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A synopsis of factors regulating beta cell development and beta cell mass

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Abstract

The insulin-secreting beta cells in the endocrine pancreas regulate blood glucose levels, and loss of functional beta cells leads to insulin deficiency, hyperglycemia (high blood glucose) and diabetes mellitus. Current treatment strategies for type-1 (autoimmune) diabetes are islet transplantation, which has significant risks and limitations, or normalization of blood glucose with insulin injections, which is clearly not ideal. The type-1 patients can lack insulin counter-regulatory mechanism; therefore, hypoglycemia is a potential risk. Hence, a cell-based therapy offers a better alternative for the treatment of diabetes. Past research was focused on attempting to generate replacement beta cells from stem cells; however, recently there has been an increasing interest in identifying mechanisms that will lead to the conversion of pre-existing differentiated endocrine cells into beta cells. The goal of this review is to provide an overview of several of the key factors that regulate new beta cell formation (neogenesis) and beta cell proliferation.

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Abbreviations

BMP:

Bone morphogenetic proteins

DT:

Diphtheria toxin

EGFR:

Epidermal growth factor receptor

FGF:

Fibroblast growth factor

GIP:

Glucose-dependent insulinotropic polypeptide

PDL:

Pancreatic duct ligation

VEGF:

Vascular endothelial growth factor

BrdU:

Bromodeoxyuridine (5-bromo-2′-deoxyuridine)

EGF:

Epidermal growth factor

GCGR:

Glucagon receptor

MafA:

V-maf musculoaponeurotic fibrosarcoma oncogene homolog A

MafB:

V-maf musculoaponeurotic fibrosarcoma oncogene homolog B

Ngn3:

Neurogenin-3

Nkx2.2:

NK2 homeobox 2

Nkx6.1:

NK6 transcription factor related, locus 1

Nkx6.2:

NK6 transcription factor related, locus 2

Pax4:

Paired box gene 4

Pax6:

Paired box gene 6

Pdx1:

Pancreatic duodenal homeobox-1

PP:

Pancreatic polypeptide

Ptf1A:

Pancreas-specific transcription factor-1a

TGF:

Transforming growth factor

TGFbRI:

Transforming growth factor-β type I receptor

TGFbRII:

Transforming growth factor-β type II receptor

References

  1. Chung CH, Hao E, Piran R, Keinan E, Levine F (2010) Pancreatic beta-cell neogenesis by direct conversion from mature alpha-cells. Stem Cells 28(9):1630–1638

    Article  CAS  PubMed  Google Scholar 

  2. Chung CH, Levine F (2010) Adult pancreatic alpha-cells: a new source of cells for beta-cell regeneration. Rev Diabet Stud 7(2):124–131

    Article  PubMed  PubMed Central  Google Scholar 

  3. Thorel F, Nepote V, Avril I, Kohno K, Desgraz R, Chera S, Herrera PL (2010) Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464(7292):1149–1154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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(10):2447–2457

    CAS  PubMed  Google Scholar 

  5. Gradwohl G, Dierich A, LeMeur M, Guillemot F (2000) Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA 97(4):1607–1611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Larsson LI, Madsen OD, Serup P, Jonsson J, Edlund H (1996) Pancreatic-duodenal homeobox 1—role in gastric endocrine patterning. Mech Dev 60(2):175–184

    Article  CAS  PubMed  Google Scholar 

  7. Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF (1997) Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 15(1):106–110

    Article  CAS  PubMed  Google Scholar 

  8. Li H, Arber S, Jessell TM, Edlund H (1999) Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9. Nat Genet 23(1):67–70

    Article  CAS  PubMed  Google Scholar 

  9. Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, Coleman RJ, Garrett C, Gloyn AL, Edghill EL, Hattersley AT, Wellauer PK, Goodwin G, Houlston RS (2004) Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 36(12):1301–1305

