Skip to main content

Cell Cycle Regulation in Human Pancreatic Beta Cells

  • Chapter
  • First Online:
Book cover Stem Cell Therapy for Diabetes

Abstract

For decades, it had been assumed that pancreatic β cells were terminally differentiated and thus unable to replicate, and that β-cell replication did not exist in any quantitatively meaningful way. This view has changed dramatically in the past decade, with abundant data demonstrating that fetal, neonatal, and adult rodent β cells replicate at physiologically important rates. These new data have resulted in a plethora of new reports exploring the nutrient, growth factor, and signaling cascades that lie upstream and regulate the cell cycle machinery that controls rodent β-cell replication. Moreover, myriad reports of murine genetic models of cell cycle molecule knockout or overexpression have appeared and have documented unequivocally the importance and therapeutic relevance of cell cycle regulatory mechanisms in murine β cells. These events contrast with the pace of development of new knowledge regarding human β-cell replication. It seems clear that unlike in rodents, spontaneous replication of adult human β cells is uncommon. Further, standard manipulations, nutrients, and growth factors that induce rodent β-cell replication fail to do so in human β cells. In this chapter we focus on the molecular control of cell cycle progression in human β cells, illustrate the differences between human and rodent β-cell cycle regulatory control, and provide examples of approaches to inducing human β-cell replication.

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

Access this chapter

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

Institutional subscriptions

References

  • Agarwal SK, Mateo CM, Marx SJ. (2009) Rare germline mutations in cyclin-dependent kinse inhibitor genes in MEN-1 and related states. J Clin Endocrinol Metab (e-pub ahead of print).

    Google Scholar 

  • Alonso LC, Yokoe T, Zhang P, et al. (2007) Glucose infusion in mice: a new model to induce β-cell replication. Diabetes. 56:1792–1801.

    Article  CAS  PubMed  Google Scholar 

  • Bar Y, Russ HA, Knoller S, et al. (2008) HES1 is involved in adaptation of adult human β cells to proliferation in vitro. Diabetes. 57:2413–2420.

    Article  CAS  PubMed  Google Scholar 

  • Brissova M, Fowler MJ, Nicholson WE, et al. (2005) Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem. 53:1087–1097.

    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 diabetes. Diabetes. 52:102–110.

    Article  CAS  PubMed  Google Scholar 

  • Cabrera O, Berman D, Kenyon NS. (2006) The unique architecture of the human pancreatic islet has implications for islet cell function. Proc Nat Acad Sci USA. 103:2334–2339.

    Article  CAS  PubMed  Google Scholar 

  • Cavazzana-Calvo M, Thrasher A, Mavillo F. (2004) The future of gene therapy. Nature. 427:779–781.

    Article  CAS  PubMed  Google Scholar 

  • Cozar-Castellano I, Fiaschi-Taesch N, Bigatel TA, et al. (2006a) Molecular control of cell cycle progression in the pancreatic beta cell. Endocr Rev. 27:356–370.

    Article  CAS  PubMed  Google Scholar 

  • Cozar-Castellano I, Harb G, Selk K, et al. (2008) Lessons from the first comprehensive characterization of cell cycle control in rodent insulinoma cell lines. Diabetes. 57:3056–3068.

    Article  CAS  PubMed  Google Scholar 

  • Cozar-Castellano I, Haught M, Stewart AF. (2006b) The cell cycle inhibitory protein, p21cip, is Not essential for maintaining beta cell cycle arrest or beta cell function in Vivo. Diabetes. 55:3271–3278.

    Article  CAS  PubMed  Google Scholar 

  • Cozar-Castellano I, Takane KK, Bottino R, et al. (2004) Induction of beta cell proliferation and retinoblastoma protein phosphorylation in rat and human islets using adenoviral delivery 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. (2006c) Comprehensive characterization of the G1/S proteome in the islets of mice transgenic for hepatocyte growth factor, placental lactogen, or both: unique involvement of p21cip. Diabetes. 55:70–77.

