Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The replication of β cells in normal physiology, in disease and for therapy

Nature Clinical Practice Endocrinology & Metabolism volume 3, pages 758–768 (2007)Cite this article

Abstract

Replication of β cells is an important source of β-cell expansion in early childhood. The recent linkage of type 2 diabetes with several transcription factors involved in cell cycle regulation implies that growth of the β-cell mass in early childhood might be an important determinant of risk for type 2 diabetes. Under some circumstances, including obesity and pregnancy, the β-cell mass is adaptively increased in adult humans. The mechanisms by which this adaptive growth occurs and the relative contributions of β-cell replication or of mechanisms independent of β-cell replication are unknown. Also, although there is interest in the potential for β-cell regeneration as a therapeutic approach in both type 1 and 2 diabetes, little is yet known about the potential sources of new β cells in adult humans. In common with other cell types, replicating β cells have an increased vulnerability to apoptosis, which is likely to limit the therapeutic value of inducing β-cell replication in the proapoptotic environment of type 1 and 2 diabetes unless applied in conjunction with a strategy to suppress increased apoptosis.

Key Points

  • Replication of β-cells is important in growth of the β-cell mass during infancy in humans but is infrequent in adults, implying that most β cells are then quiescent

  • The β-cell mass increases in response to obesity and pregnancy in humans, implying some ongoing capacity for β-cell turnover but much less than that in rodents

  • The range of β-cell mass in nondiabetic humans far exceeds the adaptive increase in response to chronic insulin resistance, implying a wide range of growth in β-cell mass during infancy

  • Sources of new β cells that do not rely on β-cell replication have been proposed but are as yet unproven in humans

  • Newly forming β cells have an increased vulnerability to apoptosis, probably limiting potential β-cell regeneration

  • Although β-cell regeneration has been proposed as a therapy for type 1 and type 2 diabetes, neither the extent that β-cell regeneration can be accomplished nor the mechanisms involved have been established in humans

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The somatic cell cycle.
Figure 2: Regulation of the β-cell mass.
Figure 3: The β-cell mass in diabetes.
Figure 4: Replication of β cells is increased in early type 1 diabetes.
Figure 5: Relationship between β-cell mass and FPG concentration in humans.

Similar content being viewed by others

References

  1. Meier JJ and Butler PC (2005) Insulin secretion. In Endocrinology, edn 5, 961–973 (Eds DeGroot LJ and Jameson JL) Philadelphia: Elsevier Saunders

    Google Scholar 

  2. Stefan Y et al. (1982) Quantitation of endocrine cell content in the pancreas of nondiabetic and diabetic humans. Diabetes 31: 694–700

    Article  CAS  PubMed  Google Scholar 

  3. Service FJ (1999) Classification of hypoglycemic disorders. Endocrinol Metab Clin North Am 28: 501–517, vi

    Article  CAS  PubMed  Google Scholar 

  4. Stanger BZ et al. (2007) Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature 445: 886–891

    Article  CAS  PubMed  Google Scholar 

  5. Georgia S et al. (2006) p57 and Hes1 coordinate cell cycle exit with self-renewal of pancreatic progenitors. Dev Biol 298: 22–31

    Article  CAS  PubMed  Google Scholar 

  6. Kassem SA et al. (2000) β-Cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 49: 1325–1333

    Article  CAS  PubMed  Google Scholar 

  7. Dor Y 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 

  8. Teta M 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 

  9. Rane SG 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 

  10. Georgia S et al. (2004) β Cell replication is the primary mechanism for maintaining postnatal β cell mass. J Clin Invest 114: 963–968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vasavada RC 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 

  13. Krishnamurthy J et al. (2006) p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443: 453–457

    Article  CAS  PubMed  Google Scholar 

  14. Uchida T 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 

  15. Georgia S et al. (2006) p27 Regulates the transition of β-cells from quiescence to proliferation. Diabetes 55: 2950–2956

