The pancreas is a mixed gland that contains endocrine and exocrine components. Within the pancreatic islets, β cells produce insulin and control the glycemia. Their deficiency leads to diabetes and several potential complications. In the last decade, numerous studies have focused on pancreas development. The objective was to characterize the cellular and molecular factors that control the differentiation of endocrine and exocrine cell types. Investigation of the role of transcription factors by using genetic approaches led to the discovery of key molecules that are expressed both in rodents and humans. Some of them are ubiquitous, and some others are specifically involved in endocrine or exocrine specification. In addition to these intrinsic factors, recent studies have focused on the role of environmental factors. In the present review, we describe the roles of nutrients and oxygen in the embryonic pancreas. Interestingly, these extrinsic parameters can interfere with β-cell differentiation and function. Altogether, these data should help to generate β cells in vitro and define strategies for a cell-based therapy of type 1 diabetes.

1.
Duvillie B, Stetsyuk V, Filhoulaud G, Guillemain G, Scharfmann R: Control of pancreatic development by intercellular signals. Biochem Soc Trans 2008;36:276–279.
2.
Scharfmann R, Duvillie B, Stetsyuk V, Attali M, Filhoulaud G, Guillemain G: Beta-cell development: the role of intercellular signals. Diabetes Obes Metab 2008;10(suppl 4):195–200.
3.
Bonal C, Herrera PL: Genes controlling pancreas ontogeny. Int J Dev Biol 2008;52:823–835.
4.
Collombat P, Hecksher-Sorensen J, Serup P, Mansouri A: Specifying pancreatic endocrine cell fates. Mech Dev 2006;123:501–512.
5.
Ahlgren U, Jonsson J, Edlund H: The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. Development 1996;122:1409–1416.
6.
Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF: Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997;15:106–110.
7.
Pin CL, Rukstalis JM, Johnson C, Konieczny SF: The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity. J Cell Biol 2001;155:519–530.
8.
Krapp A, Knofler M, Ledermann B, Burki K, Berney C, Zoerkler N, Hagenbuchle O, Wellauer PK: The bHLH protein Ptf1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev 1998;12:3752–3763.
9.
Li H, Arber S, Jessell TM, Edlund H: Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9. Nat Genet 1999;23:67–70.
10.
Gradwohl G, Dierich A, LeMeur M, Guillemot F: Neurogenin-3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA 2000;97:1607–1611.
11.
Mellitzer G, Bonne S, Luco RF, Van De Casteele M, Lenne-Samuel N, Collombat P, Mansouri A, Lee J, Lan M, Pipeleers D, Nielsen FC, Ferrer J, Gradwohl G, Heimberg H: IA1 is NGN3-dependent and essential for differentiation of the endocrine pancreas. EMBO J 2006;25:1344–1352.
12.
Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ: Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev 1997;11:2323–2334.
13.
Smith SB, Ee HC, Conners JR, German MS: Paired-homeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development. Mol Cell Biol 1999;19:8272–8280.
14.
Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P: The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas. Nature 1997;386:399–402.
15.
Collombat P, Mansouri A, Hecksher-Sorensen J, Serup P, Krull J, Gradwohl G, Gruss P: Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev 2003;17:2591–2603.
16.
Nishimura W, Kondo T, Salameh T, El Khattabi I, Dodge R, Bonner-Weir S, Sharma A: A switch from MafB to MafA expression accompanies differentiation to pancreatic β cells. Dev Biol 2006;293:526–539.
17.
Heller RS, Stoffers DA, Liu A, Schedl A, Crenshaw EB 3rd, Madsen OD, Serup P: The role of Brn4/Pou3f4 and Pax6 in forming the pancreatic glucagon cell identity. Dev Biol 2004;268:123–134.
18.
Sussel L, Kalamaras J, Hartigan-O’Connor DJ, Meneses JJ, Pedersen RA, Rubenstein JL, German MS: Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic β cells. Development 1998;125:2213–2221.
19.
Sander M, Sussel L, Conners J, Scheel D, Kalamaras J, Dela Cruz F, Schwitzgebel V, Hayes-Jordan A, German M: Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of β-cell formation in the pancreas. Development 2000;127:5533–5540.
20.
Henseleit KD, Nelson SB, Kuhlbrodt K, Hennings JC, Ericson J, Sander M: NKX6 transcription factor activity is required for α- and β-cell development in the pancreas. Development 2005;132:3139–3149.
21.