    Article  CAS  PubMed  Google Scholar 

  • Davalli AM, Ogawa Y, Ricordi C, et al. (1995) A selective decrease in β cell mass of human islets transplanted into diabetic nude mice. Transplantation. 59:817–820.

    CAS  PubMed  Google Scholar 

  • De Leon DD, Deng S, Madani R. (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, Qartier E, et al. (1995) Human and rat β cells differ in glucose transporter but not glucokinase gene expression. J Clin Invest. 96:2489–2495.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Dufayet de la Tour D, Halvorsen T, Demeterco C, et al. (2001) Beta cell differentiation from a human pancreatic cell line in Vitro and in vivo. Mol Endocrinol. 15:476–483.

    Article  Google Scholar 

  • Efrat S, Linde S, Kofod H, et al. (1988) Beta-cell derived from transgenic mice expressing a hybrid insulin gene-oncogene. Proc Nat Acad Sci USA. 85:9037–9041.

    Article  CAS  PubMed  Google Scholar 

  • Fatrai S, Elghazi L, Balcazar N, et al. (2006) Akt Induces β-cell proliferation by regulating cyclin D1, Cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity. Diabetes. 55:318–325.

    Article  CAS  PubMed  Google Scholar 

  • Fiaschi-Taesch NM, Berman-Weinberg D, Sicari BM, et al. (2008) Hepatocyte growth factor (HGF) enhances engraftment and function of non-human primate islets. Diabetes. 57:2745–2754.

    Article  CAS  PubMed  Google Scholar 

  • Fiaschi-Taesch NM, Bigatel TA, Sicari BM, et al. (2009) A survey of the human pancreatic beta cell G1/S proteome reveals a potential therapeutic role for Cdk-6 and cyclin D1 in enhancing human beta cell replication and function in Vivo. Diabetes (e-pub ahead of print).

    Google Scholar 

  • Florez JC. (2008) Newly identified loci highlight β cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes?. Diabetologia. 51:1100–1110.

    Article  CAS  PubMed  Google Scholar 

  • Flotte TR. (2007) Gene therapy: the first two decades and the current state of the art. J Cell Physiol. 213:301–305.

    Article  CAS  PubMed  Google Scholar 

  • Franklin DS, Godfrey VL, O’Brien DA, et al. (2000) Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Mol Cell Biol. 20:6147–6158.

    Article  CAS  PubMed  Google Scholar 

  • Fueger PT, Schisler J, Lu D, et al. (2008) Trefoil factor-3 stimulates human and rodent pancreatic β cell replication with retention of function. Mol Endocrinol. 22:1251–1259.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Ocaña A, Vasavada RC, Takane KK, et al. (2001) Using Beta Cell Growth Factors to Enhance Human Pancreatic Islet Transplantation. J. Clin. Endocrinol. Metab. 86:984–988.

    Article  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Georgitsi M, Raitila A, Karhu A, et al. (2007) Germline CDKN1B/p27kip1 mutation in multiple endocrine neoplasia. J Clin Endocrinol Metab. 92:3321–3325.

    Article  CAS  PubMed  Google Scholar 

  • Gradwohl G, Dierich A, LeMeur M, et al. (2000) Neurogenin-3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Nat Acad Sci USA. 97:1607–1611.

    Article  CAS  PubMed  Google Scholar 

  • Gump JM, Dowdy SF. (2007) TAT protein transduction: the molecular mechanism and therapeutic prospects. Trends in Molec Med. 13:443–448.

    Article  CAS  Google Scholar 

  • Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. (2008) Insertional oncogenesis in four patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 118:3132–3142.

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D. (1985) Heritable formation of pancreatic ß-cell tumors in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature. 315:115–122.

    Article  CAS  PubMed  Google Scholar 

  • Harb G, Cozar-Castellano I, Fiaschi-Taesch NM, et al. (2009) Cell cycle control in the pancreatic beta cell. In: Kandeel F (ed.) Islet Transplantation: Biology, Immunology and Clinical Applications. Springer; New York (in press).

    Google Scholar 

  • Hayek A, Beattie GM. (1997) Experimental transplantation of human fetal and adult pancreatic islets. J Clin Endocrinol Metab. 82:2471–2475.

    Article  CAS  PubMed  Google Scholar 

  • Hayek A, Beattie GM, Cirulli V. (1995) Growth factor/matrix-induced proliferation of human adult ß-cells. Diabetes. 44:1458–1460.

    Article  CAS  PubMed  Google Scholar 

  • Heit JJ, Karnik SK, Kim SK. (2006) Intrinsic regulators of pancreatic β-cell proliferation. Ann Rev Cell Dev Biol. 22:311–338.

    Article  CAS  Google Scholar 

  • Hohmeier H, Newgard CB. (2004) Cell lines derived from pancreatic islets. Mol Cell Endo. 228:121–128.

    Article  CAS  Google Scholar 

  • Hughes CM, Rosenblatt-Rozen O, Milne TA, et al. (2004) Menin associates with a trithorax family histone methyltransferase complex and with the Hoxc8 locus. Molecular Cell. 13:587–597.

    Article  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 

  • Kaiser J. (2003) Seeking the cause of induced leukemias in X-SCID trial. Science. 299:495.

    Article  CAS  PubMed  Google Scholar 

  • Kaiser J. (2007) Gene transfer an unlikely contributor to patient’s death. Science. 318:1535.

    Article  CAS  PubMed  Google Scholar 

  • Karnick 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 Nat Acad Sci USA. 102:14659–14664.

    Article  CAS  Google Scholar 

  • Kassem SA, Ariel I, Thornton PS, et al. (2000) Beta cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes. 49:1325–1333.

    Article  CAS  PubMed  Google Scholar 

  • Klein D, Ribeiro MM, Mendoza V, et al. (2004) Delivery of Bcl-XL or its BH4 domain by protein transduction inhibits apoptosis in human islets. Biochem Biophys Res Comm. 323:473–478.

    Article  CAS  PubMed  Google Scholar 

  • Krishnamurthy J, Ramsey MR, Ligon KL. (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. Nature Biotechnol. 26:443–452.

    Article  CAS  Google Scholar 

  • Kulkarni RN, Brüning JC, Winnay JN, et al. (1999) Tissue-specific knockout of the insulin receptor on β cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell. 96:329–339.

    Article  CAS  PubMed  Google Scholar 

  • Kumar AF, Greussner RWG, Seaquist ER, et al. (2008) Risk of glucose intolerance and diabetes in hemipancreatectomized donors selected for normal preoperative glucose metabolism. Diabetes Care. 31:1639–1643.

    Article  PubMed  Google Scholar 

  • Kushner J, 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 

  • Lavine JA, Raess PW, Davis DB, et al. (2008) Overexpression of pre-pro-cholecystokinin stimulates β cell proliferation in mouse and human islets with retention of islet function. Mol Endocrinol. 22:2716–2728.

    Article  CAS  PubMed  Google Scholar 

  • Lindgren CM, McCarthy MI. (2008) Mechanisms of disease: genetic insights into the etiology of type 2 diabetes and obesity. Nat Clin Pract Endocrinol Metab. 4:156–163.

    Article  CAS  PubMed  Google Scholar 

  • Malumbres M, Barbacid M. (2005) Mammalian cyclin-dependent kinases. Trends Biol Sci. 30:630–641.

    Article  CAS  Google Scholar 

  • Martin J, Hunt SL, Dubus P, et al. (2003) Genetic rescue of cdk-4-null mice restores pancreatic β cell proliferation but not homeostatic cell number. Oncogene. 22:5261–5269.

    Article  CAS  PubMed  Google Scholar 

  • Matveyenko AV, Butler PC. (2006) Beta cell deficit due to increased apoptosis in the human islet amyloid polypeptide transgenic (HIP) rat recapitulates the metabolic defects present in type 2 diabetes. Diabetes. 55:2106–2114.

    Article  CAS  PubMed  Google Scholar 

  • Meier JJ, Bushan A, Butler AE, et al. (2005) Sustained β cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration?. Diabetologia. 48:2221–2228.

    Article  CAS  PubMed  Google Scholar 

  • Meier JJ, Butler AE, Saisho Y, et al. (2008) Beta cell replication is the primary mechanism subserving the postnatal expansion of β cell mass in humans. Diabetes. 57:1584–1594.

    Article  CAS  PubMed  Google Scholar 

  • Menge BA, Tannapfel A, Belyaev O, et al. (2008) Partial pancreatectomy in adult humans does not provoke β cell regeneration. Diabetes. 57:142–149.

    Article  CAS  PubMed  Google Scholar 

  • Milo-Landesman D, Surana M, Berkovich I, et al. (2001) Correction of hyperglycemia in diabetic mice transplanted with reversibly immortalized pancreatic β cells controlled by the tet-on regulatory system. Cell Transplant. 10:645–650.

    CAS  PubMed  Google Scholar 

  • Narushima M, Kobayashi N, Okitsu T, et al. (2005) A human ß-cell line for transplantation therapy to control type 1 diabetes. Nature Biotechnol. 23:1274–1282.

    Article  CAS  Google Scholar 

  • Park I-H, Aroroa N, Huo H, et al. (2008) Disease-specific pluripotent stem cells. Cell. 134:877–886.

    Article  CAS  PubMed  Google Scholar 

  • Parnaud G, Bosco D, Berney T, et al. (2008) Proliferation of sorted human and rat β cells. Diabetologia. 51:91–100.

    Article  CAS  PubMed  Google Scholar 

  • Pellegrata NS, Quintillana-Martinez L, Siggelkow H, et al. (2006) Germline mutation in p27kip1 causes a multiple endocrine neoplasia syndrome in rats and humans. Proc Nat Acad Sci USA. 103:15558–15563.

    Article  CAS  Google Scholar 

  • Pestell RG, Albanese C, Reutens AT, et al. (1999) The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation. Endocr Rev. 20:501–534.

    Article  CAS  PubMed  Google Scholar 

  • Pontoglio M, Sreenan S, Roe M, et al. (1998) Defective insulin secretion in hepatocyte nuclear factor 1 α-deficient mice. J Clin Invest. 101:2215–2222.

    Article  CAS  PubMed  Google Scholar 

  • Rane S, Dubus P, Mettus RV, et al. (1999) Loss of expression of cdk4 causes insulin-deficient diabetes and cdk4 activation results in β cell hyperplasia. Nature Genet. 22:44–52.

    Article  CAS  PubMed  Google Scholar 

  • Rao P, Roccisana J, Takane KK, et al. (2005) Gene transfer of constitutively active Akt markedly improves human islet transplant outcomes in diabetic SCID mice. Diabetes. 54:1664–1675.

    Article  CAS  PubMed  Google Scholar 

  • Russ HA, Bar Y, Ravassard P, et al. (2008) In vitro proliferation of cells derived from adult human β cells revealed by cell-lineage tracing. Diabetes. 57:1575–1583.

    Article  CAS  PubMed  Google Scholar 

  • Ryan EA, Paty BW, Senior PA, et al. (2005) Five year follow-up after clinical islet transplantation. Diabetes. 54:2060–2069.

    Article  CAS  PubMed  Google Scholar 

  • Schuit FC. (1997) Is glut-2 required for glucose sensing?. Diabetologia. 40:104–111.

    Article  CAS  PubMed  Google Scholar 

  • Shapiro AMJ, Lakey JRT, Ryan EA, et al. (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. New Engl J Med. 343:230–238.

    Article  CAS  PubMed  Google Scholar 

  • Song WJ, Schreiber WE, Zhong E, et al. (2008) Exendin-4 stimulation of cyclin A2 in β-cell proliferation. Diabetes. 57:2371–2381.

    Article  CAS  PubMed  Google Scholar 

  • Stoffel M, Duncan SA. (1997) The maturity-onset diabetes of the young (MODY1) transcription factor HNF1α regulates expression of genes required for glucose transport and metabolism. Proc Nat Acad Sci USA. 94:13209–13214.

    Article  CAS  PubMed  Google Scholar 

  • Stratakis CA, Marx SJ. (2005) Multiple endocrine neoplasias in the era of translational medicine. Horm Metab Res. 37:343–346.

    Article  CAS  PubMed  Google Scholar 

  • Suarez-Pinzon WL, Yan Y, Power R, et al. (2005) Combination therapy with epidermal growth factor and gastrin increases β cell mass and reverses hyperglycemia in diabetic NOD mice. Diabetes. 54:2596–2601.

    Article  CAS  PubMed  Google Scholar 

  • Tateishi K, He J, Taranova O, et al. (2008) Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem. 283:31601–31607.

    Article  CAS  PubMed  Google Scholar 

  • Tsutsui T, Hesabi B, Moons D, et al. (1999) Targeted disruption of cdk4 delays cell cycle entry with enhanced p27-kip activity. Mol Cell Biol. 19:7011–7019.

    CAS  PubMed  Google Scholar 

  • Tyrberg B, Eizirik DL, Hellerstrom C, et al. (1996) Human pancreatic β cell deoxyribonucleic acid synthesis in islet grafts decreases with increasing organ donor age but increases in response to glucose stimulation in vitro. Endocrinology. 137:5694–5699.

    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. Nature Med. 11:175–182.

    Article  CAS  PubMed  Google Scholar 

  • Vasavada RC, Wang L, Fujinaka Y, et al. (2007) Protein kinase C-ζ activation markedly enhances ß-cell proliferation: an essential role in growth factor-mediated ß-cell mitogenesis. Diabetes. 56:2732–2743.

    Article  CAS  PubMed  Google Scholar 

  • Wang S, Beattie GM, Mally MI, et al. (1997) Isolation and characterization of a cell line from the epithelial cells of the human fetal pancreas. Cell Transplant. 6:59–67.

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Cortina G, Wu V, et al. (2006) Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med. 355:270–280.

    Article  CAS  PubMed  Google Scholar 

  • Yoon KH, Ko H, Cho JH. (2003) Selective ß cell loss and α cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab. 88:2300–2308.

    Article  CAS  PubMed  Google Scholar 

  • Yorifuji T, Kurokawa K, Mamada M, et al. (2004) Neonatal diabetes mellitus and neonatal polycystic dysplastic kidneys: phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor 1β gene due to germline mosaicism. J Clin Endocrinol Metab. 89:2905–2908.

    Article  CAS  PubMed  Google Scholar 

  • Zaret KS, Grompe M. (2008) Generation and regeneration of cells of the liver and pancreas. Science. 322:1490–1494.

    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 

Download references

Acknowledgments

The authors wish to thank the Juvenile Diabetes Research Foundation, the American Diabetes Association and the National Institutes of Health (NIDDK R-01 55023) for their support of this work. We also thank the Don and Arleen Wagner Family Foundation and Pam and Scott Kroh for their support of this work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nathalie Fiaschi-Taesch .

Editor information

Editors and Affiliations

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

Fiaschi-Taesch, N., Harb, G., Karsiloglu, E., Takane, K.K., Stewart, A.F. (2010). Cell Cycle Regulation in Human Pancreatic Beta Cells. 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_3

Download citation

Publish with us

Policies and ethics