosis factor-α-induced apoptosis independent of nitric oxide production,” Journal of Endocrinology, vol. 187, no. 1, pp. 25–36, 2005. View at Publisher · View at Google Scholar · View at Scopus
  230. D. L. Krebs and D. J. Hilton, “SOCS proteins: negative regulators of cytokine signaling,” Stem Cells, vol. 19, no. 5, pp. 378–387, 2001. View at Scopus
  231. K. Lindberg, S. G. Rønn, D. Tornehave et al., “Regulation of pancreatic β-cell mass and proliferation by SOCS-3,” Journal of Molecular Endocrinology, vol. 35, no. 2, pp. 231–243, 2005. View at Publisher · View at Google Scholar · View at Scopus
  232. J. C. Jonas, D. R. Laybutt, G. M. Steil et al., “High glucose stimulates early response gene c-Myc expression in rat pancreatic β cells,” The Journal of Biological Chemistry, vol. 276, no. 38, pp. 35375–35381, 2001. View at Publisher · View at Google Scholar · View at Scopus
  233. H. Elouil, A. K. Cardozo, D. L. Eizirik, J. C. Henquin, and J. C. Jonas, “High glucose and hydrogen peroxide increase c-Myc and haeme-oxygenase 1 mRNA levels in rat pancreatic islets without activating NFκB,” Diabetologia, vol. 48, no. 3, pp. 496–505, 2005. View at Publisher · View at Google Scholar · View at Scopus
  234. P. Steiner, A. Philipp, J. Lukas et al., “Identification of a Myc-dependent step during the formation of active G1 cyclin-cdk complexes,” EMBO Journal, vol. 14, no. 19, pp. 4814–4826, 1995. View at Scopus
  235. K. Berns, E. M. Hijmans, and R. Bernards, “Repression of c-Myc responsive genes in cycling cells causes G1 arrest through reduction of cyclin E/CDK2 kinase activity,” Oncogene, vol. 15, no. 11, pp. 1347–1356, 1997. View at Scopus
  236. C. Bouchard, K. Thieke, A. Maier et al., “Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27,” EMBO Journal, vol. 18, no. 19, pp. 5321–5333, 1999. View at Publisher · View at Google Scholar · View at Scopus
  237. H. Hermeking, C. Rago, M. Schuhmacher et al., “Identification of CDK4 as a target of c-MYC,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 5, pp. 2229–2234, 2000. View at Publisher · View at Google Scholar · View at Scopus
  238. S. Pelengaris and M. Khan, “Oncogenic co-operation in β-cell tumorigenesis,” Endocrine-Related Cancer, vol. 8, no. 4, pp. 307–314, 2001. View at Publisher · View at Google Scholar
  239. I. Perez-Roger, S. H. Kim, B. Griffiths, A. Sewing, and H. Land, “Cyclins D1 and D2 mediate Myc-induced proliferation via sequestration of p27Kip1 and p21Cip1,” EMBO Journal, vol. 18, no. 19, pp. 5310–5320, 1999. View at Publisher · View at Google Scholar · View at Scopus
  240. P. G. Hogan, L. Chen, J. Nardone, and A. Rao, “Transcriptional regulation by calcium, calcineurin, and NFAT,” Genes and Development, vol. 17, no. 18, pp. 2205–2232, 2003. View at Publisher · View at Google Scholar · View at Scopus
  241. D. Demozay, S. Tsunekawa, I. Briaud, R. Shah, and C. J. Rhodes, “Specific glucose-induced control of insulin receptor substrate-2 expression is mediated via Ca2+-dependent calcineurin/NFAT signaling in primary pancreatic islet β-cells,” Diabetes, vol. 60, no. 11, pp. 2892–2902, 2011. View at Publisher · View at Google Scholar