    Article  CAS  PubMed  Google Scholar 

  16. Karnik SK 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  PubMed Central  Google Scholar 

  17. Teta M et al. (2005) Very slow turnover of β-cells in aged adult mice. Diabetes 54: 2557–2567

    Article  CAS  PubMed  Google Scholar 

  18. Van Assche FA et al. (1978) A morphological study of the endocrine pancreas in human pregnancy. Br J Obstet Gynaecol 85: 818–820

    Article  CAS  PubMed  Google Scholar 

  19. Butler AE et al. (2003) β-Cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52: 102–110

    Article  CAS  PubMed  Google Scholar 

  20. Terauchi Y et al. (2007) Glucokinase and IRS-2 are required for compensatory β cell hyperplasia in response to high-fat diet-induced insulin resistance. J Clin Invest 117: 246–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Okamoto H et al. (2006) Role of the forkhead protein FoxO1 in β cell compensation to insulin resistance. J Clin Invest 116: 775–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kulkarni RN et al. (2004) PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest 114: 828–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cozar-Castellano I et al. (2006) Molecular control of cell cycle progression in the pancreatic β-cell. Endocr Rev 27: 356–370

    Article  CAS  PubMed  Google Scholar 

  25. Bannigan J et al. (1979) The cellular effect of 5-bromodeoxyuridine on the mammalian embryo. J Embryol Exp Morphol 50: 123–135

    CAS  PubMed  Google Scholar 

  26. Beisker W et al. (1988) Measurement of the kinetics of DNA repair synthesis after UV irradiation using immunochemical staining of incorporated 5-bromo-2'-deoxyuridine and flow cytometry. Exp Cell Res 174: 156–167

    Article  CAS  PubMed  Google Scholar 

  27. Endl E et al. (2000) The Ki-67 protein: fascinating forms and an unknown function. Exp Cell Res 257: 231–237

    Article  CAS  PubMed  Google Scholar 

  28. Zacchetti A et al. (2003) Validation of the use of proliferation markers in canine neoplastic and non-neoplastic tissues: comparison of KI-67 and proliferating cell nuclear antigen (PCNA) expression versus in vivo bromodeoxyuridine labelling by immunohistochemistry. APMIS 111: 430–438

    Article  CAS  PubMed  Google Scholar 

  29. Bullwinkel J et al. (2006) Ki-67 protein is associated with ribosomal RNA transcription in quiescent and proliferating cells. J Cell Physiol 206: 624–635

    Article  CAS  PubMed  Google Scholar 

  30. Hendzel MJ et al. (1997) Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma 106: 348–360

    Article  CAS  PubMed  Google Scholar 

  31. Butler AE et al. (2003) 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 52: 2304–2314

    Article  CAS  PubMed  Google Scholar 

  32. Ianus A 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bonner-Weir S et al. (2002) Pancreatic stem cells. J Pathol 197: 519–526

    Article  PubMed  Google Scholar 

  34. Gershengorn MC et al. (2004) Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells. Science 306: 2261–2264

    Article  CAS  PubMed  Google Scholar 

  35. Butler AE et al. (2007) Hematopoietic stem cells derived from adult donors are not a source of pancreatic β cells in adult nondiabetic humans. Diabetes 56: 1810–1806

    Article  CAS  PubMed  Google Scholar 

  36. Kayali AG et al. (2007) Limited capacity of human adult islets expanded in vitro to redifferentiate into insulin-producing β-cells. Diabetes 56: 703–708

    Article  CAS  PubMed  Google Scholar 

  37. Hess D et al. (2003) Bone marrow-derived stem cells initiate pancreatic regeneration. Nat Biotechnol 21: 763–770

    Article  CAS  PubMed  Google Scholar 

  38. Voltarelli JC et al. (2007) Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 297: 1568–1576

    Article  CAS  PubMed  Google Scholar 

  39. Atkinson MA (2005) ADA Outstanding Scientific Achievement Lecture 2004. Thirty years of investigating the autoimmune basis for type 1 diabetes: why can't we prevent or reverse this disease? Diabetes 54: 1253–1263

    Article  CAS  PubMed  Google Scholar 

  40. Foulis AK et al. (1984) The pancreas in recent-onset type 1 (insulin-dependent) diabetes mellitus: insulin content of islets, insulitis and associated changes in the exocrine acinar tissue. Diabetologia 26: 456–461

