Cell Biochemistry and Biophysics

, Volume 48, Issue 2–3, pp 127–137 | Cite as

The role of Islet Neogenesis-Associated Protein (INGAP) in islet neogenesis

  • Mark Lipsett
  • Stephen Hanley
  • Mauro Castellarin
  • Emily Austin
  • Wilma L. Suarez-Pinzon
  • Alex Rabinovitch
  • Lawrence RosenbergEmail author
Original Paper


Islet Neogenesis-Associated Protein (INGAP) is a member of the Reg family of proteins implicated in various settings of endogenous pancreatic regeneration. The expression of INGAP and other RegIII proteins has also been linked temporally and spatially with the induction of islet neogenesis in animal models of disease and regeneration. Furthermore, administration of a peptide fragment of INGAP (INGAP peptide) has been demonstrated to reverse chemically induced diabetes as well as improve glycemic control and survival in an animal model of type 1 diabetes. Cultured human pancreatic tissue has also been shown to be responsive to INGAP peptide, producing islet-like structures with function, architecture and gene expression matching that of freshly isolated islets. Likewise, studies in normoglycemic animals show evidence of islet neogenesis. Finally, recent clinical studies suggest an effect of INGAP peptide to improve insulin production in type 1 diabetes and glycemic control in type 2 diabetes.


INGAP Islet neogenesis Pancreatic plasticity Regeneration Diabetes 



The authors would like to thank Drs. Diane Finegood and Fraser Scott for generously sharing tissue samples. GMP Endotherapeutics is thanked for providing tissue samples from pre-clinical animal studies. SH is supported by a fellowship from the Canadian Diabetes Association (CDA) and the Canadian Institutes of Health Research (CIHR). ML is supported by a fellowship from the CIHR and the Diabetic Children’s Foundation. EA is supported by a fellowship from the Research Institute of the McGill University Health Centre. LR is a chercheur national (national scientist) of the Fonds de Recherche Scientifique du Québec (FRSQ). This work was supported by the CDA, CIHR and Juvenile Diabetes Research Foundation. The statements, opinions, and conclusions contained in this article are strictly those of the authors and do not represent the statements, opinions, or conclusions of any company, including any sponsor of the studies, or any research organization, or university.


  1. 1.
    Tan, M. H., & MacLean, D. R. (1995). Epidemiology of diabetes mellitus in Canada. Clinical and Investigative Medicine, 18, 240–246.PubMedGoogle Scholar
  2. 2.
    Meltzer, S., Leiter, L., Daneman, D., Gerstein, H. C., Lau, D., Ludwig, S., Yale, J. F., Zinman, B., & Lillie, D. (1998). 1998 clinical practice guidelines for the management of diabetes in Canada. Canadian Medical Association Journal, 159, S1–S29.PubMedGoogle Scholar
  3. 3.
    Atkinson, M. A., & Eisenbarth, G. S. (2001). Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet, 358, 221–229.CrossRefPubMedGoogle Scholar
  4. 4.
    Saltiel, A. R. (2001). New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell, 104, 517–529.CrossRefPubMedGoogle Scholar
  5. 5.
    The Diabetes Control and Complications Trial Research Group (1993). 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, 329, 977–986.Google Scholar
  6. 6.
    Diabetes Control, Complications Trial (DCCT) Research Group (2003). Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Journal of the American Medical Association, 290, 2159–2167.Google Scholar
  7. 7.
    Sutherland, D. E., Gruessner, A., & Hering, B. J. (2004). Beta-cell replacement therapy (pancreas and islet transplantation) for treatment of diabetes mellitus: an integrated approach. Endocrinology and Metabolism Clinics of North America, 33, 135–148.CrossRefPubMedGoogle Scholar
  8. 8.
    Bonner-Weir, S., Taneja, M., Weir, G. C., Tatarkiewicz, K., Song, K. H., Sharma, A., & O’Neil, J. J. (2000). In vitro cultivation of human islets from expanded ductal tissue. Proceedings of the National Academy of Science, 97, 7999–8004.CrossRefGoogle Scholar
  9. 9.
    Seaberg, R. M., Smukler, S. R., Kieffer, T. J., Enikolopov, G., Asghar, Z., Wheeler, M. B., Korbutt, G., & van der Kooy, D. (2004). Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nature Biotechnology, 22, 1115–1124.CrossRefPubMedGoogle Scholar
  10. 10.
