UNSW Embryology

Endocrine Development - Pancreas

© Dr Mark Hill (2011)

Acknowledgements

Introduction

This section of notes gives an overview of how the pancreas develops. 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. (More? Molecular mechanisms)

The mature pancreas has both exocrine (GIT enzymes) and endocrine (hormonal) functions. Pancreatic GIT enzyme function is to digest proteins. (More? GIT Notes- Pancreas) Pancreatic hormonal function is to secrete insulin and glucagon which together regulate blood glucose levels and also somaostatin.

Stage 22 Embryo 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.

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.

Page Links: Introduction | Some Recent Findings | Reading | Development Overview | Serial Images | Stage 22 Human | Pancreas Hormones | Pancreas Digestive | Pancreas Histology | Pancreatic Duct | Pancreas History | Abnormalities | Diabetes Mellitus | Molecular Mechanisms | WWW Links | References | Glossary

Other Pages: GIT Notes- Pancreas | Abnormal Development - Maternal Diabetes

Some Recent Findings

Pancreatic Duct Kamisawa T, Okamoto A. Pancreatographic investigation of pancreatic duct system and pancreaticobiliary malformation. J Anat. 2008 Feb;212(2):125-34.

"The long-type accessory pancreatic duct represents a continuation of the main duct of the dorsal pancreatic bud. The short-type accessory pancreatic duct is probably formed by the proximal main duct of the dorsal pancreatic bud and its long inferior branch."

SOX9 is involved in pancreas organogenesis as a progenitor cell specific marker and maintenance factor. Seymour PA, Freude KK, Tran MN, Mayes EE, Jensen J, Kist R, Scherer G, Sander M. SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci U S A. 2007 Jan 31) (More? OMIM Sox9 | Protein Sox9)

"We show that Sox9 maintains pancreatic progenitors by stimulating their proliferation, survival, and persistence in an undifferentiated state. Our finding that SOX9 regulates the Notch-effector HES1 suggests a Notch-dependent mechanism and establishes a possible genetic link between SOX factors and Notch."

Reading

Human Embryology (2nd ed.) Larson The Developing Human: Clinically Oriented Embryology (6th ed.) Moore and Persaud Ch10: p230-233, Ch12: p280-282, Ch13: p319-347 Before We Are Born (5th ed.) Moore and Persaud Essentials of Human Embryology Larson Human Embryology Fitzgerald and Fitzgerald Ch24: p166-167

Historic drawing of the Pancreas

Development Overview

Pancreas

• Functions- exocrine (amylase, alpha-fetoprotein) and endocrine (pancreatic islets)
• Pancreatic buds- endoderm, covered in splanchnic mesoderm
• Pancreatic bud formation – duodenal level endoderm, splanchnic mesoderm forms dorsal and ventral mesentery, dorsal bud (larger, first), ventral bud (smaller, later)
• 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, which cells bud off to form islets
• 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
• Beta cells - stimulate fetal growth, continue to proliferate through to postnatal in infancy, most abundant
• Maternal diabetes mellitus – hypertrophy of fetal beta cells

Serial Images

Stage 13/14 Embryo D7 - Duodenum below stomach showing dorsal mesogastrium

Stage 22 Human Embryo F1 - Developing pancreas lying between stomac and duodenum.

Stage 22 Human Embryo High Power

HPF1 - cross-section of embryo showing the level of the pancreas in the abdomen

HPF2 - Detail of developing pancreas lying beside the duodenum

Stage 22 Human Embryo Images

Carnegie stage stage 22 Human Embryo

Detail of developing pancreas lying beside the duodenum

Pancreas Hormones

Timetable

• Islet cells (Islets of Langerhans) - cords of endodermal cells form ducts, which cells bud off to form islets
• Week 7 to 20 – pancreatic hormones secretion increases, small amount maternal insulin
• Week 10 – three different cell types responsible for hormone secretion; glucagon (alpha) differentiate first, somatostatin (delta), insulin (beta) cells differentiate, insulin secretion begins
• Week 15 – glucagon detectable in fetal plasma
• Beta cells - stimulate fetal growth, continue to proliferate through to postnatal in infancy, most abundant
• Maternal diabetes mellitus – hypertrophy of fetal beta cells

Pancreatic Islet Cells

Alpha Cells differentiate first in the developing pancreas and secrete glucagon (29 amino acid peptide hormone) which increases blood glucose levels by acting on the liver to convert glycogen into glucose.