    Article  CAS  PubMed  Google Scholar 

  41. Meier JJ et al. (2006) Increased islet β cell replication adjacent to intrapancreatic gastrinomas in humans. Diabetologia 49: 2689–2696

    Article  CAS  PubMed  Google Scholar 

  42. Meier JJ 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 

  43. Sit KH et al. (1997) Transient G2M arrest and subsequent release of apoptotic and mitotic cells in vanadyl(4)-prepulsed human Chang liver cells. Cell Death Differ 4: 216–223

    Article  CAS  PubMed  Google Scholar 

  44. Webb SJ et al. (1997) Apoptosis: an overview of the process and its relevance in disease. Adv Pharmacol 41: 1–34

    Article  CAS  PubMed  Google Scholar 

  45. Ritzel RA et al. (2003) Replication increases β-cell vulnerability to human islet amyloid polypeptide-induced apoptosis. Diabetes 52: 1701–1708

    Article  CAS  PubMed  Google Scholar 

  46. Sladek R et al. (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445: 881–885

    Article  CAS  PubMed  Google Scholar 

  47. Zeggini E et al. (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316: 1336–1341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Scott LJ et al. (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316: 1341–1345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bort R et al. (2004) Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas. Development 131: 797–806

    Article  CAS  PubMed  Google Scholar 

  50. Stickens D et al. (1996) The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nat Genet 14: 25–32

    Article  CAS  PubMed  Google Scholar 

  51. Spagnoli FM et al. (2006) The RNA-binding protein, Vg1RBP, is required for pancreatic fate specification. Dev Biol 292: 442–456

    Article  CAS  PubMed  Google Scholar 

  52. Saxena R et al. (2006) Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 55: 2890–2895

    Article  CAS  PubMed  Google Scholar 

  53. Ubeda M et al. (2006) Inhibition of cyclin-dependent kinase 5 activity protects pancreatic β cells from glucotoxicity. J Biol Chem 281: 28858–28864

    Article  CAS  PubMed  Google Scholar 

  54. Ritzel RA et al. (2006) Relationship between β-cell mass and fasting blood glucose concentration in humans. Diabetes Care 29: 717–718

    Article  PubMed  Google Scholar 

  55. Barker DJ et al. (1993) Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36: 62–67

    Article  CAS  PubMed  Google Scholar 

  56. de Rooij SR et al. (2006) Glucose tolerance at age 58 and the decline of glucose tolerance in comparison with age 50 in people prenatally exposed to the Dutch famine. Diabetologia 49: 637–643

    Article  CAS  PubMed  Google Scholar 

  57. Fakhrai-Rad H et al. (2000) Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats. Hum Mol Genet 9: 2149–2158

    Article  CAS  PubMed  Google Scholar 

  58. Nath DS et al. (2005) Outcomes of pancreas transplants for patients with type 2 diabetes mellitus. Clin Transplant 19: 792–797

    Article  PubMed  Google Scholar 

  59. Robertson RP et al. (1999) Normoglycemia and preserved insulin secretory reserve in diabetic patients 10-18 years after pancreas transplantation. Diabetes 48: 1737–1740

    Article  CAS  PubMed  Google Scholar 

  60. Bonner-Weir S et al. (1983) Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J Clin Invest 71: 1544–1553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  62. Robertson RP et al. (2002) Relationship between diabetes and obesity 9 to 18 years after hemipancreatectomy and transplantation in donors and recipients. Transplantation 73: 736–741

    Article  PubMed  Google Scholar 

  63. Matveyenko AV et al. (2006) Mechanisms of impaired fasting glucose and glucose intolerance induced by an approximate 50% pancreatectomy. Diabetes 55: 2347–2356

    Article  CAS  PubMed  Google Scholar 

  64. Stagner JI et al. (1991) Deterioration of islet β-cell function after hemipancreatectomy in dogs. Diabetes 40: 1472–1479

    Article  CAS  PubMed  Google Scholar 

  65. Meier JJ et al. (2006) Direct evidence of attempted β cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia 49: 1838–1844