    Article  CAS  PubMed  Google Scholar 

  10. Fukuda A, Kawaguchi Y, Furuyama K, Kodama S, Horiguchi M, Kuhara T, Kawaguchi M, Terao M, Doi R, Wright CV, Hoshino M, Chiba T, Uemoto S (2008) Reduction of Ptf1a gene dosage causes pancreatic hypoplasia and diabetes in mice. Diabetes 57(9):2421–2431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dohrmann C, Gruss P, Lemaire L (2000) Pax genes and the differentiation of hormone-producing endocrine cells in the pancreas. Mech Dev 92(1):47–54

    Article  CAS  PubMed  Google Scholar 

  12. St-Onge L, Sosa-Pineda B, Chowdhury K, Mansouri A, Gruss P (1997) Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature 387(6631):406–409

    Article  CAS  PubMed  Google Scholar 

  13. Jenny M, Uhl C, Roche C, Duluc I, Guillermin V, Guillemot F, Jensen J, Kedinger M, Gradwohl G (2002) Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J 21(23):6338–6347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ (1997) Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev 11(18):2323–2334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Brink C, Chowdhury K, Gruss P (2001) Pax4 regulatory elements mediate beta cell specific expression in the pancreas. Mech Dev 100(1):37–43

    Article  CAS  PubMed  Google Scholar 

  16. Sussel L, Kalamaras J, Hartigan-O’Connor DJ, Meneses JJ, Pedersen RA, Rubenstein JL, German MS (1998) Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development 125(12):2213–2221

    CAS  PubMed  Google Scholar 

  17. Sander M, Sussel L, Conners J, Scheel D, Kalamaras J, Dela Cruz F, Schwitzgebel V, Hayes-Jordan A, German M (2000) Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development 127(24):5533–5540

    CAS  PubMed  Google Scholar 

  18. Artner I, Hang Y, Mazur M, Yamamoto T, Guo M, Lindner J, Magnuson MA, Stein R (2010) MafA and MafB regulate genes critical to beta-cells in a unique temporal manner. Diabetes 59(10):2530–2539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nishimura W, Kondo T, Salameh T, El Khattabi I, Dodge R, Bonner-Weir S, Sharma A (2006) A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. Dev Biol 293(2):526–539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Abdellatif AM, Ogata K, Kudo T, Xiafukaiti G, Chang YH, Katoh MC, El-Morsy SE, Oishi H, Takahashi S (2015) Role of large MAF transcription factors in the mouse endocrine pancreas. Exp Anim 64(3):305–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nishimura W, Bonner-Weir S, Sharma A (2009) Expression of MafA in pancreatic progenitors is detrimental for pancreatic development. Dev Biol 333(1):108–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nishimura W, Rowan S, Salameh T, Maas RL, Bonner-Weir S, Sell SM, Sharma A (2008) Preferential reduction of beta cells derived from Pax6-MafB pathway in MafB deficient mice. Dev Biol 314(2):443–456

    Article  CAS  PubMed  Google Scholar 

  23. Moses HL, Arteaga CL, Alexandrow MG, Dagnino L, Kawabata M, Pierce DF Jr, Serra R (1994) TGF beta regulation of cell proliferation. Princess Takamatsu Symp 24:250–263

    CAS  PubMed  Google Scholar 

  24. Moses HL, Coffey RJ Jr, Leof EB, Lyons RM, Keski-Oja J (1987) Transforming growth factor beta regulation of cell proliferation. J Cell Physiol Suppl Suppl 5:1–7

    Article  CAS  PubMed  Google Scholar 

  25. Moses HL, Yang EY, Pietenpol JA (1990) TGF-beta stimulation and inhibition of cell proliferation: new mechanistic insights. Cell 63(2):245–247

    Article  CAS  PubMed  Google Scholar 

  26. Wrighton KH, Lin X, Feng XH (2009) Phospho-control of TGF-beta superfamily signaling. Cell Res 19(1):8–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Matsuzaki K (2013) Smad phospho-isoforms direct context-dependent TGF-beta signaling. Cytokine Growth Factor Rev 24(4):385–399