Beta Cells secrete insulin.

Delta Cells (D cells) secrete somatostatin (growth hormone inhibiting hormone, GHIH; somatotropin release-inhibiting factor, SRIF). This peptide hormone (14 amino acid and 28 amino acid) is mainly produced by the hypothalamus (periventricular nucleus neuroendocrine neurons) and also the intestine. Hormone acts on the gastrointestinal tract to reduce the rate at which food is absorbed from the intestine.

Gamma Cells secrete pancreatic polypeptide (36 amino acid peptide hormone) which reduces appetite.

Pancreatic Duct

The pancreatic duct is associated with the gastrointestinal tract exocrine function of the pancreas and is covered in detail in Gastrointestinal Tract Pancreas - Pancreatic Duct Variations.

The pancreatic duct(s) exist as a number of anatomical variations due to the embryological origin from the dorsal and ventral panceas buds formation and later fusion.

Pancreas Histology

(Human, H&E)	(Rat, immunohistochemistry)
(More? Pancreas Exocrine Histology)	(Images: Lutz Slomianka, UWA Blue Histology)

Pancreas History

1642 - main pancreatic duct (MPD) discovered by Johann Georg Wirsung (1589 - 1643) a German physician who worked as a prosector in Padua. The duct is also called Wirsung's duct.

1724 - accessory pancreatic duct (APD) dissected and delineated by Giovanni Domenico Santorini (1681 - 1737) an Italian anatomist. The duct is also called Santorini's duct.

1833 - Amylase, the form enzyme also found in exocrine pancreas, isolated from a malt solution by Anselme Payen.

1893 - Islets of Langerhans named in honour of Paul Langerhans (1847-1888) by Gustave-Edouard Laguesse (1861-1927) a french histopathologist.

1922 - discovery of insulin by Frederick Banting and John Macleod, two Canadian researchers, and they subsequently win the 1923 Nobel Prize in Medicine. Banting shared his part of the prize money with a younger coworker Charles Best.

1953 - glucagon, originally called "hyperglycemic glycogenolytic factor", purified by Staub, Sinn and Behrens. See also book JM. Howard and W, Hess (2002) "History of the Pancreas: Mysteries of a Hidden Organ".

References:

Glucagon - STAUB A, SINN L, BEHRENS OK. Purification and crystallization of hyperglycemic glycogenolytic factor (HGF). Science. 1953 Jun 5;117(3049):628-9. | STAUB A, SINN L, BEHRENS OK. Purification and crystallization of glucagon. J Biol Chem. 1955 Jun;214(2):619-32. | BROMER WW, SINN LG, STAUB A, BEHRENS OK. The amino acid sequence of glucagon. Diabetes. 1957 May-Jun;6(3):234-8.

Links: Nobel Lecture, September 15, 1925 | Amazon - History of the Pancreas: Mysteries of a Hidden Organ | PDF Article - Purification and Crystallization of Glucagon |

Pancreas Digestive

The digestive function of the pancreas is covered in GIT Notes- Pancreas

• Pancreatic buds- endoderm, covered in splanchnic mesoderm
• Pancreatic bud formation – duodenal level endoderm, splanchnic mesoderm forms dorsal and ventral mesentery, dorsal bud (larger, first), ventral bud (smaller, later)
• 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

Functions - exocrine (amylase, alpha-fetoprotein)

Pancreatic amylase digests starch to maltose. Postnatally, a blood test to detect amylase can be used to diagnose and monitor acute or chronic pancreatitis (pancreas inflammation).

Pancreatic alpha-fetoprotein has been found to change in expression level (in rats) during developent and has been suggested to influence pancreas development.

Liu L, Guo J, Yuan L, Cheng M, Cao L, Shi H, Tong H, Wang N, De W. Alpha-fetoprotein is dynamically expressed in rat pancreas during development. Dev Growth Differ. 2007 Oct;49(8):669-81.

