Skip to main content
SpringerLink
Log in
Book cover

Stem Cell Therapy for Diabetes pp 105–122Cite as

Islet Regeneration

  • Chapter
  • First Online:

  • 1306 Accesses

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

Although the mechanisms controlling endocrine progenitor-cell differentiation during pancreas development have been described in considerable detail, our knowledge of islet-cell renewal in the postnatal pancreas was based until recently on indirect evidence and remained quite descriptive. This has changed with recent genetic lineage-tracing studies, which have provided evidence for a central role of β-cell replication in islet turnover in the adult pancreas, both under normal physiological conditions and following moderate injury. In contrast, recent work from our group demonstrates that severe tissue injury activates multipotent islet-cell progenitors, which can differentiate in vitro into all types of islet cells. In this chapter we provide an overview of experimental models available for studying β-cell renewal and the major mechanisms underlying this process.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Ackermann Misfeldt A, Costa RH, Gannon M. (2008) Beta-cell proliferation, but not neogenesis, following 60% partial pancreatectomy is impaired in the absence of FoxM1. Diabetes. 57:3069–3077.

    Article  PubMed  CAS  Google Scholar 

  • Baeyens L, De Breuck S, Lardon J, et al. (2005) In vitro generation of insulin-producing β cells from adult exocrine pancreatic cells. Diabetologia. 48:49–57.

    Article  CAS  PubMed  Google Scholar 

  • Bernard-Kargar C, Ktorza A. (2001) Endocrine pancreas plasticity under physiological and pathological conditions. Diabetes. 50:S30–S35.

    Article  CAS  PubMed  Google Scholar 

  • Berrocal T, Luque AA, Pinilla I, et al. (2005) Pancreatic regeneration after near-total pancreatectomy in children with nesidioblastosis. Pediatr Radiol. 35:1066–1070.

    Article  PubMed  Google Scholar 

  • Bonner-Weir S. (2001) β-cell turnover: its assessment and implications. Diabetes. 50(Suppl 1):S20–S24.

    Article  CAS  PubMed  Google Scholar 

  • Bonner-Weir S, Trent DF, Honey RN, et al. (1981) Responses of neonatal rat islets to streptozotocin: limited B-cell regeneration and hyperglycemia. Diabetes. 30:64–69.

    Article  CAS  PubMed  Google Scholar 

  • Bonner-Weir S, Trent DF, Weir GC. (1983) Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J Clin Invest. 71:1544–1553.

    Article  CAS  PubMed  Google Scholar 

  • Bonner-Weir S, Baxter LA, Schuppin GT, et al. (1993) A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes. 42:1715–1720.

    Article  CAS  PubMed  Google Scholar 

  • Bonner-Weir S, Taneja M, Weir GC, et al. (2000) In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA. 97:7999–8004.

    Article  CAS  PubMed  Google Scholar 

  • Bonner-Weir S, Toschi E, Inada A, et al. (2004) The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr Diabetes. 5(Suppl 2):16–22.

    Article  PubMed  Google Scholar 

  • Bouwens L. (1998) Transdifferentiation versus stem cell hypothesis for the regeneration of islet β-cells in the pancreas. Microsc Res Tech. 43:332–336.

    Article  CAS  PubMed  Google Scholar 

  • Bouwens L, Rooman I. (2005) Regulation of pancreatic β-cell mass. Physiol Rev. 85:1255–1270.

    Article  CAS  PubMed  Google Scholar 

  • Brennand K, Huangfu D, Melton D. (2007) All β cells contribute equally to islet growth and maintenance. PLoS Biol. 5:e163.

    Article  PubMed  Google Scholar 

  • Brockenbrough JS, Weir GC, Bonner-Weir S. (1988) Discordance of exocrine and endocrine growth after 90% pancreatectomy in rats. Diabetes. 37:232–236.

    Article  CAS  PubMed  Google Scholar 

  • Bruning JC, Winnay J, Bonner-Weir S, et al. (1997) Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell. 88:561–572.

    Article  CAS  PubMed  Google Scholar 

  • Butler AE, Janson J, Bonner-Weir S, et al. (2003) Beta-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes. 52:102–110.

    Article  CAS  PubMed  Google Scholar 

  • Cano DA, Rulifson IC, Heiser PW, et al. (2008) Regulated β-cell regeneration in the adult mouse pancreas. Diabetes. 57:958–966.

    Article  CAS  PubMed  Google Scholar 

  • Cleaver O, Melton DA. (2003) Endothelial signaling during development. Nat Med. 9:661–668.

    Article  CAS  PubMed  Google Scholar 

  • Cozar-Castellano I, Takane KK, Bottino R, et al. (2004) Induction of β-cell proliferation and retinoblastoma protein phosphorylation in rat and human islets using adenovirus-mediated transfer of cyclin-dependent kinase-4 and cyclin D1. Diabetes. 53:149–159.

    Article  CAS  PubMed  Google Scholar 

  • Cozar-Castellano I, Weinstock M, Haught M, et al. (2006) 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 p21cip. Diabetes. 55:70–77.

    Article  CAS  PubMed  Google Scholar 

  • De Breuck S, Baeyens L, Bouwens L. (2006) Expression and function of leukaemia inhibitory factor and its receptor in normal and regenerating rat pancreas. Diabetologia. 49:108–116.

    Article  PubMed  CAS  Google Scholar 

  • De Leon DD, Deng SP, Madani R, et al. (2003) Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy. Diabetes. 52:365–371.

    Article  PubMed  Google Scholar 

  • De Vos A, Heimberg H, Quartier E, et al. (1995) Human and rat β cells differ in glucose transporter but not in glucokinase gene expression. J Clin Invest. 96:2489–2495.

    Article  PubMed  Google Scholar 

  • Desai BM, Oliver-Krasinski J, De Leon DD, et al. (2007) Preexisting pancreatic acinar cells contribute to acinar cell, but not islet β cell, regeneration. J Clin Invest. 117:971–977.

    Article  CAS  PubMed  Google Scholar 

  • Dor Y, Brown J, Martinez OI, et al. (2004) Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature. 429:41–46.

    Article  CAS  PubMed  Google Scholar 

  • Fajas L, Annicotte JS, Miard S, et al. (2004) Impaired pancreatic growth, β cell mass, and β cell function in E2F1 (–/–)mice. J Clin Invest. 113:1288–1295.

    CAS  PubMed  Google Scholar 

  • Fernandes A, King LC, Guz Y, et al. (1997) Differentiation of new insulin-producing cells is induced by injury in adult pancreatic islets. Endocrinology. 138:1750–1762.

    Article  CAS  PubMed  Google Scholar 

  • Finegood DT, Scaglia L, Bonner-Weir S. (1995) Dynamics of β-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes. 44:249–256.

    Article  CAS  PubMed  Google Scholar 

  • Finegood DT, Weir GC, Bonner-Weir S. (1999) Prior streptozotocin treatment does not inhibit pancreas regeneration after 90% pancreatectomy in rats. Am J Physiol. 276:E822–E827.

    CAS  PubMed  Google Scholar 

  • George M, Ayuso E, Casellas A, et al. (2002) Beta cell expression of IGF-I leads to recovery from type 1 diabetes. J Clin Invest. 109:1153–1163.

    CAS  PubMed  Google Scholar 

  • Georgia S, Bhushan A. (2004) Beta cell replication is the primary mechanism for maintaining postnatal β cell mass. J Clin Invest. 114:963–968.

    CAS  PubMed  Google Scholar 

  • Georgia S, Bhushan A. (2006) p27 Regulates the transition of β-cells from quiescence to proliferation. Diabetes. 55:2950–2956.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Gupta RK, Gao N, Gorski RK, et al. (2007) Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4alpha. Genes Dev. 21:756–769.