    Gershengorn, M. C., Hardikar, A. A., Wei, C., Geras-Raaka, E., Marcus-Samuels, B., & Raaka, B. M. (2004). Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells. Science, 306, 2261–2264.CrossRefPubMedGoogle Scholar
  11. 11.
    Lechner, A., Nolan, A. L., Blacken, R. A., & Habener, J. F. (2005). Redifferentiation of insulin-secreting cells after in vitro expansion of adult human pancreatic islet tissue. Biochemical and Biophysical Research Communications, 327, 581–588.CrossRefPubMedGoogle Scholar
  12. 12.
    Jamal, A. M., Lipsett, M., Sladek, R., Laganiere, S., Hanley, S., & Rosenberg, L. (2005). Morphogenetic plasticity of adult human pancreatic islets of Langerhans. Cell Death and Differentiation, 12, 702–712.CrossRefPubMedGoogle Scholar
  13. 13.
    Dor, Y., Brown, J., Martinez, O. I., & Melton, D. A. (2004). Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature, 429, 41–46.CrossRefPubMedGoogle Scholar
  14. 14.
    Bonner-Weir, S., Baxter, L. A., Schuppin, G. T., & Smith, F. E. (1993). A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes, 42, 1715–1720.CrossRefPubMedGoogle Scholar
  15. 15.
    Rosenberg, L. (1995). In vivo cell transformation: neogenesis of beta cells from pancreatic ductal cells. Cell Transplantation, 4, 371–383.CrossRefPubMedGoogle Scholar
  16. 16.
    Meier, J. J., Bhushan, A., Butler, A. E., Rizza, R. A., & Butler, P. C. (2005). Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia, 48, 2221–2228.CrossRefPubMedGoogle Scholar
  17. 17.
    Smith, F. E., Rosen, K. M., Villa-Komaroff, L., Weir, G. C., & Bonner-Weir, S. (1991). Enhanced insulin-like growth factor I gene expression in regenerating rat pancreas. Proceedings of the National Academy of Science, 88, 6152–6156.CrossRefGoogle Scholar
  18. 18.
    George, M., Ayuso, E., Casellas, A., Costa, C., Devedjian, J. C., & Bosch, F. (2002) Beta cell expression of IGF-I leads to recovery from type 1 diabetes. The Journal of Clinical Investigation, 109, 1153–1163.CrossRefPubMedGoogle Scholar
  19. 19.
    Nielsen, J. H., Svensson, C., Galsgaard, E. D., Moldrup, A., & Billestrup, N. (1999). Beta cell proliferation and growth factors. Journal of Molecular Medicine, 77, 62–66.CrossRefPubMedGoogle Scholar
  20. 20.
    Brand, S. J., Tagerud, S., Lambert, P., Magil, S. G., Tatarkiewicz, K., Doiron, K., & Yan, Y. (2002). Pharmacological treatment of chronic diabetes by stimulating pancreatic beta-cell regeneration with systemic co-administration of EGF and gastrin. Pharmacology & Toxicology, 91, 414–420.CrossRefGoogle Scholar
  21. 21.
    Rooman, I., Lardon, J., & Bouwens, L. (2002). Gastrin stimulates beta-cell neogenesis and increases islet mass from transdifferentiated but not from normal exocrine pancreas tissue. Diabetes, 51, 686–690.CrossRefPubMedGoogle Scholar
  22. 22.
    Suarez-Pinzon, W. L., Lakey, J. R., Brand, S. J., & Rabinovitch, A. (2005). 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. The Journal of Clinical Endocrinology and Metabolism, 90, 3401–3409.CrossRefPubMedGoogle Scholar
  23. 23.
    Sandgren, E. P., Luetteke, N. C., Palmiter, R. D., Brinster, R. L., & Lee, D. C. (1990). Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell, 61(6), 1121–1135.CrossRefPubMedGoogle Scholar
  24. 24.
    Wang, T. C., Bonner-Weir, S., Oates, P. S., Chulak, M., Simon, B., Merlino, G. T., Schmidt, E. V., & Brand, S. J. (1993). Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells. The Journal of Clinical Investigation, 92, 1349–1356.PubMedGoogle Scholar
  25. 25.