"Immunolocalization for AFP revealed that a positive reactivity was detectable at E15.5 pancreas, became stronger in the cytoplasm of mesenchyme cells at E18.5, and declined after birth to a nearly undetectable level in adults."

Abnormalities

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. (More? Diabetes Mellitus | Maternal Diabetes)

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

References:Holemans K, Aerts L, Van Assche FA.Lifetime consequences of abnormal fetal pancreatic development. J Physiol. 2003 Feb 15;547(Pt 1):11-20.

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

Diabetes Mellitus

Treatment is generally by insulin injections, oral delivery difficult as insulin is degraded enzymatically in the gut. Some research on conjugated insulin for oral delivery is currently underway.

Maternal diabetes mellitus – hypertrophy of fetal beta cells, fetal abnormalities.

Poor diabetes mellitus control at the time of fetal organogenesis is teratogenic, producing malformations in the heart, nervous system and skeleton. The seriousness of fetal abnormalities is related to degree of diabetic control and has been termed ‘fuel-mediated teratogenesis’. (More? Abnormal Development - Maternal diabetes)

A recent study suggests that in the adult diabetes may have a role in impaired neural function. Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci. 2008 Mar;11(3):309-317. Epub 2008 Feb 17.

(More? Abnormal Development - Maternal diabetes)

Genes

Molecular Mechanisms of Pancreas Development

Epithelial-mesenchymal cell interactions regulate growth, epithelial branching, and cell differentiation in the embryonic pancreas (Golosow and Grobstein 1962; Wessells and Cohen 1967).

Additional cell interactions, involving pancreatic epithelium and midline mesoderm-derived tissues, essential for normal pancreatic development (Kim et al. 1997a).

Signaling pathways involved

• transforming growth factor-beta (TGF-beta)
• Notch
• Hedgehog,
• Fibroblast growth factor (FGF)
• Epidermal growth factor (EGF)
• Descriptions of these pathways may be found in recent reviews by Artavanis-Tsakonas et al. 1999; Hackel et al. 1999; Massague´ and Chen 2000; Bailey et al. 2000; McMahon 2000; Zaret 2000.

(text modified from Seung K. Kim and Matthias Hebrok Intercellular signals regulating pancreas development and function. Genes & Development 15:111-127 2001)

 

Mouse Pancreas Development

• Pancreas develops from distinct dorsal and ventral primordia.
• Dorsal pancreas
  • midline endoderm in posterior foregut is a single layer of epithelial cells that contacts notochord, an axial mesoderm-derived structure
• Ventral pancreas
  • Laterally, endoderm fated to form ventral pancreas is adjacent to both splanchnic mesoderm and aortic endothelial cells but is not in direct contact with notochord.
• The notochord and dorsal prepancreatic endoderms remain in contact until about the 13-somite stage in mice, 8.5 d postcoitum (dpc), when midline fusion of the paired dorsal aortas occurs.
• The first indication of morphogenesis occurs at 22-25 somites in mice (9.5 dpc)
  • dorsal mesenchyme condenses and underlying endoderm evaginates, forming a recognizable dorsal pancreatic bud
  • the ventral bud appears later at ~30 somites (10.25-10.5 dpc). Stimulated by mesenchymal signals, pancreatic epithelial cells proliferate and branch.
• The accumulated evidence is consistent with the possibility that a unique cell gives rise to all pancreatic cell lineages. The existence of such a pancreatic "stem" cell remains debatable.

(text modified from Seung K. Kim and Matthias Hebrok Intercellular signals regulating pancreas development and function. Genes & Development 15:111-127 2001)

NEUROD1

• Both humans and mice with NEUROD1 deficiency develop diabetes because of abnormalities in pancreas development.
• basic helix-loop-helix factor NEUROD1 (also known as BETA2)
• Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Naya, F.J., Huang, H.P., Qiu, Y., Mutoh, H., DeMayo, F.J., Leiter, A.B., and Tsai, M.J. 1997. Genes & Dev. 11: 2323-2334.

Neurogenin-3 (NEUROG3)

• Expressed in endocrine progenitor cells (including pancrea islet cells) and required for endocrine cell development in pancreas and intestine.
• Mutation in this gene depletes intestinal enteroendocrine cells resulting in malabsorptive diarrhea.
• Has been used as marker for fetal pancreatic cells to isolate islet progenitor cells by FACS

Ghrelin

• Ghrelin is a peptide hormone (28 amino acid)
• During fetal development (in animal models) Ghrelin has been correlated with insulin secretion, beta-cell development, and diabetes.
• Synthesis of ghrelin occurs mainly in epithelial cells lining the fundus of the stomach
• Smaller amounts are produced in the placenta, kidney, pituitary and hypothalamus.

References

Links: Journals | Online Textbooks | Search Textbooks | PubMed | | Search PubMed | Glossary

See also book JM. Howard and W, Hess (2002) "History of the Pancreas: Mysteries of a Hidden Organ" (Amazon Link).

Journals

Pancreas

Pancreas The official journal of the American Pancreatic Association and the Japan Pancreas Society

Pancreatology Official Journal of the International Association of Pancreatology (IAP); European Pancreatic Club (EPC)and 16 other societies and study groups.

Journal of the Pancreas electronic journal of pancreatology

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

Earlier reference search results Pancreas Development (1999)

PubMed

Reviews

1. Gasa R. Transcriptional control of pancreatic endocrine cell development. Drug News Perspect. 2005 Nov;18(9):567-76. Review.
2. Holemans K, Aerts L, Van Assche FA.Lifetime consequences of abnormal fetal pancreatic development. J Physiol. 2003 Feb 15;547(Pt 1):11-20.
3. Lucas MJ. Diabetes complicating pregnancy. Obstet Gynecol Clin North Am. 2001 Sep;28(3):513-36. Review.

Articles

1. Kamisawa T, Okamoto A. Pancreatographic investigation of pancreatic duct system and pancreaticobiliary malformation. J Anat. 2008 Feb;212(2):125-34.
2. Liu L, Guo J, Yuan L, Cheng M, Cao L, Shi H, Tong H, Wang N, De W. Alpha-fetoprotein is dynamically expressed in rat pancreas during development. Dev Growth Differ. 2007 Oct;49(8):669-81.
3. Collombat P, Hecksher-Sorensen J, Serup P, Mansouri A. Specifying pancreatic endocrine cell fates. Mech Dev. 2006 Jul;123(7):501-12. "... apparently identical pool of cells originating from the early gut endoderm, which are successively specified towards the pancreatic, endocrine, and hormone-expressing cell lineages. Numerous studies have outlined the crucial roles exerted by transcription factors in promoting the cell destiny, defining the cell identity and maintaining a particular cell fate. This review focuses on the mechanisms regulating the morphogenesis of the pancreas with particular emphasis on recent findings concerning the transcription factor hierarchy orchestrating endocrine cell fate allocation."
4. Duvillie B, Attali M, Bounacer A, Ravassard P, Basmaciogullari A, Scharfmann R. The mesenchyme controls the timing of pancreatic beta-cell differentiation. Diabetes. 2006 Mar;55(3):582-9. "...mesenchyme controls the timing of beta-cell differentiation both upstream and downstream of transcription factor neurogenin 3 (Ngn3)."
5. Sheffield JS, Butler-Koster EL, Casey BM, McIntire DD, Leveno KJ. Maternal diabetes mellitus and infant malformations. Obstet Gynecol. 2002 Nov;100(5 Pt 1):925-30.
6. Schaefer-Graf UM, Buchanan TA, Xiang A, Songster G, Montoro M, Kjos SL. Patterns of congenital anomalies and relationship to initial maternal fasting glucose levels in pregnancies complicated by type 2 and gestational diabetes. Am J Obstet Gynecol. 2000 Feb;182(2):313-20.
7. Schaefer UM, Songster G, Xiang A, Berkowitz K, Buchanan TA, Kjos SL. Congenital malformations in offspring of women with hyperglycemia first detected during pregnancy. Am J Obstet Gynecol. 1997 Nov;177(5):1165-71.

Search PubMed

Search Feb2008 "pancreas development" 9,492 reference articles of which 1,467 were reviews.

Search PubMed: term= pancreas+development

Earlier reference search results Pancreas Development (1999)

Web Links

• Society for Endocrinology (UK)
• British Association of Endocrine Surgeons
• American Association of Clinical Endocrinologists

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