  242. S. A. Soleimanpour, M. F. Crutchlow, A. M. Ferrari et al., “Calcineurin signaling regulates human islet β-cell survival,” The Journal of Biological Chemistry, vol. 285, no. 51, pp. 40050–40059, 2010. View at Publisher · View at Google Scholar · View at Scopus
  243. E. Bernal-Mizrachi, C. Cras-Méneur, B. R. Ye, J. D. Johnson, and M. A. Permutt, “Transgenic overexpression of active calcineurin in β-cells results in decreased β-cell mass and hyperglycemia,” PLoS ONE, vol. 5, no. 8, article e11969, 2010. View at Publisher · View at Google Scholar
  244. S. Fatrai, L. Elghazi, N. Balcazar et al., “Akt induces β-cell proliferation by regulating cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity,” Diabetes, vol. 55, no. 2, pp. 318–325, 2006. View at Publisher · View at Google Scholar · View at Scopus
  245. X. H. Pei, F. Bai, T. Tsutsui, H. Kiyokawa, and Y. Xiong, “Genetic evidence for functional dependency of p18Ink4c on Cdk4,” Molecular and Cellular Biology, vol. 24, no. 15, pp. 6653–6664, 2004. View at Publisher · View at Google Scholar · View at Scopus
  246. S. G. Rane and E. P. Reddy, “Cell cycle control of pancreatic beta cell proliferation,” Front Biosci, vol. 5, pp. D1–19, 2000. View at Scopus
  247. C. J. Sherr, “The INK4a/ARF network in tumour suppression,” Nature Reviews Molecular Cell Biology, vol. 2, no. 10, pp. 731–737, 2001. View at Publisher · View at Google Scholar · View at Scopus
  248. S. A. Kassem, I. Ariel, P. S. Thornton et al., “p57KIP2 expression in normal islet cells and in hyperinsulinism of infancy,” Diabetes, vol. 50, no. 12, pp. 2763–2769, 2001. View at Scopus
  249. S. Georgia and A. Bhushan, “p27 regulates the transition of β-cells from quiescence to proliferation,” Diabetes, vol. 55, no. 11, pp. 2950–2956, 2006. View at Publisher · View at Google Scholar · View at Scopus
  250. V. Ambros, “The functions of animal microRNAs,” Nature, vol. 431, no. 7006, pp. 350–355, 2004. View at Publisher · View at Google Scholar · View at Scopus
  251. D. P. Bartel, “MicroRNAs: genomics, biogenesis, mechanism, and function,” Cell, vol. 116, no. 2, pp. 281–297, 2004. View at Publisher · View at Google Scholar · View at Scopus
  252. P. Lovis, E. Roggli, D. R. Laybutt et al., “Alterations in microRNA expression contribute to fatty acid-induced pancreatic β-cell dysfunction,” Diabetes, vol. 57, no. 10, pp. 2728–2736, 2008. View at Publisher · View at Google Scholar · View at Scopus
  253. E. Roggli, A. Britan, S. Gattesco et al., “Involvement of microRNAs in the cytotoxic effects exerted by proinflammatory cytokines on pancreatic β-cells,” Diabetes, vol. 59, no. 4, pp. 978–986, 2010. View at Publisher · View at Google Scholar · View at Scopus
  254. F. A. Van Assche, L. Aerts, and F. De Prins, “A morphological study of the endocrine pancreas in human pregnancy,” British Journal of Obstetrics and Gynaecology, vol. 85, no. 11, pp. 818–820, 1978.
  255. L. Scaglia, F. E. Smith, and S. Bonner-Weir, “Apoptosis contributes to the involution of β cell mass in the post partum rat pancreas,” Endocrinology, vol. 136, no. 12, pp. 5461–5468, 1995. View at Scopus
  256. J. A. Parsons, A. Bartke, and R. L. Sorenson, “Number and size of islets of langerhans in pregnant, human growth hormone- expressing transgenic, and pituitary dwarf mice: effect of lactogenic hormones,” Endocrinology, vol. 136, no. 5, pp. 2013–2021, 1995. View at Scopus
  257. S. Rieck, P. White, J. Schug et al., “The transcriptional response of the islet to pregnancy in mice,” Molecular Endocrinology, vol. 23, no. 10, pp. 1702–1712, 2009. View at Publisher · View at Google Scholar · View at Scopus
  258. A. E. Butler, L. Cao-Minh, R. Galasso et al., “Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy,” Diabetologia, vol. 53, no. 10, pp. 2167–2176, 2010. View at Publisher · View at Google Scholar · View at Scopus
  259. R. C. Vasavada, A. Garcia-Ocaña, W. S. Zawalich et al., “Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation, and hypoglycemia,” The Journal of Biological Chemistry, vol. 275, no. 20, pp. 15399–15406, 2000. View at Publisher · View at Google Scholar · View at Scopus
  260. H. Kim, Y. Toyofuku, F. C. Lynn et al., “Serotonin regulates pancreatic beta cell mass during pregnancy,” Nature Medicine, vol. 16, no. 7, pp. 804–808, 2010. View at Publisher · View at Google Scholar · View at Scopus
  261. C. Bole-Feysot, V. Goffin, M. Edery, N. Binart, and P. A. Kelly, “Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice,” Endocrine Reviews, vol. 19, no. 3, pp. 225–268, 1998. View at Scopus
  262. L. E. Stout, A. M. Svensson, and R. L. Sorenson, “Prolactin regulation of islet-derived INS-1 cells: characteristics and immunocytochemical analysis of STAT5 translocation,” Endocrinology, vol. 138, no. 4, pp. 1592–1603, 1997. View at Publisher · View at Google Scholar · View at Scopus
  263. T. C. Brelje, D. W. Scharp, P. E. Lacy et al., “Effect of homologous placental lactogens, prolactins, and growth hormones on islet B-cell division and insulin secretion in rat, mouse, and human islets: implication for placental lactogen regulation of islet function during pregnancy,” Endocrinology, vol. 132, no. 2, pp. 879–887, 1993. View at Publisher · View at Google Scholar · View at Scopus
  264. I. Cozar-Castellano, M. Weinstock, M. Haught, S. Velázquez-Garcia, D. Sipula, and A. F. Stewart, “Evaluation of β-cell replication in mice transgenic for hepatocyte growth factor and placental lactogen: comprehensive characterization of the G1/S regulatory proteins reveals unique involvement of p21 cip,” Diabetes, vol. 55, no. 1, pp. 70–77, 2006. View at Publisher · View at Google Scholar · View at Scopus
  265. M. Freemark, I. Avril, D. O. N. Fleenor et al., “Targeted deletion of the PRL receptor: effects on islet development, insulin production, and glucose tolerance,” Endocrinology, vol. 143, no. 4, pp. 1378–1385, 2002. View at Publisher · View at Google Scholar · View at Scopus
  266. C. Huang, F. Snider, and J. C. Cross, “Prolactin receptor is required for normal glucose homeostasis and modulation of β-cell mass during pregnancy,” Endocrinology, vol. 150, no. 4, pp. 1618–1626, 2009. View at Publisher · View at Google Scholar · View at Scopus
  267. T. C. Brelje, L. E. Stout, N. V. Bhagroo, and R. L. Sorenson, “Distinctive roles for prolactin and growth hormone in the activation of signal transducer and activator of transcription 5 in pancreatic islets of Langerhans,” Endocrinology, vol. 145, no. 9, pp. 4162–4175, 2004. View at Publisher · View at Google Scholar · View at Scopus
  268. M. E. C. Amaral, D. A. Cunha, G. F. Anhê et al., “Participation of prolactin receptors and phosphatidylinositol 3-kinase and MAP kinase pathways in the increase in pancreatic islet mass and sensitivity to glucose during pregnancy,” Journal of Endocrinology, vol. 183, no. 3, pp. 469–476, 2004. View at Publisher · View at Google Scholar · View at Scopus
  269. M. E. C. Amaral, M. Ueno, J. B. Carvalheira et al., “Prolactin-signal transduction in neonatal rat pancreatic islets and interaction with the insulin-signaling pathway,” Hormone and Metabolic Research, vol. 35, no. 5, pp. 282–289, 2003. View at Publisher · View at Google Scholar · View at Scopus
  270. E. Hughes and C. Huang, “Participation of Akt, menin, and p21 in pregnancy-induced β-cell proliferation,” Endocrinology, vol. 152, no. 3, pp. 847–855, 2011. View at Publisher · View at Google Scholar
  271. H. Sone and Y. Kagawa, “Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice,” Diabetologia, vol. 48, no. 1, pp. 58–67, 2005. View at Publisher · View at Google Scholar · View at Scopus