Lyttle BM, Li J, Krishnamurthy M, Fellows F, Wheeler MB, Goodyer CG, Wang R: Transcription factor expression in the developing human fetal endocrine pancreas. Diabetologia 2008;51:1169–1180.
22.
Soyer J, Flasse L, Raffelsberger W, Beucher A, Orvain C, Peers B, Ravassard P, Vermot J, Voz ML, Mellitzer G, Gradwohl G: Rfx6 is an Ngn3-dependent winged helix transcription factor required for pancreatic islet cell development. Development 2010;137:203–212.
23.
Smith SB, Qu HQ, Taleb N, Kishimoto NY, Scheel DW, Lu Y, Patch AM, Grabs R, Wang J, Lynn FC, Miyatsuka T, Mitchell J, Seerke R, Desir J, Eijnden SV, Abramowicz M, Kacet N, Weill J, Renard ME, Gentile M, Hansen I, Dewar K, Hattersley AT, Wang R, Wilson ME, Johnson JD, Polychronakos C, German MS: Rfx6 directs islet formation and insulin production in mice and humans. Nature 463:775–780.
24.
Ait-Lounis A, Baas D, Barras E, Benadiba C, Charollais A, Nlend Nlend R, Liegeois D, Meda P, Durand B, Reith W: Novel function of the ciliogenic transcription factor RFX3 in development of the endocrine pancreas. Diabetes 2007;56:950–959.
25.
Lammert E, Cleaver O, Melton D: Induction of pancreatic differentiation by signals from blood vessels. Science 2001;294:564–567.
26.
Li Z, Manna P, Kobayashi H, Spilde T, Bhatia A, Preuett B, Prasadan K, Hembree M, Gittes GK: Multifaceted pancreatic mesenchymal control of epithelial lineage selection. Dev Biol 2004;269:252–263.
27.
Miralles F, Czernichow P, Ozaki K, Itoh N, Scharfmann R: Signaling through fibroblast growth factor receptor 2b plays a key role in the development of the exocrine pancreas. Proc Natl Acad Sci USA 1999;96:6267–6272.
28.
Duvillie B, Attali M, Bounacer A, Ravassard P, Basmaciogullari A, Scharfmann R: The mesenchyme controls the timing of pancreatic β-cell differentiation. Diabetes 2006;55:582–589.
29.
Nelson CM, Jean RP, Tan JL, Liu WF, Sniadecki NJ, Spector AA, Chen CS: Emergent patterns of growth controlled by multicellular form and mechanics. Proc Natl Acad Sci USA 2005;102:11594–11599.
30.
Breant B, Gesina E, Blondeau B: Nutrition, glucocorticoids and pancreas development. Horm Res 2006;65(suppl 3):98–104.
31.
Hill DJ, Duvillie B: Pancreatic development and adult diabetes. Pediatr Res 2000;48:269–274.
32.
Arany E, Strutt B, Romanus P, Remacle C, Reusens B, Hill DJ: Taurine supplement in early life altered islet morphology, decreased insulitis and delayed the onset of diabetes in non-obese diabetic mice. Diabetologia 2004;47:1831–1837.
33.
Armitage JA, Taylor PD, Poston L: Experimental models of developmental programming: consequences of exposure to an energy rich diet during development. J Physiol 2005;565:3–8.
34.
Boujendar S, Arany E, Hill D, Remacle C, Reusens B: Taurine supplementation of a low protein diet fed to rat dams normalizes the vascularization of the fetal endocrine pancreas. J Nutr 2003;133:2820–2825.
35.
Dumortier O, Blondeau B, Duvillie B, Reusens B, Breant B, Remacle C: Different mechanisms operating during different critical time-windows reduce rat fetal β cell mass due to a maternal low-protein or low-energy diet. Diabetologia 2007;50:2495–2503.
36.
Garofano A, Czernichow P, Breant B: Impaired β-cell regeneration in perinatally malnourished rats: a study with STZ. FASEB J 2000;14:2611–2617.
37.
Petrik J, Reusens B, Arany E, Remacle C, Coelho C, Hoet JJ, Hill DJ: A low protein diet alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and is associated with a reduced pancreatic expression of insulin-like growth factor II. Endocrinology 1999;140:4861–4873.
38.
Petrik J, Srinivasan M, Aalinkeel R, Coukell S, Arany E, Patel MS, Hill DJ: A long-term high-carbohydrate diet causes an altered ontogeny of pancreatic islets of Langerhans in the neonatal rat. Pediatr Res 2001;49:84–92.
39.