    Wang, R. N., Rehfeld, J. F., Nielsen, F. C., & Kloppel, G. (1997). Expression of gastrin and transforming growth factor-alpha during duct to islet cell differentiation in the pancreas of duct-ligated adult rats. Diabetologia, 40, 887–893.CrossRefPubMedGoogle Scholar
  26. 26.
    Song, S. Y., Gannon, M., Washington, M. K., Scoggins, C. R., Meszoely, I. M., Goldenring, J. R., Marino, C. R., Sandgren, E. P., Coffey, R. J. Jr., Wright, C. V., & Leach, S. D. (1999). Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis in transgenic mice overexpressing transforming growth factor alpha. Gastroenterology, 117, 1416–1426.CrossRefPubMedGoogle Scholar
  27. 27.
    Buteau, J., Foisy, S., Joly, E., & Prentki, M. (2003). Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes, 52, 124–132.CrossRefPubMedGoogle Scholar
  28. 28.
    Lipsett, M., Hanley, S., Radzioch, D., Compton, O., Wang, G. S., Scott, F., Finegood, D., & Rosenberg, L. (2003). INGAP: A critical mediator of islet neogenesis? Diabetes, 52, A360.Google Scholar
  29. 29.
    Rosenberg, L., Lipsett, M., Yoon, J. W., Prentki, M., Wang, R., Jun, H. S., Pittenger, G. L., Taylor-Fishwick, D., & Vinik, A. I. (2004). A pentadecapeptide fragment of islet neogenesis-associated protein increases beta-cell mass and reverses diabetes in C57BL/6J mice. Annals of Surgery, 240, 875–884.CrossRefPubMedGoogle Scholar
  30. 30.
    Pospisilik, J. A., Martin, J., Doty, T., Ehses, J. A., Pamir, N., Lynn, F. C., Piteau, S., Demuth, H. U., McIntosh, C. H., & Pederson, R. A. (2003). Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes, 52, 741–750.CrossRefPubMedGoogle Scholar
  31. 31.
    Nauck, M. A. (2004). Glucagon-like peptide 1 (GLP-1) in the treatment of diabetes. Hormone and Metabolic Research, 36, 852–858.CrossRefPubMedGoogle Scholar
  32. 32.
    Gallwitz, B. (2005). Glucagon-like peptide-1 as a treatment option for type 2 diabetes and its role in restoring beta-cell mass. Diabetes Technology & Therapeutics, 7, 651–657.CrossRefGoogle Scholar
  33. 33.
    Xu, G., Stoffers, D. A., Habener, J. F., & Bonner-Weir, S. (1999). Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes, 48, 2270–2276.CrossRefPubMedGoogle Scholar
  34. 34.
    Tourrel, C., Bailbe, D., Meile, M. J., Kergoat, M., & Portha, B. (2001). Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes, 50, 1562–1570.CrossRefPubMedGoogle Scholar
  35. 35.
    Holz, G. G., & Chepurny, O. G. (2003). Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus. Current Medicinal Chemistry, 10, 2471–2483.CrossRefPubMedGoogle Scholar
  36. 36.
    Gedulin, B. R., Nikoulina, S. E., Smith, P. A., Gedulin, G., Nielsen, L. L., Baron, A. D., Parkes, D. G., & Young, A. A. (2005). Exenatide (exendin-4) improves insulin sensitivity and {beta}-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight. Endocrinology, 146, 2069–2076.CrossRefPubMedGoogle Scholar
  37. 37.
    Xu, G., Kaneto, H., Lopez-Avalos, M. D., Weir, G. C., & Bonner-Weir, S. (2006). GLP-1/exendin-4 facilitates beta-cell neogenesis in rat and human pancreatic ducts. Diabetes Research and Clinical Practice, 73, 107–110.CrossRefPubMedGoogle Scholar
  38. 38.
    Service, G. J., Thompson, G. B., Service, F. J., Andrews, J. C., Collazo-Clavell, M. L., & Lloyd, R. V. (2005). Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. The New England Journal of Medicine, 353, 249–254.CrossRefPubMedGoogle Scholar
  39. 39.
    Kaiser, A. M. (2005). To the editor: Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. The New England Journal of Medicine, 353, 2192–2193.CrossRefPubMedGoogle Scholar
  40. 40.
    Carpenter, T., Trautmann, M. E., & Baron, A. D. (2005). To the editor: Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. The New England Journal of Medicine, 353, 2192.CrossRefPubMedGoogle Scholar
  41. 41.