    Article  CAS  PubMed  Google Scholar 

  • Guz Y, Nasir I, Teitelman G. (2001) Regeneration of pancreatic β cells from intra-islet precursor cells in an experimental model of diabetes. Endocrinology. 142:4956–4968.

    Article  CAS  PubMed  Google Scholar 

  • Hao E, Tyrberg B, Itkin-Ansari P, et al. (2006) Beta-cell differentiation from nonendocrine epithelial cells of the adult human pancreas. Nat Med. 12:310–316.

    Article  CAS  PubMed  Google Scholar 

  • Hardikar AA, Karandikar MS, Bhonde RR. (1999) Effect of partial pancreatectomy on diabetic status in BALB/c mice. J Endocrinol. 162:189–195.

    Article  CAS  PubMed  Google Scholar 

  • Harvey M, Vogel H, Lee EY, et al. (1995) Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin. Cancer Res. 55:1146–1151.

    CAS  PubMed  Google Scholar 

  • Hess D, Li L, Martin M, et al. (2003) Bone marrow derived stem cells initiate pancreatic regeneration. Nat Biotechnol. 21:763–770.

    Article  CAS  PubMed  Google Scholar 

  • Holland AM, Gonez LJ, Naselli G, et al. (2005) Conditional expression demonstrates the role of the homeodomain transcription factor Pdx1 in maintenance and regeneration of β-cells in the adult pancreas. Diabetes. 54:2586–2595.

    Article  CAS  PubMed  Google Scholar 

  • Hultquist GT, Joensson LE. (1965) Ligation of the pancreatic duct in rats. Acta Soc Med Ups. 70:82–88.

    CAS  PubMed  Google Scholar 

  • Ianus A, Holz GG, Theise ND, et al. (2003) In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest. 111:843–850.

    CAS  PubMed  Google Scholar 

  • Iglesias A, Murga M, Laresgoiti U, et al. (2004) Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice. J Clin Invest. 113:1398–1407.

    CAS  PubMed  Google Scholar 

  • Inada A, Nienaber C, Katsuta H, et al. (2008) Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci USA. [Epub ahead of print].

    Google Scholar 

  • Johansson M, Mattsson G, Andersson A, et al. (2006) Islet endothelial cells and pancreatic β-cell proliferation: studies in vitro and during pregnancy in adult rats. Endocrinology. 147:2315–2324.

    Article  CAS  PubMed  Google Scholar 

  • Karnik SK, Chen H, McLean GW, et al. (2007) Menin controls growth of pancreatic β-cells in pregnant mice and promotes gestational diabetes mellitus. Science. 318:806–809.

    Article  CAS  PubMed  Google Scholar 

  • Karnik SK, Hughes CM, Gu X, et al. (2005) Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci USA. 102:14659–14664.

    Article  CAS  PubMed  Google Scholar 

  • Klein T, Ling Z, Heimberg H, et al. (2003) Nestin is expressed in vascular endothelial cells in the adult human pancreas. J Histochem Cytochem. 51:697–706.

    CAS  PubMed  Google Scholar 

  • Kloppel G, Lohr M, Habich K, et al. (1985) Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res. 4:110–125.

    CAS  PubMed  Google Scholar 

  • Kodama S, Toyonaga T, Kondo T, et al. (2005) Enhanced expression of PDX-1 and Ngn3 by exendin-4 during β cell regeneration in STZ-treated mice. Biochem Biophys Res Commun. 327:1170–1178.

    Article  CAS  PubMed  Google Scholar 

  • Krakowski ML, Kritzik MR, Jones EM, et al. (1999) Transgenic expression of epidermal growth factor and keratinocyte growth factor in β-cells results in substantial morphological changes. J Endocrinol. 162:167–175.

    Article  CAS  PubMed  Google Scholar 

  • Krishnamurthy J, Ramsey MR, Ligon KL, et al. (2006) p16INK4a induces an age-dependent decline in islet regenerative potential. Nature. 443:453–457.

    Article  CAS  PubMed  Google Scholar 

  • Kroon E, Martinson LA, Kadoya K, et al. (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 26:443–452.