    Article  CAS  PubMed  Google Scholar 

  28. Xiao X, Wiersch J, El-Gohary Y, Guo P, Prasadan K, Paredes J, Welsh C, Shiota C, Gittes GK (2013) TGFbeta receptor signaling is essential for inflammation-induced but not beta-cell workload-induced beta-cell proliferation. Diabetes 62(4):1217–1226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ungefroren H, Groth S, Sebens S, Lehnert H, Gieseler F, Fandrich F (2011) Differential roles of Smad2 and Smad3 in the regulation of TGF-beta1-mediated growth inhibition and cell migration in pancreatic ductal adenocarcinoma cells: control by Rac1. Mol Cancer 10:67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ungefroren H, Sebens S, Groth S, Gieseler F, Fandrich F (2011) The Src family kinase inhibitors PP2 and PP1 block TGF-beta1-mediated cellular responses by direct and differential inhibition of type I and type II TGF-beta receptors. Curr Cancer Drug Targets 11(4):524–535

    Article  CAS  PubMed  Google Scholar 

  31. Goulley J, Dahl U, Baeza N, Mishina Y, Edlund H (2007) BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion. Cell Metab 5(3):207–219

    Article  CAS  PubMed  Google Scholar 

  32. Smart NG, Apelqvist AA, Gu X, Harmon EB, Topper JN, MacDonald RJ, Kim SK (2006) Conditional expression of Smad7 in pancreatic beta cells disrupts TGF-beta signaling and induces reversible diabetes mellitus. PLoS Biol 4(2):e39

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Gittes GK (2009) Developmental biology of the pancreas: a comprehensive review. Dev Biol 326(1):4–35

    Article  CAS  PubMed  Google Scholar 

  34. Maldonado TS, Kadison AS, Crisera CA, Grau JB, Alkasab SL, Longaker MT, Gittes GK (2000) Ontogeny of activin B and follistatin in developing embryonic mouse pancreas: implications for lineage selection. J Gastrointest Surg 4(3):269–275

    Article  CAS  PubMed  Google Scholar 

  35. Miralles F, Czernichow P, Scharfmann R (1998) Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development. Development 125(6):1017–1024

    CAS  PubMed  Google Scholar 

  36. Szabat M, Johnson JD, Piret JM (2010) Reciprocal modulation of adult beta cell maturity by activin A and follistatin. Diabetologia 53(8):1680–1689

    Article  CAS  PubMed  Google Scholar 

  37. Gittes GK, Galante PE, Hanahan D, Rutter WJ, Debase HT (1996) Lineage-specific morphogenesis in the developing pancreas: role of mesenchymal factors. Development 122(2):439–447

    CAS  PubMed  Google Scholar 

  38. Rose MI, Crisera CA, Colen KL, Connelly PR, Longaker MT, Gittes GK (1999) Epithelio-mesenchymal interactions in the developing mouse pancreas: morphogenesis of the adult architecture. J Pediatr Surg 34(5):774–779 (discussion 780)

    Article  CAS  PubMed  Google Scholar 

  39. Zhang YQ, Cleary MM, Si Y, Liu G, Eto Y, Kritzik M, Dabernat S, Kayali AG, Sarvetnick N (2004) Inhibition of activin signaling induces pancreatic epithelial cell expansion and diminishes terminal differentiation of pancreatic beta-cells. Diabetes 53(8):2024–2033

    Article  CAS  PubMed  Google Scholar 

  40. Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, Groffen J (1995) Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial–mesenchymal interaction. Nat Genet 11(4):415–421

    Article  CAS  PubMed  Google Scholar 

  41. Sanford LP, Ormsby I, Gittenberger-de Groot AC, Sariola H, Friedman R, Boivin GP, Cardell EL, Doetschman T (1997) TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 124(13):2659–2670

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D et al (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359(6397):693–699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bottinger EP, Jakubczak JL, Haines DC, Bagnall K, Wakefield LM (1997) Transgenic mice overexpressing a dominant-negative mutant type II transforming growth factor beta receptor show enhanced tumorigenesis in the mammary gland and lung in response to the carcinogen 7,12-dimethylbenz-[a]-anthracene. Cancer Res 57(24):5564–5570