    Article  CAS  PubMed  Google Scholar 

  66. Meier JJ et al. (2006) The potential for stem cell therapy in diabetes. Pediatr Res 59: 65R–73R

    Article  PubMed  Google Scholar 

  67. Meier JJ et al. (2006) Increased vulnerability of newly forming β cells to cytokine-induced cell death. Diabetologia 49: 83–89

    Article  CAS  PubMed  Google Scholar 

  68. Herold KC et al. (2002) Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346: 1692–1698

    Article  CAS  PubMed  Google Scholar 

  69. Leslie RD (2004) Preventing type 1 diabetes mellitus: hype and hope. Clin Med 4: 442–446

    Article  Google Scholar 

  70. Buchanan TA et al. (2002) Preservation of pancreatic β-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 51: 2796–2803

    Article  CAS  PubMed  Google Scholar 

  71. Suarez-Pinzon WL 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 

  72. Rhodes CJ (2000) IGF-I and GH post-receptor signaling mechanisms for pancreatic β-cell replication. J Mol Endocrinol 24: 303–311

    Article  CAS  PubMed  Google Scholar 

  73. Meier JJ et al. (2005) Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabetes Metab Res Rev 21: 91–117

    Article  CAS  PubMed  Google Scholar 

  74. Marchetti P et al. (2004) Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab 89: 5535–5541

    Article  CAS  PubMed  Google Scholar 

  75. (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352: 854–865

  76. Kahn SE et al. (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355: 2427–2443

    Article  CAS  PubMed  Google Scholar 

  77. Lin CY et al. (2005) Activation of peroxisome proliferator-activated receptor-γ by rosiglitazone protects human islet cells against human islet amyloid polypeptide toxicity by a phosphatidylinositol 3'-kinase-dependent pathway. J Clin Endocrinol Metab 90: 6678–6686

    Article  CAS  PubMed  Google Scholar 

  78. Nissen SE et al. (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356: 2457–2471

    Article  CAS  PubMed  Google Scholar 

  79. Matthews DR et al. (1998) UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group. Diabet Med 15: 297–303

    Article  CAS  PubMed  Google Scholar 

  80. Maedler K et al. (2005) Sulfonylurea induced β-cell apoptosis in cultured human islets. J Clin Endocrinol Metab 90: 501–506

    Article  CAS  PubMed  Google Scholar 

  81. Lupi R et al. (2006) The direct effects of the angiotensin-converting enzyme inhibitors, zofenoprilat and enalaprilat, on isolated human pancreatic islets. Eur J Endocrinol 154: 355–361

    Article  CAS  PubMed  Google Scholar 

  82. Bosch J et al. (2006) Effect of ramipril on the incidence of diabetes. N Engl J Med 355: 1551–1562

    Article  PubMed  Google Scholar 

  83. Kjems LL et al. (2001) Decrease in β-cell mass leads to impaired pulsatile insulin secretion, reduced postprandial hepatic insulin clearance, and relative hyperglucagonemia in the minipig. Diabetes 50: 2001–2012

    Article  CAS  PubMed  Google Scholar 

  84. Matveyenko AV et al. (2006) β-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 

Download references

Author information

Authors and Affiliations

  1. PC Butler is a Professor of Medicine and Director, JJ Meier is a Clinical Research Fellow, and AE Butler and A Bhushan are Assistant Professors of Medicine, at the Larry Hillblom Islet Research Center, University of California at Los Angeles (UCLA) David Geffen School of Medicine, Los Angeles, CA, USA.,

    Peter C Butler, Juris J Meier, Alexandra E Butler & Anil Bhushan

Authors
  1. Peter C Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juris J Meier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexandra E Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anil Bhushan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter C Butler.

Ethics declarations

Competing interests

PC Butler has received investigator-initiated research grant funding from Merck, Novo Nordisk and Pfizer. The other authors declared no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Butler, P., Meier, J., Butler, A. et al. The replication of β cells in normal physiology, in disease and for therapy. Nat Rev Endocrinol 3, 758–768 (2007). https://doi.org/10.1038/ncpendmet0647

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpendmet0647

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing