Endocrine - Pancreas Development

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Contents

Introduction

Human Pancreatic Islets (Islets of Langerhans)[1]

The pancreas is a two-headed organ, not only in origin but also in function. In origin, the pancreas develops from two separate primordia. In function, the organ has both endocrine function in relation to regulating blood glucose (and also other hormone secretions) and gastrointestinal function as an exocrine (digestive) organ, see Gastrointestinal Tract - Pancreas Development.

In recent years there has been much research due to the increasing incidence of diabetes in humans and the potential for stem cell therapeutics. Much is now known about the epithelial/mesenchymal and molecular regulation of pancres development.

At the foregut/midgut junction the septum transversum generates 2 pancreatic buds (dorsal and ventral endoderm) which will fuse to form the pancreas. The dorsal bud arises first and generates most of the pancreas. The ventral bud arises beside the bile duct and forms only part of the head and uncinate process of the pancreas.

In the fetal period islet cell clusters (icc) differentiate from pancratic bud endoderm. These cell clusters form acini and ducts (exocrine). On the edge of these cell clusters pancreatic islets (endocrine) also form. Pancreatic hormonal function is to secrete insulin and glucagon which together regulate blood glucose levels and also somaostatin.

The pancreas exocrine function begins after birth, while the endocrine function (hormone release) can be measured from 10 to 15 weeks onward. At this stage, it is not clear what the exact roles of these hormones are in regulating fetal growth.

Pancreas adult
  • Functions - exocrine (amylase, alpha-fetoprotein), 99% by volume; endocrine (pancreatic islets) 1% by volume
  • Exocrine function - begins after birth
  • Endocrine function - from 10 to 15 weeks onward hormone release
    • exact roles of hormones in regulating fetal growth?


Endocrine Links: Introduction | BGD Lecture | Science Lecture | Pineal | Hypothalamus‎ | Pituitary | Thyroid | Parathyroid | Thymus‎ | Pancreas‎ | Adrenal‎ | Gonad‎ | Placenta‎ | Other Tissues | Stage 22 | Abnormalities | Hormones | Category:Endocrine | Lecture - Gastrointestinal Development | Abnormal Development - Maternal Diabetes | Gastrointestinal Tract - Pancreas Development


Historic Embryology: 1912 Pancreas Development

Some Recent Findings

  • Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation[2] "Pancreatic β-cells are an essential source of insulin and their destruction because of autoimmunity causes type I diabetes. We conducted a chemical screen to identify compounds that would induce the differentiation of insulin-producing β-cells in vivo. To do this screen, we brought together the use of transgenic zebrafish as a model of β-cell differentiation, a unique multiwell plate that allows easy visualization of lateral views of swimming larval fish and a library of clinical drugs. We identified six hits that can induce precocious differentiation of secondary islets in larval zebrafish. Three of these six hits were known drugs with a considerable background of published data on mechanism of action. Using pharmacological approaches, we have identified and characterized two unique pathways in β-cell differentiation in the zebrafish, including down-regulation of GTP production and retinoic acid biosynthesis."
  • Pancreatic mesenchyme regulates epithelial organogenesis throughout development[3] "The developing pancreatic epithelium gives rise to all endocrine and exocrine cells of the mature organ. During organogenesis, the epithelial cells receive essential signals from the overlying mesenchyme. ...Our results demonstrate that mesenchymal cells regulate pancreatic growth and branching at both early and late developmental stages by supporting proliferation of precursors and differentiated cells, respectively."
  • Relative roles of the different Pax6 domains for pancreatic alpha cell development.[4] "The transcription factor Pax6 functions in the specification and maintenance of the differentiated cell lineages in the endocrine pancreas. It has two DNA binding domains, the paired domain and the homeodomain, in addition to a C-terminal transactivation domain. The phenotype of Pax6-/- knockout mice suggests non-redundant functions of the transcription factor in the development of glucagon-expressing alpha-cells as this cell type is absent in the mutants."

Pancreas Development

Pancreatic buds and duct developing
  • Pancreatic buds - duodenal level endoderm, splanchnic mesoderm forms dorsal and ventral mesentery, dorsal bud (larger, first), ventral bud (smaller, later)
  • Pancreas Endoderm - pancreas may be opposite of liver
    • Heart cells promote/notochord prevents liver formation
    • Notochord may promote pancreas formation
    • Heart may block pancreas formation
  • Duodenum growth/rotation - brings ventral and dorsal buds together, fusion of buds
  • Pancreatic duct - ventral bud duct and distal part of dorsal bud, exocrine function
  • Islet cells - cords of endodermal cells form ducts, from which cells bud off to form islets

PMID 18508724

Human Pancreas Timeline

Human (week 4) pancreatic buds
Human (week 8, Stage 22) pancreas
  • Week 7 to 20 - pancreatic hormones secretion increases, small amount maternal insulin
  • Week 10 - glucagon (alpha) differentiate first, somatostatin (delta), insulin (beta) cells differentiate, insulin secretion begins
  • Week 15 - glucagon detectable in fetal plasma

Mouse-pancreas duct formation.jpg

Mouse pancreas duct development cartoon

Bailey273.jpg Bailey274.jpg Bailey275.jpg Bailey278 279.jpg

Bailey280.jpg

Pig embryo (14 mm CRL) (ventral and dorsal)

Fetal Pancreas

Human fetal pancreas anatomy cartoon.jpg

Fetal topographical anatomy of the pancreatic head and duodenum with special reference to courses of the pancreaticoduodenal arteries.[5]

A diagram showing joining processes between the dorsal and ventral primordia of the pancreas as well as the hypothetical rotation of the duodenum along a left-right axis. Viewed from the posterosuperior side of the body. A horizontal plane including most parts of the duodenum is shown to emphasize, in contrast to adults, the course of the second portion (D2) directing posteriorly rather than inferiorly.

Developing Pancreatic Islets

Model of endocrine cell and vessel organization in human islets[6]

Model of human pancreatic islet.jpg

A α-Cells (green) and β-cells (red) are organized into a thick folded plate lined at both sides with vessels (blue).
  • α-Cells are mostly at the periphery of the plate and in close contact with vessels.
  • β-Cells occupy a more central part of the plate and most of them develop cytoplasmic extension that runs between α-cells and reaches the surface of vessels.





B The plate with adjacent vessels is folded so that it forms an islet.


(Text based on original reference legend)

Adult Pancreatic Islets

Human pancreatic islet in 3D[6]
Pancreas islet structure human and rat

The adult pancreatic islets (Islets of Langerhans) contain four distinct endocrine cell types.

Alpha Cells

Human- pancreatic adult islet-glucagon.jpg

  • glucagon, mobilizes lipid

Beta Cells

Human- pancreatic adult islet-insulin.jpg pancreas structure

  • insulin, increase glucose uptake
  • stimulate fetal growth, continue to proliferate to postnatal, in infancy most abundant

Delta Cells

  • somatostatin, inhibits glucagon, insulin secretion

F-cells

  • pancreatic polypeptide

Rat- pancreatic islet development

Rat - pancreatic islet development[7]


Islet size for Different Species

The following species comparison table has been slightly modified from Table 1 data in a recent paper by Kim etal., 2009.[8]

  • Islet size is described as an effective diameter of a circle, which depicts the same area as a measured islet area.
  • β-cell ratio is the area ratio of β-cells in an islet.
  • Both data sets are expressed as the mean value with its standard deviation.
Species Age Islet size (μm) β-cell ratio
Human 39 years (adult) 50 ± 29 0.64 ± 0.21
Monkey 1 year 67 ± 38* 0.79 ± 0.14*
Pig 6 month 49 ± 15a 0.89 ± 0.11*
Rabbit 6 month 64 ± 28* 0.79 ± 0.17*
Bird 40 day 24 ± 6* 0.46 ± 0.24*
Wild-type mouse 6 month 116 ± 80* 0.85 ± 0.14*
Pregnant mouse 3 month 112 ± 94* 0.84 ± 0.22*
ob/ob mouse 15 week 86 ± 76* 0.92 ± 0.11*
db/db mouse 15 week 47 ± 24b 0.53 ± 0.24c

*p < 0.0001 ap = 0.65 bp = 0.42 cp = 0.0004 compared with human.

Hormones

Insulin

  • Source - synthesized by the beta cells of the islets of Langerhans.
  • Protein
    • 2 dissimilar polypeptide chains, A and B, which are linked by 2 disulphide bonds.
    • both chains are derived from a 1-chain precursor, proinsulin.
    • proinsulin - converted to insulin by the enzymatic removal of a segment that connects the amino end of the A chain to the carboxyl end of the B chain.


Links: OMIM

Glucagon

  • Source - synthesized by the alpha cells of the islets of Langerhans.
  • Protein
    • 29-amino acid hormone
    • human, rabbit, rat, pig, and cow proteins are identical.
    • member of a multigene family that includes - secretin, vasoactive intestinal peptide, gastric inhibitory peptide, glicentin, and others.
  • Function
    • counteracts the glucose-lowering action of insulin
    • stimulates glycogenolysis and gluconeogenesis.


Links: OMIM

Pancreas Histology

Pancreas Histology Links: overview (label) | exocrine (label) | endocrine (label) | blood vessels (label) | insulin (label) | overview | exocrine | endocrine | blood vessels | insulin | Islet labeled for insulin and Glucagon | Insulin (Fl) | Glucagon (Fl) | GIT Histology

Diabetes

Australian trends diabetes prevalence 19990-2008.jpg

Links: Maternal Diabetes

Abnormalities

Listed below are a number of pancreatic developmental abnormalities, see also the 2003 article "Lifetime consequences of abnormal fetal pancreatic development"[9].

Accessory Pancreatic Tissue - pancreatic tissue located in associated gastrointestinal tract tissues/organs such as the wall of the stomach, duodenum, jejunum or Meckel's diverticulum.

Annular Pancreas - (1 in 7,000 people) pancreas forms as a "ring" of tissue surrounding the duodenum which is subsequently narrowed.

Diabetes Mellitus - Maternal diabetes (and hyperglycaemia) have been shown to lead to increased fetal islet hyperplasia of the insulin producing beta cells and insulin secretion.

Intrauterine growth restriction - can lead to a delayed development of the insulin producing beta cells and low insulin secretion.

Tumours - Serous Cystadenoma (endocrine tumour), Somatostatinoma (tumour of delta cell origin), intraductal papillary-mucinous neoplasm


Links: NIH Genes and Disease Chapter 41 - Endocrine | Medline Plus - Annular Pancreas |

References

  1. Raphaël Scharfmann, Xiangwei Xiao, Harry Heimberg, Jacques Mallet, Philippe Ravassard Beta cells within single human islets originate from multiple progenitors. PLoS ONE: 2008, 3(10);e3559 PMID:18958289 | PLoS ONE
  2. Meritxell Rovira, Wei Huang, Shamila Yusuff, Joong Sup Shim, Anthony A Ferrante, Jun O Liu, Michael J Parsons Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation. Proc Natl Acad Sci U S A: 2011; PMID:22084084 | Proc Natl Acad Sci U S A.
  3. Limor Landsman, Amar Nijagal, Theresa J Whitchurch, Renee L Vanderlaan, Warren E Zimmer, Tippi C Mackenzie, Matthias Hebrok Pancreatic mesenchyme regulates epithelial organogenesis throughout development. PLoS Biol.: 2011, 9(9);e1001143 PMID:21909240 | PLoS Biol.
  4. Petra Dames, Ramona Puff, Michaela Weise, Klaus G Parhofer, Burkhard Göke, Magdalena Götz, Jochen Graw, Jack Favor, Andreas Lechner Relative roles of the different Pax6 domains for pancreatic alpha cell development. BMC Dev. Biol.: 2010, 10();39 PMID:20377917
  5. Zhe Wu Jin, Hee Chul Yu, Baik Hwan Cho, Hyoung Tae Kim, Wataru Kimura, Mineko Fujimiya, Gen Murakami Fetal topographical anatomy of the pancreatic head and duodenum with special reference to courses of the pancreaticoduodenal arteries. Yonsei Med. J.: 2010, 51(3);398-406 PMID:20376893 | Yonsei Med J.
  6. 6.0 6.1 Domenico Bosco, Mathieu Armanet, Philippe Morel, Nadja Niclauss, Antonino Sgroi, Yannick D Muller, Laurianne Giovannoni, Géraldine Parnaud, Thierry Berney Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes: 2010, 59(5);1202-10 PMID:20185817 | PMC2857900 | Diabetes.
  7. Siraam Cabrera-Vásquez, Víctor Navarro-Tableros, Carmen Sánchez-Soto, Gabriel Gutiérrez-Ospina, Marcia Hiriart Remodelling sympathetic innervation in rat pancreatic islets ontogeny. BMC Dev. Biol.: 2009, 9();34 PMID:19534767
  8. Abraham Kim, Kevin Miller, Junghyo Jo, German Kilimnik, Pawel Wojcik, Manami Hara Islet architecture: A comparative study. Islets: , 1(2);129-36 PMID:20606719
  9. K Holemans, L Aerts, F A Van Assche Lifetime consequences of abnormal fetal pancreatic development. J. Physiol. (Lond.): 2003, 547(Pt 1);11-20 PMID:12562919


Journals

Online Textbooks

Endocrinology: An Integrated Approach Nussey, S.S. and Whitehead, S.A. Oxford, UK: BIOS Scientific Publishers, Ltd; 2001. table of Contents

NIH Genes & Disease Chapter 41 - Endocrine

Pathophysiology of the Endocrine System The Endocrine Pancreas

Developmental Biology (6th ed) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000.

Molecular Biology of the Cell (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002. table 15-1. Some Hormone-induced Cell Responses Mediated by Cyclic AMP

Health Services/Technology Assessment Text (HSTAT) Bethesda (MD): National Library of Medicine (US), 2003 Oct.

Search NLM Online Textbooks- "pancreas development" : Endocrinology | Molecular Biology of the Cell | The Cell- A molecular Approach

Search Bookshelf Pancreas Development

Reviews

Amaresh K Ranjan, Mugdha V Joglekar, Anandwardhan A Hardikar Endothelial cells in pancreatic islet development and function. Islets: , 1(1);2-9 PMID:21084843

Mary D Kinkel, Victoria E Prince On the diabetic menu: zebrafish as a model for pancreas development and function. Bioessays: 2009, 31(2);139-52 PMID:19204986

George K Gittes Developmental biology of the pancreas: a comprehensive review. Dev. Biol.: 2009, 326(1);4-35 PMID:19013144

Claire Bonal, Pedro L Herrera Genes controlling pancreas ontogeny. Int. J. Dev. Biol.: 2008, 52(7);823-35 PMID:18956314

Jennifer M Oliver-Krasinski, Doris A Stoffers On the origin of the beta cell. Genes Dev.: 2008, 22(15);1998-2021 PMID:18676806


Articles

Bernard Portha, Audrey Chavey, Jamileh Movassat Early-life origins of type 2 diabetes: fetal programming of the Beta-cell mass. Exp Diabetes Res: 2011, 2011();105076 PMID:22110471

M J Riedel, A Asadi, R Wang, Z Ao, G L Warnock, T J Kieffer Immunohistochemical characterisation of cells co-producing insulin and glucagon in the developing human pancreas. Diabetologia: 2011; PMID:22038519

Fengxia Ma, Cécile Haumaitre, Fang Chen, Zhongchao Han Comparison of murine embryonic pancreatic development in vitro and in vivo. Pancreas: 2011, 40(7);1012-7 PMID:21926540

Erin McDonald, Jinming Li, Mansa Krishnamurthy, George F Fellows, Cynthia G Goodyer, Rennian Wang SOX9 regulates endocrine cell differentiation during human fetal pancreas development. Int J Biochem Cell Biol: 2011; PMID:21983268

Kai-Ming Yang, Wang Yong, Ai-Dong Li, Hui-Jun Yang Insulin-producing cells are bi-potential and differentiatorsprior to proliferation in early human development. World J Diabetes: 2011, 2(4);54-8 PMID:21537461

Juris J Meier, Christina U Köhler, Bacel Alkhatib, Consolato Sergi, Theresa Junker, Harald H Klein, Wolfgang E Schmidt, Helga Fritsch Beta-cell development and turnover during prenatal life in humans. Eur. J. Endocrinol.: 2010, 162(3);559-68 PMID:20022941

Jongmin Jeon, Mayrin Correa-Medina, Camillo Ricordi, Helena Edlund, Juan A Diez Endocrine cell clustering during human pancreas development. J. Histochem. Cytochem.: 2009, 57(9);811-24 PMID:19365093

Jennifer M Oliver-Krasinski, Margaret T Kasner, Juxiang Yang, Michael F Crutchlow, Anil K Rustgi, Klaus H Kaestner, Doris A Stoffers The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice. J. Clin. Invest.: 2009, 119(7);1888-98 PMID:19487809

D Eberhard, D Tosh, J M W Slack Origin of pancreatic endocrine cells from biliary duct epithelium. Cell. Mol. Life Sci.: 2008, 65(21);3467-80 PMID:18810318

Raphaël Scharfmann, Xiangwei Xiao, Harry Heimberg, Jacques Mallet, Philippe Ravassard Beta cells within single human islets originate from multiple progenitors. PLoS ONE: 2008, 3(10);e3559 PMID:18958289

K Piper, S Brickwood, L W Turnpenny, I T Cameron, S G Ball, D I Wilson, N A Hanley Beta cell differentiation during early human pancreas development. J. Endocrinol.: 2004, 181(1);11-23 PMID:15072563 | J Endocrinol.

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Cite this page: Hill, M.A. (2014) Embryology Endocrine - Pancreas Development. Retrieved April 23, 2014, from http://embryology.med.unsw.edu.au/embryology/index.php?title=Endocrine_-_Pancreas_Development

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Dr Mark Hill 2014, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G
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