    CAS  PubMed  Google Scholar 

  44. Bottinger EP, Jakubczak JL, Roberts IS, Mumy M, Hemmati P, Bagnall K, Merlino G, Wakefield LM (1997) Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas. EMBO J 16(10):2621–2633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tulachan SS, Tei E, Hembree M, Crisera C, Prasadan K, Koizumi M, Shah S, Guo P, Bottinger E, Gittes GK (2007) TGF-beta isoform signaling regulates secondary transition and mesenchymal-induced endocrine development in the embryonic mouse pancreas. Dev Biol 305(2):508–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Brorson M, Hougaard DM, Nielsen JH, Tornehave D, Larsson LI (2001) Expression of SMAD signal transduction molecules in the pancreas. Histochem Cell Biol 116(3):263–267

    Article  CAS  PubMed  Google Scholar 

  47. Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, Ishibashi M, Kageyama R, Guillemot F, Serup P, Madsen OD (2000) Control of endodermal endocrine development by Hes-1. Nat Genet 24(1):36–44

    Article  CAS  PubMed  Google Scholar 

  48. Boerner BP, George NM, Targy NM, Sarvetnick NE (2013) TGF-beta superfamily member Nodal stimulates human beta-cell proliferation while maintaining cellular viability. Endocrinology 154(11):4099–4112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. El-Gohary Y, Tulachan S, Guo P, Welsh C, Wiersch J, Prasadan K, Paredes J, Shiota C, Xiao X, Wada Y, Diaz M, Gittes G (2013) Smad signaling pathways regulate pancreatic endocrine development. Dev Biol 378(2):83–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yamanaka Y, Friess H, Buchler M, Beger HG, Gold LI, Korc M (1993) Synthesis and expression of transforming growth factor beta-1, beta-2, and beta-3 in the endocrine and exocrine pancreas. Diabetes 42(5):746–756

    Article  CAS  PubMed  Google Scholar 

  51. El-Gohary Y, Tulachan S, Wiersch J, Guo P, Welsh C, Prasadan K, Paredes J, Shiota C, Xiao X, Wada Y, Diaz M, Gittes G (2014) A smad signaling network regulates islet cell proliferation. Diabetes 63(1):224–236

    Article  CAS  PubMed  Google Scholar 

  52. Criscimanna A, Coudriet GM, Gittes GK, Piganelli JD, Esni F (2014) Activated macrophages create lineage-specific microenvironments for pancreatic acinar- and beta-cell regeneration in mice. Gastroenterology 147(5):1106–18 e11

    Article  CAS  PubMed  Google Scholar 

  53. Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, Song Z, El-Gohary Y, Prasadan K, Shiota C, Gittes GK (2014) M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci USA 111(13):E1211–E1220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Prasadan K, Daume E, Preuett B, Spilde T, Bhatia A, Kobayashi H, Hembree M, Manna P, Gittes GK (2002) Glucagon is required for early insulin-positive differentiation in the developing mouse pancreas. Diabetes 51(11):3229–3236

    Article  CAS  PubMed  Google Scholar 

  55. El-Gohary Y, Wiersch J, Tulachan S, Xiao X, Guo P, Rymer C, Fischbach S, Prasadan K, Shiota C, Gaffar I, Song Z, Galambos C, Esni F, Gittes GK (2016) Intraislet pancreatic ducts can give rise to insulin-positive cells. Endocrinology 157(1):166–175

    Article  CAS  PubMed  Google Scholar 

  56. Vuguin PM, Kedees MH, Cui L, Guz Y, Gelling RW, Nejathaim M, Charron MJ, Teitelman G (2006) Ablation of the glucagon receptor gene increases fetal lethality and produces alterations in islet development and maturation. Endocrinology 147(9):3995–4006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Schwitzgebel VM, Scheel DW, Conners JR, Kalamaras J, Lee JE, Anderson DJ, Sussel L, Johnson JD, German MS (2000) Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development 127(16):3533–3542

    CAS  PubMed  Google Scholar 

  58. Rall LB, Pictet RL, Williams RH, Rutter WJ (1973) Early differentiation of glucagon-producing cells in embryonic pancreas: a possible developmental role for glucagon. Proc Natl Acad Sci USA 70(12):3478–3482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lee YC, Damholt AB, Billestrup N, Kisbye T, Galante P, Michelsen B, Kofod H, Nielsen JH (1999) Developmental expression of proprotein convertase 1/3 in the rat. Mol Cell Endocrinol 155(1–2):27–35

    Article  CAS  PubMed  Google Scholar 

  60. Wilson ME, Kalamaras JA, German MS (2002) Expression pattern of IAPP and prohormone convertase 1/3 reveals a distinctive set of endocrine cells in the embryonic pancreas. Mech Dev 115(1–2):171–176

    Article  CAS  PubMed  Google Scholar 

  61. Whalley NM, Pritchard LE, Smith DM, White A (2011) Processing of proglucagon to GLP-1 in pancreatic alpha-cells: is this a paracrine mechanism enabling GLP-1 to act on beta-cells? J Endocrinol 211(1):99–106

    Article  CAS  PubMed  Google Scholar 

  62. Masur K, Tibaduiza EC, Chen C, Ligon B, Beinborn M (2005) Basal receptor activation by locally produced glucagon-like peptide-1 contributes to maintaining beta-cell function. Mol Endocrinol 19(5):1373–1382

    Article  CAS  PubMed  Google Scholar 

  63. Ryan AS, Egan JM, Habener JF, Elahi D (1998) Insulinotropic hormone glucagon-like peptide-1-(7–37) appears not to augment insulin-mediated glucose uptake in young men during euglycemia. J Clin Endocrinol Metab 83(7):2399–2404

    CAS  PubMed  Google Scholar 

  64. Parkes DG, Pittner R, Jodka C, Smith P, Young A (2001) Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro. Metabolism 50(5):583–589

    Article  CAS  PubMed  Google Scholar 

  65. Kemp DM, Habener JF (2001) Insulinotropic hormone glucagon-like peptide 1 (GLP-1) activation of insulin gene promoter inhibited by p38 mitogen-activated protein kinase. Endocrinology 142(3):1179–1187

    CAS  PubMed  Google Scholar 

  66. Abraham EJ, Leech CA, Lin JC, Zulewski H, Habener JF (2002) Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. Endocrinology 143(8):3152–3161

    Article  CAS  PubMed  Google Scholar 

  67. Bai L, Meredith G, Tuch BE (2005) Glucagon-like peptide-1 enhances production of insulin in insulin-producing cells derived from mouse embryonic stem cells. J Endocrinol 186(2):343–352

    Article  CAS  PubMed  Google Scholar 

  68. Yew KH, Prasadan KL, Preuett BL, Hembree MJ, McFall CR, Benjes CL, Crowley AR, Sharp SL, Li Z, Tulachan SS, Mehta SS, Gittes GK (2004) Interplay of glucagon-like peptide-1 and transforming growth factor-beta signaling in insulin-positive differentiation of AR42J cells. Diabetes 53(11):2824–2835

    Article  CAS  PubMed  Google Scholar 

  69. Zhou J, Wang X, Pineyro MA, Egan JM (1999) Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells. Diabetes 48(12):2358–2366

    Article  CAS  PubMed  Google Scholar 

  70. Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, Cui L, Obici S, Tang B, Holst JJ, Fledelius C, Johansen PB, Rossetti L, Jelicks LA, Serup P, Nishimura E, Charron MJ (2003) Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA 100(3):1438–1443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Stanojevic V, Habener JF (2015) Evolving function and potential of pancreatic alpha cells. Best Pract Res Clin Endocrinol Metab 29(6):859–871

    Article  CAS  PubMed  Google Scholar 

  72. Habener JF, Stanojevic V (2013) Alpha cells come of age. Trends Endocrinol Metab 24(3):153–163

    Article  CAS  PubMed  Google Scholar 

  73. Kedees MH, Grigoryan M, Guz Y, Teitelman G (2009) Differential expression of glucagon and glucagon-like peptide 1 receptors in mouse pancreatic alpha and beta cells in two models of alpha cell hyperplasia. Mol Cell Endocrinol 311(1–2):69–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Longuet C, Robledo AM, Dean ED, Dai C, Ali S, McGuinness I, de Chavez V, Vuguin PM, Charron MJ, Powers AC, Drucker DJ (2013) Liver-specific disruption of the murine glucagon receptor produces alpha-cell hyperplasia: evidence for a circulating alpha-cell growth factor. Diabetes 62(4):1196–1205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Conarello SL, Jiang G, Mu J, Li Z, Woods J, Zycband E, Ronan J, Liu F, Roy RS, Zhu L, Charron MJ, Zhang BB (2007) Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia. Diabetologia 50(1):142–150

    Article  CAS  PubMed  Google Scholar 

  76. Sloop KW, Cao JX, Siesky AM, Zhang HY, Bodenmiller DM, Cox AL, Jacobs SJ, Moyers JS, Owens RA, Showalter AD, Brenner MB, Raap A, Gromada J, Berridge BR, Monteith DK, Porksen N, McKay RA, Monia BP, Bhanot S, Watts LM, Michael MD (2004) Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors. J Clin Invest 113(11):1571–1581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ali S, Lamont BJ, Charron MJ, Drucker DJ (2011) Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis. J Clin Invest 121(5):1917–1929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Postic C, Magnuson MA (2000) DNA excision in liver by an albumin-Cre transgene occurs progressively with age. Genesis 26(2):149–150

    Article  CAS  PubMed  Google Scholar 

  79. Chen M, Mema E, Kelleher J, Nemechek N, Berger A, Wang J, Xie T, Gavrilova O, Drucker DJ, Weinstein LS (2011) Absence of the glucagon-like peptide-1 receptor does not affect the metabolic phenotype of mice with liver-specific G(s)alpha deficiency. Endocrinology 152(9):3343–3350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Steenberg VR, Jensen SM, Pedersen J, Madsen AN, Windelov JA, Holst B, Quistorff B, Poulsen SS, Holst JJ (2016) Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes. Diabetologia 59:363–370

    Article  CAS  PubMed  Google Scholar 

  81. Al-Hasani K, Pfeifer A, Courtney M, Ben-Othman N, Gjernes E, Vieira A, Druelle N, Avolio F, Ravassard P, Leuckx G, Lacas-Gervais S, Ambrosetti D, Benizri E, Hecksher-Sorensen J, Gounon P, Ferrer J, Gradwohl G, Heimberg H, Mansouri A, Collombat P (2013) Adult duct-lining cells can reprogram into beta-like cells able to counter repeated cycles of toxin-induced diabetes. Dev Cell 26(1):86–100

    Article  CAS  PubMed  Google Scholar 

  82. Sasaki S, Miyatsuka T, Matsuoka TA, Takahara M, Yamamoto Y, Yasuda T, Kaneto H, Fujitani Y, German MS, Akiyama H, Watada H, Shimomura I (2015) Activation of GLP-1 and gastrin signalling induces in vivo reprogramming of pancreatic exocrine cells into beta cells in mice. Diabetologia 58(11):2582–2591

    Article  CAS  PubMed  Google Scholar 

  83. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA (2008) In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455(7213):627–632

    Article  CAS  PubMed  Google Scholar 

  84. Li L, Shen J, Bala MM, Busse JW, Ebrahim S, Vandvik PO, Rios LP, Malaga G, Wong E, Sohani Z, Guyatt GH, Sun X (2014) Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies. BMJ 348:g2366

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Gier B, Matveyenko AV, Kirakossian D, Dawson D, Dry SM, Butler PC (2012) Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model. Diabetes 61(5):1250–1262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Fujita Y, Wideman RD, Asadi A, Yang GK, Baker R, Webber T, Zhang T, Wang R, Ao Z, Warnock GL, Kwok YN, Kieffer TJ (2010) Glucose-dependent insulinotropic polypeptide is expressed in pancreatic islet alpha-cells and promotes insulin secretion. Gastroenterology 138(5):1966–1975

    Article  CAS  PubMed  Google Scholar 

  87. Prasadan K, Koizumi M, Tulachan S, Shiota C, Lath N, Paredes J, Guo P, El-Gohary Y, Malek M, Shah S, Gittes GK (2011) The expression and function of glucose-dependent insulinotropic polypeptide in the embryonic mouse pancreas. Diabetes 60(2):548–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Herbach N, Goeke B, Schneider M, Hermanns W, Wolf E, Wanke R (2005) Overexpression of a dominant negative GIP receptor in transgenic mice results in disturbed postnatal pancreatic islet and beta-cell development. Regul Pept 125(1–3):103–117