Blondeau B, Lesage J, Czernichow P, Dupouy JP, Breant B: Glucocorticoids impair fetal β-cell development in rats. Am J Physiol 2001;281:E592–E599.
40.
Chamson-Reig A, Thyssen SM, Hill DJ, Arany E: Exposure of the pregnant rat to low protein diet causes impaired glucose homeostasis in the young adult offspring by different mechanisms in males and females. Exp Biol Med (Maywood) 2009;234:1425–1436.
41.
Chamson-Reig A, Arany EJ, Summers K, Hill DJ: A low protein diet in early life delays the onset of diabetes in the non-obese diabetic mouse. J Endocrinol 2009;201:231–239.
42.
Fronczak CM, Baron AE, Chase HP, Ross C, Brady HL, Hoffman M, Eisenbarth GS, Rewers M, Norris JM: In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care 2003;26:3237–3242.
43.
Dahlquist G, Bennich SS, Kallen B: Intrauterine growth pattern and risk of childhood onset insulin-dependent (type 1) diabetes: population-based case-control study. BMJ 1996;313:1174–1177.
44.
Filhoulaud G, Guillemain G, Scharfmann R: The hexosamine biosynthesis pathway is essential for pancreatic β-cell development. J Biol Chem 2009;284:24583–24594.
45.
Guillemain G, Filhoulaud G, Da Silva-Xavier G, Rutter GA, Scharfmann R: Glucose is necessary for embryonic pancreatic endocrine cell differentiation. J Biol Chem 2007;282:15228–15237.
46.
Simon MC, Keith B: The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol 2008;9:285–296.
47.
Cantley J, Selman C, Shukla D, Abramov AY, Forstreuter F, Esteban MA, Claret M, Lingard SJ, Clements M, Harten SK, Asare-Anane H, Batterham RL, Herrera PL, Persaud SJ, Duchen MR, Maxwell PH, Withers DJ: Deletion of the von Hippel-Lindau gene in pancreatic β cells impairs glucose homeostasis in mice. J Clin Invest 2009;119:125–135.
48.
Puri S, Cano DA, Hebrok M: A role for von Hippel-Lindau protein in pancreatic β-cell function. Diabetes 2009;58:433–441.
49.
Zehetner J, Danzer C, Collins S, Eckhardt K, Gerber PA, Ballschmieter P, Galvanovskis J, Shimomura K, Ashcroft FM, Thorens B, Rorsman P, Krek W: PVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells. Genes Dev 2008;22:3135–3146.
50.
Heinis M, Simon MT, Ilc K, Mazure N, Pouyssegur J, Scharfmann R, Duvillie B: Oxygen tension regulates pancreatic β-cell differentiation through HIF1α. Diabetes 2010; 59:662–669.
51.
Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, Ruas JL, Poellinger L, Lendahl U, Bondesson M: Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 2005;9:617–628.
52.
Diez H, Fischer A, Winkler A, Hu CJ, Hatzopoulos AK, Breier G, Gessler M: Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Exp Cell Res 2007;313:1–9.
53.
Fraker CA, Ricordi C, Inverardi L, Dominguez-Bendala J: Oxygen: a master regulator of pancreatic development? Biol Cell 2009;101:431–440.
54.
Fraker CA, Alvarez S, Papadopoulos P, Giraldo J, Gu W, Ricordi C, Inverardi L, Dominguez-Bendala J: Enhanced oxygenation promotes β-cell differentiation in vitro. Stem Cells 2007;25:3155–3164.
55.
Provot S, Zinyk D, Gunes Y, Kathri R, Le Q, Kronenberg HM, Johnson RS, Longaker MT, Giaccia AJ, Schipani E: HIF-1α regulates differentiation of limb bud mesenchyme and joint development. J Cell Biol 2007;177:451–464.
56.
Gunton JE, Kulkarni RN, Yim S, Okada T, Hawthorne WJ, Tseng YH, Roberson RS, Ricordi C, O’Connell PJ, Gonzalez FJ, Kahn CR: Loss of ARNT/HIF1β mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 2005;122:337–349.
57.
Kaelin WG: Proline hydroxylation and gene expression. Annu Rev Biochem 2005;74:115–128.
58.
Nagy G, Kovacs-Nagy R, Kereszturi E, Somogyi A, Szekely A, Nemeth N, Hosszufalusi N, Panczel P, Ronai Z, Sasvari-Szekely M: Association of hypoxia-inducible factor-1α gene polymorphism with both type 1 and type 2 diabetes in a Caucasian (Hungarian) sample. BMC Med Genet 2009;10:79.
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