    Rafaeloff, R., Pittenger, G. L., Barlow, S. W., Qin, X. F., Yan, B., Rosenberg, L., Duguid, W. P., & Vinik, A. I. (1997). Cloning and sequencing of the pancreatic islet neogenesis associated protein (INGAP) gene and its expression in islet neogenesis in hamsters. The Journal of Clinical Investigation, 99, 2100–2109.PubMedGoogle Scholar
  42. 42.
    Terazono, K., Yamamoto, H., Takasawa, S., Shiga, K., Yonemura, Y., Tochino, Y., & Okamoto, H. (1988). A novel gene activated in regenerating islets. The Journal of Biological Chemistry, 263, 2111–2114.PubMedGoogle Scholar
  43. 43.
    Iovanna, J., Orelle, B., Keim, V., & Dagorn, J. C. (1991). Messenger RNA sequence and expression of rat pancreatitis-associated protein, a lectin-related protein overexpressed during acute experimental pancreatitis. The Journal of Biological Chemistry, 266, 24664–24669.PubMedGoogle Scholar
  44. 44.
    Gross, J., Carlson, R. I., Brauer, A. W., Margolies, M. N., Warshaw, A. L., & Wands, J. R. (1985). Isolation, characterization, and distribution of an unusual pancreatic human secretory protein. The Journal of Clinical Investigation, 76, 2115–2126.PubMedGoogle Scholar
  45. 45.
    Sarles, H., de Caro, A., Multinger, L., & Martin, E. (1982). Giant pancreatic stones in teetotal women due to absence of the “stone protein”? Lancet, 2, 714–715.CrossRefPubMedGoogle Scholar
  46. 46.
    Lasserre, C., Christa, L., Simon, M. T., Vernier, P., & Brechot, C. (1992). A novel gene (HIP) activated in human primary liver cancer. Cancer Research, 52, 5089–5095.PubMedGoogle Scholar
  47. 47.
    Motoo, Y., Itoh, T., Su, S. B., Nakatani, M. T., Watanabe, H., Okai, T., & Sawabu, N. (1998). Expression of pancreatitis-associated protein (PAP) mRNA in gastrointestinal cancers. International Journal of Pancreatology, 23, 11–16.PubMedGoogle Scholar
  48. 48.
    Orelle, B., Keim, V., Masciotra, L., Dagorn, J. C., & Iovanna, J. L. (1992). Human pancreatitis-associated protein. Messenger RNA cloning and expression in pancreatic diseases. The Journal of Clinical Investigation, 90, 2284–2291.PubMedCrossRefGoogle Scholar
  49. 49.
    Multigner, L., De Caro, A., Lombardo, D., Campese, D., & Sarles, H. (1983). Pancreatic stone protein, a phosphoprotein which inhibits calcium carbonate precipitation from human pancreatic juice. Biochemical and Biophysical Research Communications, 110, 69–74.CrossRefPubMedGoogle Scholar
  50. 50.
    Bimmler, D., Graf, R., Scheele, G. A., & Frick, T. W. (1997). Pancreatic stone protein (lithostathine), a physiologically relevant pancreatic calcium carbonate crystal inhibitor? The Journal of Biological Chemistry, 272, 3073–3082.CrossRefPubMedGoogle Scholar
  51. 51.
    Dieckgraefe, B. K., Crimmins, D. L., Landt, V., Houchen, C., Anant, S., Porche-Sorbet, R., & Ladenson, J. H. (2002). Expression of the regenerating gene family in inflammatory bowel disease mucosa: Reg Ialpha upregulation, processing, and antiapoptotic activity. Journal of Investigative Medicine, 50, 421–434.PubMedGoogle Scholar
  52. 52.
    Vasseur, S., Folch-Puy, E., Hlouschek, V., Garcia, S., Fiedler, F., Lerch, M. M., Dagorn, J. C., Closa, D., & Iovanna, J. L. (2004). p8 improves pancreatic response to acute pancreatitis by enhancing the expression of the anti-inflammatory protein pancreatitis-associated protein I. The Journal of Biological Chemistry, 279, 7199–7207.CrossRefPubMedGoogle Scholar
  53. 53.
    Christa, L., Carnot, F., Simon, M. T., Levavasseur, F., Stinnakre, M. G., Lasserre, C., Thepot, D., Clement, B., Devinoy, E., & Brechot, C. (1996). HIP/PAP is an adhesive protein expressed in hepatocarcinoma, normal Paneth, and pancreatic cells. The American Journal of Physiology, 271, G993–G1002.PubMedGoogle Scholar
  54. 54.
    Carrere, J., Guy-Crotte, O., Gaia, E., & Figarella, C. (1999). Immunoreactive pancreatic Reg protein in sera from cystic fibrosis patients with and without pancreatic insufficiency. Gut, 44, 545–551.PubMedCrossRefGoogle Scholar
  55. 55.
    Viterbo, D., Bluth, M., Mueller, C. M., Callender, G., Lin, Y. Y., Murray, S., Ocasio, V., DiMaio, T., & Zenilman, M. (2005). Anti-reg I and III antibodies worsen pancreatitis in vivo. Gastroenterology, 128, A791.Google Scholar
  56. 56.
    Yonemura, Y., Takashima, T., Miwa, K., Miyazaki, I., Yamamoto, H., & Okamoto, H. (1984). Amelioration of diabetes mellitus in partially depancreatized rats by poly(ADP-ribose) synthetase inhibitors. Evidence of islet B-cell regeneration. Diabetes, 33, 401–404.CrossRefPubMedGoogle Scholar
  57. 57.
    Terazono, K., Uchiyama, Y., Ide, M., Watanabe, T., Yonekura, H., Yamamoto, H., & Okamoto, H. (1990). Expression of reg protein in rat regenerating islets and its co-localization with insulin in the beta cell secretory granules. Diabetologia, 33, 250–252.CrossRefPubMedGoogle Scholar
  58. 58.
    Rouquier, S., Verdier, J. M., Iovanna, J., Dagorn, J. C., & Giorgi, D. (1991). Rat pancreatic stone protein messenger RNA. Abundant expression in mature exocrine cells, regulation by food content, and sequence identity with the endocrine reg transcript. The Journal of Biological Chemistry, 266, 786–791.PubMedGoogle Scholar
  59. 59.
    Watanabe, T., Yonemura, Y., Yonekura, H., Suzuki, Y., Miyashita, H., Sugiyama, K., Moriizumi, S., Unno, M., Tanaka, O., Kondo, H., et al. (1994). Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein. Proceedings of the National Academy of Sciences of the United States of America, 91, 3589–3592.CrossRefPubMedGoogle Scholar
  60. 60.
    Gross, D. J., Weiss, L., Reibstein, I., van den Brand, J., Okamoto, H., Clark, A., & Slavin, S. (1998). Amelioration of diabetes in nonobese diabetic mice with advanced disease by linomide-induced immunoregulation combined with Reg protein treatment. Endocrinology, 139, 2369–2374.CrossRefPubMedGoogle Scholar
  61. 61.
    Baeza, N. J., Moriscot, C. I., Renaud, W. P., Okamoto, H., Figarella, C. G., & Vialettes, B. H. (1996). Pancreatic regenerating gene overexpression in the nonobese diabetic mouse during active diabetogenesis. Diabetes, 45, 67–70.CrossRefPubMedGoogle Scholar
  62. 62.
    Baeza, N., Sanchez, D., Vialettes, B., & Figarella, C. (1997). Specific reg II gene overexpression in the non-obese diabetic mouse pancreas during active diabetogenesis. FEBS Letters, 416, 364–368.CrossRefPubMedGoogle Scholar
  63. 63.
    Sanchez, D., Baeza, N., Blouin, R., Devaux, C., Grondin, G., Mabrouk, K., Guy-Crotte, O., & Figarella, C. (2000). Overexpression of the reg gene in non-obese diabetic mouse pancreas during active diabetogenesis is restricted to exocrine tissue. The Journal of Histochemistry and Cytochemistry, 48, 1401–1410.PubMedGoogle Scholar
  64. 64.
    Lu, Y., Ponton, A., Okamoto, H., Takasawa, S., Herrera, P. L., & Liu, J. L. (2006). Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas. American Journal of Physiology–Endocrinology and Metabolism, 291, E50–E58.CrossRefPubMedGoogle Scholar
  65. 65.
    De Leon, D. D., Farzad, C., Crutchlow, M. F., Brestelli, J., Tobias, J., Kaestner, K. H., & Stoffers, D. A. (2006). Identification of transcriptional targets during pancreatic growth after partial pancreatectomy and exendin-4 treatment. Physiological Genomics, 24, 133–143.CrossRefPubMedGoogle Scholar
  66. 66.
    Zenilman, M. E., Magnuson, T. H., Swinson, K., Egan, J., Perfetti, R., & Shuldiner, A. R. (1996). Pancreatic thread protein is mitogenic to pancreatic-derived cells in culture. Gastroenterology, 110, 1208–1214.CrossRefPubMedGoogle Scholar
  67. 67.
    Levine, J. L., Patel, K. J., Zheng, Q., Shuldiner, A. R., & Zenilman, M. E. (2000). A recombinant rat regenerating protein is mitogenic to pancreatic derived cells. The Journal of Surgical Research, 89, 60–65.CrossRefPubMedGoogle Scholar
  68. 68.
    Ortiz, E. M., Dusetti, N. J., Vasseur, S., Malka, D., Bodeker, H., Dagorn, J. C., & Iovanna, J. L. (1998). The pancreatitis-associated protein is induced by free radicals in AR4–2J cells and confers cell resistance to apoptosis. Gastroenterology, 114, 808–816.CrossRefPubMedGoogle Scholar
  69. 69.
    Unno, M., Nata, K., Noguchi, N., Narushima, Y., Akiyama, T., Ikeda, T., Nakagawa, K., Takasawa, S., & Okamoto, H. (2002). Production and characterization of Reg knockout mice: reduced proliferation of pancreatic beta-cells in Reg knockout mice. Diabetes, 51, S478–S483.CrossRefPubMedGoogle Scholar
  70. 70.
    Hamblet, N. S., Bowman, A., Vinik, A. I., & Taylor-Fishwick, D. A. (2006). Analysis of islet and ductal pancreatic proliferation in transgenic mice expressing INGAP. Taos, NM: Keystone Symposia.Google Scholar
  71. 71.
    Taylor-Fishwick, D. A., Bowman, A., Hamblet, N., Bernard, P., Harlan, D. M., & Vinik, A. I. (2006). Islet neogenesis associated protein transgenic mice are resistant to hyperglycemia induced by streptozotocin. The Journal of Endocrinology, 190, 729–737.CrossRefPubMedGoogle Scholar
  72. 72.
    Okamoto, H. (1999). The Reg gene family and Reg proteins: with special attention to the regeneration of pancreatic beta-cells. Journal of Hepato-Biliary-Pancreatic Surgery, 6, 254–262.CrossRefPubMedGoogle Scholar
  73. 73.
    Namikawa, K., Fukushima, M., Murakami, K., Suzuki, A., Takasawa, S., Okamoto, H., & Kiyama, H. (2005). Expression of Reg/PAP family members during motor nerve regeneration in rat. Biochemical and Biophysical Research Communications, 332, 126–134.CrossRefPubMedGoogle Scholar
  74. 74.
    Nishimune, H., Vasseur, S., Wiese, S., Birling, M. C., Holtmann, B., Sendtner, M., Iovanna, J. L., & Henderson, C. E. (2000). Reg-2 is a motoneuron neurotrophic factor and a signalling intermediate in the CNTF survival pathway. Nature Cell Biology, 2, 906–914.CrossRefPubMedGoogle Scholar
  75. 75.
    Livesey, F. J., O’Brien, J. A., Li, M., Smith, A. G., Murphy, L. J., & Hunt, S. P. (1997). A Schwann cell mitogen accompanying regeneration of motor neurons. Nature, 390, 614–618.CrossRefPubMedGoogle Scholar
  76. 76.
    Rosenberg, L., Brown, R. A., & Duguid, W. P. (1983). A new approach to the induction of duct epithelial hyperplasia and nesidioblastosis by cellophane wrapping of the hamster pancreas. The Journal of Surgical Research, 35, 63–72.CrossRefPubMedGoogle Scholar
  77. 77.
    Rosenberg, L., Vinik, A. I., Pittenger, G. L., Rafaeloff, R., & Duguid, W. P. (1996). Islet-cell regeneration in the diabetic hamster pancreas with restoration of normoglycemia can be induced by a local growth factor(s). Diabetologia, 39, 256–262.PubMedGoogle Scholar
  78. 78.
    Graf, R., Schiesser, M., Reding, T., Appenzeller, P., Sun, L. K., Fortunato, F., Perren, A., & Bimmler, D. (2005). Exocrine meets endocrine: pancreatic stone protein and regenerating protein-two sides of the same coin. The Journal of Surgical Research, 133, 113–120.CrossRefPubMedGoogle Scholar
  79. 79.