    Article  CAS  PubMed  Google Scholar 

  89. Herbach N, Bergmayr M, Goke B, Wolf E, Wanke R (2011) Postnatal development of numbers and mean sizes of pancreatic islets and beta-cells in healthy mice and GIPR(dn) transgenic diabetic mice. PLoS One 6(7):e22814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Renner S, Fehlings C, Herbach N, Hofmann A, von Waldthausen DC, Kessler B, Ulrichs K, Chodnevskaja I, Moskalenko V, Amselgruber W, Goke B, Pfeifer A, Wanke R, Wolf E (2010) Glucose intolerance and reduced proliferation of pancreatic beta-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function. Diabetes 59(5):1228–1238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Shiota C, Prasadan K, Guo P, El-Gohary Y, Wiersch J, Xiao X, Esni F, Gittes GK (2013) Alpha-cells are dispensable in postnatal morphogenesis and maturation of mouse pancreatic islets. Am J Physiol Endocrinol Metab 305(8):E1030–E1040

    Article  CAS  PubMed  Google Scholar 

  92. Thorel F, Damond N, Chera S, Wiederkehr A, Thorens B, Meda P, Wollheim CB, Herrera PL (2011) Normal glucagon signaling and beta-cell function after near-total alpha-cell ablation in adult mice. Diabetes 60(11):2872–2882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Collombat P, Xu X, Ravassard P, Sosa-Pineda B, Dussaud S, Billestrup N, Madsen OD, Serup P, Heimberg H, Mansouri A (2009) The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell 138(3):449–462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Criscimanna A, Speicher JA, Houshmand G, Shiota C, Prasadan K, Ji B, Logsdon CD, Gittes GK, Esni F (2011) Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice. Gastroenterology 141(4):1451–1462, 1462 e1–6

  95. Yoshitomi H, Zaret KS (2004) Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Development 131(4):807–817

    Article  CAS  PubMed  Google Scholar 

  96. Lammert E, Cleaver O, Melton D (2001) Induction of pancreatic differentiation by signals from blood vessels. Science 294(5542):564–567

    Article  CAS  PubMed  Google Scholar 

  97. Heinis M, Simon MT, Ilc K, Mazure NM, Pouyssegur J, Scharfmann R, Duvillie B (2010) Oxygen tension regulates pancreatic beta-cell differentiation through hypoxia-inducible factor 1alpha. Diabetes 59(3):662–669

    Article  CAS  PubMed  Google Scholar 

  98. Heinis M, Simon MT, Duvillie B (2010) New insights into endocrine pancreatic development: the role of environmental factors. Horm Res Paediatr 74(2):77–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Shah SR, Esni F, Jakub A, Paredes J, Lath N, Malek M, Potoka DA, Prasadan K, Mastroberardino PG, Shiota C, Guo P, Miller KA, Hackam DJ, Burns RC, Tulachan SS, Gittes GK (2011) Embryonic mouse blood flow and oxygen correlate with early pancreatic differentiation. Dev Biol 349(2):342–349

    Article  CAS  PubMed  Google Scholar 

  100. Fraker CA, Alvarez S, Papadopoulos P, Giraldo J, Gu W, Ricordi C, Inverardi L, Dominguez-Bendala J (2007) Enhanced oxygenation promotes beta-cell differentiation in vitro. Stem Cells 25(12):3155–3164

    Article  CAS  PubMed  Google Scholar 

  101. Brissova M, Shostak A, Shiota M, Wiebe PO, Poffenberger G, Kantz J, Chen Z, Carr C, Jerome WG, Chen J, Baldwin HS, Nicholson W, Bader DM, Jetton T, Gannon M, Powers AC (2006) Pancreatic islet production of vascular endothelial growth factor-a is essential for islet vascularization, revascularization, and function. Diabetes 55(11):2974–2985

    Article  CAS  PubMed  Google Scholar 

  102. Dai C, Brissova M, Reinert RB, Nyman L, Liu EH, Thompson C, Shostak A, Shiota M, Takahashi T, Powers AC (2013) Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis. Diabetes 62(12):4144–4153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Movahedi B, Gysemans C, Jacobs-Tulleneers-Thevissen D, Mathieu C, Pipeleers D (2008) Pancreatic duct cells in human islet cell preparations are a source of angiogenic cytokines interleukin-8 and vascular endothelial growth factor. Diabetes 57(8):2128–2136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Xiao X, Prasadan K, Guo P, El-Gohary Y, Fischbach S, Wiersch J, Gaffar I, Shiota C, Gittes GK (2014) Pancreatic duct cells as a source of VEGF in mice. Diabetologia 57(5):991–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Cai Q, Brissova M, Reinert RB, Pan FC, Brahmachary P, Jeansson M, Shostak A, Radhika A, Poffenberger G, Quaggin SE, Jerome WG, Dumont DJ, Powers AC (2012) Enhanced expression of VEGF-A in beta cells increases endothelial cell number but impairs islet morphogenesis and beta cell proliferation. Dev Biol 367(1):40–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. D’Hoker J, De Leu N, Heremans Y, Baeyens L, Minami K, Ying C, Lavens A, Chintinne M, Stange G, Magenheim J, Swisa A, Martens G, Pipeleers D, van de Casteele M, Seino S, Keshet E, Dor Y, Heimberg H (2013) Conditional hypovascularization and hypoxia in islets do not overtly influence adult beta-cell mass or function. Diabetes 62(12):4165–4173

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Xiao X, Chen Z, Shiota C, Prasadan K, Guo P, El-Gohary Y, Paredes J, Welsh C, Wiersch J, Gittes GK (2013) No evidence for beta cell neogenesis in murine adult pancreas. J Clin Invest 123(5):2207–2217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Georgia S, Bhushan A (2004) Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J Clin Invest 114(7):963–968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Meier JJ, Butler AE, Saisho Y, Monchamp T, Galasso R, Bhushan A, Rizza RA, Butler PC (2008) Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes 57(6):1584–1594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Teta M, Rankin MM, Long SY, Stein GM, Kushner JA (2007) Growth and regeneration of adult beta cells does not involve specialized progenitors. Dev Cell 12(5):817–826

    Article  CAS  PubMed  Google Scholar 

  111. Dor Y, Brown J, Martinez OI, Melton DA (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429(6987):41–46

    Article  CAS  PubMed  Google Scholar 

  112. Gittes GK, Rutter WJ (1992) Onset of cell-specific gene expression in the developing mouse pancreas. Proc Natl Acad Sci USA 89(3):1128–1132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Brennand K, Huangfu D, Melton D (2007) All beta cells contribute equally to islet growth and maintenance. PLoS Biol 5(7):e163

    Article  PubMed  PubMed Central  Google Scholar 

  114. Nir T, Melton DA, Dor Y (2007) Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 117(9):2553–2561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Herrera PL (2000) Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127(11):2317–2322

    CAS  PubMed  Google Scholar 

  116. Vincent M, Guz Y, Rozenberg M, Webb G, Furuta M, Steiner D, Teitelman G (2003) Abrogation of protein convertase 2 activity results in delayed islet cell differentiation and maturation, increased alpha-cell proliferation, and islet neogenesis. Endocrinology 144(9):4061–4069

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Rangos Research Center, Children’s Hospital of University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA

    Krishna Prasadan, Chiyo Shiota, Xiao Xiangwei, David Ricks, Joseph Fusco & George Gittes

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  1. Krishna Prasadan
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  2. Chiyo Shiota
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  3. Xiao Xiangwei
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  6. George Gittes
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Correspondence to George Gittes.

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Prasadan, K., Shiota, C., Xiangwei, X. et al. A synopsis of factors regulating beta cell development and beta cell mass. Cell. Mol. Life Sci. 73, 3623–3637 (2016). https://doi.org/10.1007/s00018-016-2231-0

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