    Article  CAS  PubMed  Google Scholar 

  • Kulkarni RN, Jhala US, Winnay JN, et al. (2004) PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that accurs in response to insulin resistance. J Clin Invest. 114:828–836

    CAS  PubMed  Google Scholar 

  • Rankin MM, Kushner JA. (2009) Adaptive beta-cell proliferation is severely restricted with advanced age. Diabetes. 58:1365–1372.

    Article  Google Scholar 

  • Kushner JA, Ciemerych MA, Sicinska E, et al. (2005) Cyclins D2 and D1 are essential for postnatal pancreatic β-cell growth. Mol Cell Biol. 25:3752–3762.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lardon J, Rooman I, Bouwens L. (2002) Nestin expression in pancreatic stellate cells and angiogenic endothelial cells. Histochem Cell Biol. 117:535–540.

    Article  CAS  PubMed  Google Scholar 

  • Laybutt DR, Weir GC, Kaneto H, et al. (2002) Overexpression of c-Myc in β-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes. Diabetes. 51:1793–1804.

    Article  CAS  PubMed  Google Scholar 

  • Lee CS, De Leon DD, Kaestner KH, et al. (2006) Regeneration of pancreatic islets after partial pancreatectomy in mice does not involve the reactivation of neurogenin-3. Diabetes. 55:269–272.

    CAS  PubMed  Google Scholar 

  • Lenzen S. (2008) The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia. 51:216–226.

    Article  CAS  PubMed  Google Scholar 

  • Li L, Seno M, Yamada H, et al. (2001) Promotion of β-cell regeneration by betacellulin in ninety percent-pancreatectomized rats. Endocrinology. 142:5379–5385.

    Article  CAS  PubMed  Google Scholar 

  • Li L, Yi ZH, Seno M, et al. (2004) Activin A and betacellulin. Effect on regeneration of pancreatic β-cells in neonatal streptozotocin-treated rats. Diabetes. 53:608–615.

    Article  CAS  PubMed  Google Scholar 

  • Liu JL, Coschigano KT, Robertson K, et al. (2004) Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice. Am J Physiol Endocrinol Metab. 287:E405–E413.

    Article  CAS  PubMed  Google Scholar 

  • Maedler K, Schumann DM, Schulthess F, et al. (2006) Aging correlates with decreased β-cell proliferative capacity and enhanced sensitivity to apoptosis: a potential role for Fas and pancreatic duodenal homeobox-1. Diabetes. 55:2455–2462.

    Article  CAS  PubMed  Google Scholar 

  • Maestro MA, Cardalda C, Boj SF, et al. (2007) Distinct roles of HNF1β, HNF1alpha, and HNF4alpha in regulating pancreas development, β-cell function and growth. Endocr Dev. 12:33–45.

    Article  CAS  PubMed  Google Scholar 

  • Means AL, Meszoely IM, Suzuki K, et al. (2005) Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development. 132:3767–3776.

    Article  CAS  PubMed  Google Scholar 

  • Meglasson MD, Burch PT, Berner DK, et al. (1986) Identification of glucokinase as an alloxan-sensitive glucose sensor of the pancreatic β-cell. Diabetes. 35:1163–1173.

    Article  CAS  PubMed  Google Scholar 

  • Miki T, Tashiro F, Iwanaga T, et al. (1997) Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel. Proc Natl Acad Sci USA. 94:11969–11973.

    Article  CAS  PubMed  Google Scholar 

  • Minami K, Okuno M, Miyawaki K, et al. (2005) Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells. Proc Natl Acad Sci USA. 102:15116–15121.

    Article  CAS  PubMed  Google Scholar 

  • Nikolova G, Jabs N, Konstantinova I, et al. (2006) The vascular basement membrane: a niche for insulin gene expression and beta cell proliferation. Dev Cell. 10:397–405.