    Itoh, T., Tsuzuki, H., Katoh, T., Teraoka, H., Matsumoto, K., Yoshida, N., Terazono, K., Watanabe, T., Yonekura, H., Yamamoto, H., & Okamoto, H. (1990). Isolation and characterization of human reg protein produced in Saccharomyces cerevisiae. FEBS Letters, 272, 85–88.CrossRefPubMedGoogle Scholar
  80. 80.
    Drickamer, K. (1988). Two distinct classes of carbohydrate-recognition domains in animal lectins. The Journal of Biological Chemistry, 263, 9557–9560.PubMedGoogle Scholar
  81. 81.
    Laurine, E., Manival, X., Montgelard, C., Bideau, C., Berge-Lefranc, J. L., Erard, M., & Verdier, J. M. (2005). PAP IB, a new member of the Reg gene family: cloning, expression, structural properties, and evolution by gene duplication. Biochimica et Biophysica Acta, 1727, 177–187.PubMedGoogle Scholar
  82. 82.
    Flores, L. E., Garcia, M. E., Borelli, M. I., Del Zotto, H., Alzugaray, M. E., Maiztegui, B., & Gagliardino, J. J. (2003). Expression of islet neogenesis-associated protein in islets of normal hamsters. The Journal of Endocrinology, 177, 243–248.CrossRefPubMedGoogle Scholar
  83. 83.
    Del Zotto, H., Massa, L., Rafaeloff, R., Pittenger, G. L., Vinik, A., Gold, G., Reifel-Miller, A., & Gagliardino, J. J. (2000). Possible relationship between changes in islet neogenesis and islet neogenesis-associated protein-positive cell mass induced by sucrose administration to normal hamsters. The Journal of Endocrinology, 165, 725–733.CrossRefPubMedGoogle Scholar
  84. 84.
    Gagliardino, J. J., Del Zotto, H., Massa, L., Flores, L. E., & Borelli, M. I. (2003). Pancreatic duodenal homeobox-1 and islet neogenesis-associated protein: a possible combined marker of activateable pancreatic cell precursors. The Journal of Endocrinology, 177, 249–259.CrossRefPubMedGoogle Scholar
  85. 85.
    Lipsett, M. A., Austin, E. B., Castellarin, M. L., Lemay, J., & Rosenberg, L. (2006). Evidence for the homeostatic regulation of induced beta cell mass expansion. Diabetologia, 49, 2910–2919.CrossRefPubMedGoogle Scholar
  86. 86.
    Lipsett, M., & Finegood, D. T. (2002). Beta-cell neogenesis during prolonged hyperglycemia in rats. Diabetes, 51, 1834–1841.CrossRefPubMedGoogle Scholar
  87. 87.
    Wang, G. S., Rosenberg, L., & Scott, F. W. (2005). Tubular complexes as a source for islet neogenesis in the pancreas of diabetes-prone BB rats. Laboratory Investigation, 85, 675–688.CrossRefPubMedGoogle Scholar
  88. 88.
    Iovanna, J. L. (1996). Redifferentiation and apoptosis of pancreatic cells during acute pancreatitis. International Journal of Pancreatology, 20, 77–84.PubMedGoogle Scholar
  89. 89.
    Bouwens, L. (1998). Transdifferentiation versus stem cell hypothesis for the regeneration of islet beta-cells in the pancreas. Microscopy Research and Technique, 43, 332–336.CrossRefPubMedGoogle Scholar
  90. 90.
    Wagner, M., Luhrs, H., Kloppel, G., Adler, G., & Schmid, R. M. (1998). Malignant transformation of duct-like cells originating from acini in transforming growth factor transgenic mice. Gastroenterology, 115, 1254–1262.CrossRefPubMedGoogle Scholar
  91. 91.
    Bockman, D. E., Guo, J., Buchler, P., Muller, M. W., Bergmann, F., & Friess, H. (2003). Origin and development of the precursor lesions in experimental pancreatic cancer in rats. Laboratory Investigation, 83, 853–859.PubMedGoogle Scholar
  92. 92.
    Lardon, J., Huyens, N., Rooman, I., & Bouwens, L. (2004). Exocrine cell transdifferentiation in dexamethasone-treated rat pancreas. Virchows Archiv, 444, 61–65.CrossRefPubMedGoogle Scholar
  93. 93.
    Suarez-Pinzon, W. L., Yan, Y., Power, R., Brand, S. J., & Rabinovitch, A. (2005). Combination therapy with epidermal growth factor and gastrin increases beta-cell mass and reverses hyperglycemia in diabetic NOD mice. Diabetes, 54, 2596–2601.CrossRefPubMedGoogle Scholar
  94. 94.
    Borelli, M. I., Stoppiglia, L. F., Rezende, L. F., Flores, L. E., Del Zotto, H., Boschero, A. C., & Gagliardino, J. J. (2005). INGAP-related pentadecapeptide: its modulatory effect upon insulin secretion. Regulatory Peptides, 131, 97–102.CrossRefPubMedGoogle Scholar
  95. 95.
    Rosenberg, L., Duguid, W. P., Healy, M., Clas, D., & Vinik, A. I. (1992). Reversal of diabetes by the induction of islet cell neogenesis. Transplantation Proceedings, 24, 1027–1028.PubMedGoogle Scholar
  96. 96.
    Bernard-Kargar, C., & Ktorza, A. (2001). Endocrine pancreas plasticity under physiological and pathological conditions. Diabetes, 50, S30–S35.CrossRefPubMedGoogle Scholar
  97. 97.
    Butler, A. E., Janson, J., Bonner-Weir, S., Ritzel, R., Rizza, R. A., & Butler, P. C. (2003). Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes, 52, 102–110.CrossRefPubMedGoogle Scholar
  98. 98.
    Butler, A. E., Janson, J., Soeller, W. C., & Butler, P. C. (2003). Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes, 52, 2304–2314.CrossRefPubMedGoogle Scholar
  99. 99.
    Finegood, D. T., Scaglia, L., & Bonner-Weir, S. (1995). Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes, 44, 249–256.CrossRefPubMedGoogle Scholar
  100. 100.
    Jamal, A. M., Lipsett, M., Hazrati, A., Paraskevas, S., Agapitos, D., Maysinger, D., & Rosenberg, L. (2003). Signals for death and differentiation: a two-step mechanism for in vitro transformation of adult islets of Langerhans to duct epithelial structures. Cell Death and Differentiation, 10, 987–996.CrossRefPubMedGoogle Scholar
  101. 101.
    Hanley, S., Jamal, A. M., Lipsett, M., & Rosenberg, L. (2004). Inducers of islet neogenesis from adult human pancreatic progenitors. Diabetes, 53, A379.Google Scholar
  102. 102.
    Semakula, C., Pambuccian, S., Gruessner, R., Kendall, D., Pittenger, G., Vinik, A., & Seaquist, E. R. (2002). Clinical case seminar: hypoglycemia after pancreas transplantation: association with allograft nesidiodysplasia and expression of islet neogenesis-associated peptide. The Journal of Clinical Endocrinology and Metabolism, 87, 3548–3554.CrossRefPubMedGoogle Scholar
  103. 103.
    Ratner, R. E., Feeley, D., Buse, J. B., & Schwartz, S. L. (2005). Double-blind, placebo-controlled trial of islet neogenesis gene associated protein (INGAP) in type 1 diabetes (T1DM) subjects. San Diego, CA: American Diabetes Association Annual Meeting.Google Scholar
  104. 104.
    Ratner, R. E., Feeley, D., Buse, J. B., & Fischer, J. S. (2005). Double-blind, placebo-controlled trial of islet neogenesis gene associated protein (INGAP) therapy in type 2 diabetes (T2DM) subjects. San Diego, CA: American Diabetes Association Annual Meeting.Google Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Mark Lipsett
    • 1
    • 2
  • Stephen Hanley
    • 1
    • 2
  • Mauro Castellarin
    • 1
    • 2
  • Emily Austin
    • 1
    • 2
  • Wilma L. Suarez-Pinzon
    • 3
  • Alex Rabinovitch
    • 3
  • Lawrence Rosenberg
    • 1
    • 2
    Email author
  1. 1.Department of SurgeryMcGill UniversityMontrealCanada
  2. 2.Centre for Pancreatic Diseases, Research Institute of the McGill University Health CentreMontrealCanada
  3. 3.Muttart Diabetes Research Centre, University of AlbertaEdmontonCanada

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