    Article  CAS  PubMed  Google Scholar 

  • Nir T, Melton DA, Dor Y. (2007) Recovery from diabetes in mice by β cell regeneration. J Clin Invest. 117:2553–2561.

    Article  CAS  PubMed  Google Scholar 

  • Ogata T, Li L, Yamada S, et al. (2004) Promotion of β-cell differentiation by conophylline in fetal and neonatal rat pancreas. Diabetes. 53:2596–2602.

    Article  CAS  PubMed  Google Scholar 

  • Okuno M, Minami K, Okumachi A, et al. (2007) Generation of insulin-secreting cells from pancreatic acinar cells of animal models of type 1 diabetes. Am J Physiol Endocrinol Metab. 292:E158–E165.

    Article  CAS  PubMed  Google Scholar 

  • Otani K, Kulkarni RN, Baldwin AC, et al. (2004) Reduced β-cell mass and altered glucose sensing impair insulin-secretory function in βIRKO mice. Am J Physiol Endocrinol Metab. 286:E41–E49.

    Article  CAS  PubMed  Google Scholar 

  • Ouziel-Yahalom L, Zalzman M, Anker-Kitai L, et al. (2006) Expansion and redifferentiation of adult human pancreatic islet cells. Biochem Biophys Res Commun. 341:291–298.

    Article  CAS  PubMed  Google Scholar 

  • Oyama K, Minami K, Ishizaki K, et al. (2006) Spontaneous recovery from hyperglycemia by regeneration of pancreatic β-cells in Kir6.2G132S transgenic mice. Diabetes. 55:1930–1938.

    Article  CAS  PubMed  Google Scholar 

  • Pelengaris S, Khan M, Evan GI. (2002) Suppression of Myc-induced apoptosis in β cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell. 109:321–334.

    Article  CAS  PubMed  Google Scholar 

  • Peshavaria M, Larmie BL, Lausier J, et al. (2006) Regulation of pancreatic β-cell regeneration in the normoglycemic 60% partial-pancreatectomy mouse. Diabetes. 55:3289–3298.

    Article  CAS  PubMed  Google Scholar 

  • Rafaeloff R, Pittenger GL, Barlow SW, et al. (1997) Cloning and sequencing of the pancreatic islet neogenesis associated protein (INGAP) gene and its expression in islet neogenesis in hamsters. J Clin Invest. 99:2100–2109.

    Article  CAS  PubMed  Google Scholar 

  • Rane SG, Dubus P, Mettus RV, et al. (1999) Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia. Nat Genet. 22:44–52.

    Article  CAS  PubMed  Google Scholar 

  • Robertson RP. (2004) Islet transplantation as a treatment for diabetes—a work in progress. N Engl J Med. 350:694–705.

    Article  CAS  PubMed  Google Scholar 

  • Rooman I, Bouwens L. (2004) Combined gastrin and epidermal growth factor treatment induces islet regeneration and restores normoglycaemia in C57Bl6/J mice treated with alloxan. Diabetologia. 47:259–265.

    Article  CAS  PubMed  Google Scholar 

  • Rooman I, Lardon J, Flamez D, et al. (2001) Mitogenic effect of gastrin and expression of gastrin receptors in duct-like cells of rat pancreas. Gastroenterology. 121:940–949.

    Article  CAS  PubMed  Google Scholar 

  • Rooman I, Lardon J, Bouwens L. (2002) Gastrin stimulates β-cell neogenesis and increases islet mass from transdifferentiated but not from normal exocrine pancreas tissue. Diabetes. 51:686–690.

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg L. (1998) Induction of islet cell neogenesis in the adult pancreas: the partial duct obstruction model. Microsc Res Tech. 43:337–346.

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg L, Brown RA, Duguid WP. (1983) A new approach to the induction of duct epithelial hyperplasia and nesidioblastosis by cellophane wrapping of the hamster pancreas. J Surg Res. 35:63–72.

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg L, Lipsett M, Yoon JW, et al. (2004) A pentadecapeptide fragment of islet neogenesis-associated protein increases β-cell mass and reverses diabetes in C57BL/6 J mice. Ann Surg. 240:875–884.

    Article  PubMed  Google Scholar 

  • Schnedl WJ, Ferber S, Johnson JH, et al. (1994) STZ transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells. Diabetes. 43:1326–1333.

    Article  CAS  PubMed  Google Scholar 

  • Scoggins CR, Meszoely IM, Wada M, et al. (2000) p53-dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas. Am J Physiol Gastrointest Liver Physiol. 279:G827–G836.

    CAS  PubMed  Google Scholar 

  • Seaberg RM, Smukler SR, Kieffer TJ, et al. (2004) Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nat Biotechnol. 22:1115–1124.

    Article  CAS  PubMed  Google Scholar 

  • Selander L, Edlund H. (2002) Nestin is expressed in mesenchymal and not epithelial cells of the developing mouse pancreas. Mech Dev. 113:189–192.

    Article  CAS  PubMed  Google Scholar 

  • Sharma A, Zangen DH, Reitz P, et al. (1999) The homeodomain protein IDX-1 increases after an early burst of proliferation during pancreatic regeneration. Diabetes. 48:507–513.

    Article  CAS  PubMed  Google Scholar 

  • Sorenson RL, Brelje TC. (1997) Adaptation of islets of Langerhans to pregnancy: β-cell growth, enhanced insulin secretion and the role of lactogenic hormones. Horm Metab Res Hormon- und Stoffwechselforschung. 29:301–307.

    Article  CAS  Google Scholar 

  • Suzuki A, Nakauchi H, Taniguchi H. (2004) Prospective isolation of multipotent pancreatic progenitors using flow-cytometric cell sorting. Diabetes. 53:2143–2152.

    Article  CAS  PubMed  Google Scholar 

  • Swenne I. (1982) The role of glucose in the in vitro regulation of cell cycle kinetics and proliferation of fetal pancreatic B-cells. Diabetes. 31:754–760.

    CAS  PubMed  Google Scholar 

  • Swenne I. (1983) Effects of aging on the regenerative capacity of the pancreatic B-cell of the rat. Diabetes. 32:14–19.

    Article  CAS  PubMed  Google Scholar 

  • Szkudelski T. (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 50:537–546.

    CAS  PubMed  Google Scholar 

  • Taylor-Fishwick DA, Bowman A, Hamblet N, et al. (2006) Islet neogenesis associated protein transgenic mice are resistant to hyperglycemia induced by streptozotocin. J Endocrinol. 190:729–737.

    Article  CAS  PubMed  Google Scholar 

  • Teta M, Long SY, Wartschow LM, et al. (2005) Very slow turnover of β-cells in aged adult mice. Diabetes. 54:2557–2567.

    Article  CAS  PubMed  Google Scholar 

  • Teta M, Rankin MM, Long SY, et al. (2007) Growth and regeneration of adult β cells does not involve specialized progenitors. Dev Cell. 12:817–826.

    Article  CAS  PubMed  Google Scholar 

  • Thyssen S, Arany E, Hill DJ. (2006) Ontogeny of regeneration of β-cells in the neonatal rat after treatment with streptozotocin. Endocrinology. 147:2346–2356.

    Article  CAS  PubMed  Google Scholar 

  • Tourrel C, Bailbe D, Meile MJ, et al. (2001) 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. 50:1562–1570.

    Article  CAS  PubMed  Google Scholar 

  • Uchida T, Nakamura T, Hashimoto N, et al. (2005) Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. Nat Med. 11:175–182.

    Article  CAS  PubMed  Google Scholar 

  • Vasavada RC, Garcia-Ocana A, Zawalich WS, et al. (2000) Targeted expression of placental lactogen in the β cells of transgenic mice results in β cell proliferation, islet mass augmentation, and hypoglycemia. J Biol Chem. 275:15399–15406.

    Article  CAS  PubMed  Google Scholar 

  • Vasavada RC, Cozar-Castellano I, Sipula D, et al. (2007) Tissue-specific deletion of the retinoblastoma protein in the pancreatic β-cell has limited effects on β-cell replication, mass, and function. Diabetes. 56:57–64.

    Article  CAS  PubMed  Google Scholar 

  • Waguri M, Miyagawa J, Yamamoto K, et al. (1997) Morphological analysis of neo-islet formation associated with β-cell differentiation. Studies on a new diabetic mouse model induced by selective alloxan perfusion. Diabetes. 46:840–840.

    Article  Google Scholar 

  • Waldmann H, Adams E, Cobold S. (2008) Reprogramming the immune system: co-receptor blockade as a paradigm for harnessing tolerance mechanisms. Immunol Rev. 223:361–370.

    Article  CAS  PubMed  Google Scholar 

  • Wang RN, Kloppel G, Bouwens L. (1995) Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats. Diabetologia. 38:1405–1411.

    Article  CAS  PubMed  Google Scholar 

  • Wang RN, Bouwens L, Kloppel G. (1996) Beta-cell growth in adolescent and adult rats treated with streptozotocin during the neonatal period. Diabetologia. 39:548–557.

    Article  CAS  PubMed  Google Scholar 

  • Wang RN, Rehfeld JF, Nielsen FC, et al. (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.

    Article  CAS  PubMed  Google Scholar 

  • Wang ZV, Mu J, Schraw TD, et al. (2008) PANIC-ATTAC: a mouse model for inducible and reversible β-cell ablation. Diabetes. 57:2137–2148.

    Article  CAS  PubMed  Google Scholar 

  • Xie T, Spradling AC. (2000) A niche maintaining germ line stem cells in the Drosophila ovary. Science. 290:328–330.

    Article  CAS  PubMed  Google Scholar 

  • Xu G, Stoffers DA, Habener JF, et al. (1999) Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 48:2270–2276.

    Article  CAS  PubMed  Google Scholar 

  • Xu X, D’Hoker J, Stange G, et al. (2008) Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell. 132:197–207.

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto K, Miyagawa J, Waguri M, et al. (2000) Recombinant human betacellulin promotes the neogenesis of β-cells and ameliorates glucose intolerance in mice with diabetes induced by selective alloxan perfusion. Diabetes. 49:2021–2027.

    Article  CAS  PubMed  Google Scholar 

  • Yasuda H, Kataoka K, Ichimura H, et al. (1999) Cytokine expression and induction of acinar cell apoptosis after pancreatic duct ligation in mice. J Interferon Cytokine Res. 19:637–644.

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Ackermann AM, Gusarova GA, et al. (2006) The FoxM1 transcription factor is required to maintain pancreatic β-cell mass. Mol Endocrinol. 20:1853–1866.

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Gaspard JP, Mizukami Y, et al. (2005) Overexpression of cyclin D1 in pancreatic β-cells in vivo results in islet hyperplasia without hypoglycemia. Diabetes. 54:712–719.

    Article  CAS  PubMed  Google Scholar 

  • Zhou Q, Brown J, Kanarek A, et al. (2008) In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature. 455:627–632.

    Article  CAS  PubMed  Google Scholar 

  • Zulewski H, Abraham EJ, Gerlach MJ, et al. (2001) Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes. 50:521–533.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, 1090, Belgium

    Xiaobo Xu, Joke D’Hoker, Nico De Leu, Xiangwei Xiao, Yves Heremans, Mark Van De Casteele & Harry Heimberg

Authors
  1. Xiaobo Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joke D’Hoker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nico De Leu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiangwei Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yves Heremans
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark Van De Casteele
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Harry Heimberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaobo Xu .

Editor information

Editors and Affiliations

  1. Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Shimon Efrat

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Humana Press, a part of Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Xu, X. et al. (2010). Islet Regeneration. In: Efrat, S. (eds) Stem Cell Therapy for Diabetes. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-60761-366-4_4

Download citation

Publish with us

Policies and ethics

Search

Navigation