Pancreatic islets

There are about 1 million islets distributed throughout the pancreas of a healthy adult human. While islets vary in size, the average diameter is about 0.2 mm.{{cite book| veditors = Feldman M, Friedman LS, Brandt LJ |title = Sleisenger & Fordtran's gastrointestinal and liver disease pathophysiology, diagnosis, management|year = 2015|publisher = Elsevier Health Sciences|location = St. Louis, Missouri|isbn = 978-1-4557-4989-8|edition = 10th}}^:928 Each islet is separated from the surrounding pancreatic tissue by a thin, fibrous, connective tissue capsule which is continuous with the fibrous connective tissue that is interwoven throughout the rest of the pancreas.^:928

Hormones produced in the pancreatic islets are secreted directly into the blood flow by (at least) five types of cells. In rat islets, endocrine cell types are distributed as follows:{{cite journal | vauthors = Elayat AA, el-Naggar MM, Tahir M | title = An immunocytochemical and morphometric study of the rat pancreatic islets | journal = Journal of Anatomy | volume = 186 | issue = Pt 3 | pages = 629–637 | date = June 1995 | pmid = 7559135 | pmc = 1167020 | series = 186 }}

• Alpha cells producing glucagon (20% of total islet cells)
• Beta cells producing insulin and amylin (≈70%)
• PP cells (gamma cells or F cells) producing pancreatic polypeptide (<5%)
• Delta cells producing somatostatin (<10%)
• Epsilon cells producing ghrelin (<1%)

It has been recognized that the cytoarchitecture of pancreatic islets differs between species.{{cite journal | vauthors = Brissova M, Fowler MJ, Nicholson WE, Chu A, Hirshberg B, Harlan DM, Powers AC | title = Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy | journal = The Journal of Histochemistry and Cytochemistry | volume = 53 | issue = 9 | pages = 1087–1097 | date = September 2005 | pmid = 15923354 | doi = 10.1369/jhc.5C6684.2005 | doi-access = free }}{{cite journal | vauthors = Ichii H, Inverardi L, Pileggi A, Molano RD, Cabrera O, Caicedo A, Messinger S, Kuroda Y, Berggren PO, Ricordi C | title = A novel method for the assessment of cellular composition and beta-cell viability in human islet preparations | journal = American Journal of Transplantation | volume = 5 | issue = 7 | pages = 1635–1645 | date = July 2005 | pmid = 15943621 | doi = 10.1111/j.1600-6143.2005.00913.x | s2cid = 234176 | citeseerx = 10.1.1.578.5893 }}{{cite journal | vauthors = Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A | title = The unique cytoarchitecture of human pancreatic islets has implications for islet cell function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 7 | pages = 2334–2339 | date = February 2006 | pmid = 16461897 | pmc = 1413730 | doi = 10.1073/pnas.0510790103 | doi-access = free | bibcode = 2006PNAS..103.2334C }}

In particular, while rodent islets are characterized by a predominant proportion of insulin-producing beta cells in the core of the cluster and by scarce alpha, delta and PP cells in the periphery, human islets display alpha and beta cells in close relationship with each other throughout the cluster.

The proportion of beta cells in islets varies depending on the species, in humans it is about 40–50%. In addition to endocrine cells, there are stromal cells (fibroblasts), vascular cells (endothelial cells, pericytes), immune cells (granulocytes, lymphocytes, macrophages, dendritic cells,) and neural cells.{{cite journal | vauthors = Jansson L, Barbu A, Bodin B, Drott CJ, Espes D, Gao X, Grapensparr L, Källskog Ö, Lau J, Liljebäck H, Palm F, Quach M, Sandberg M, Strömberg V, Ullsten S, Carlsson PO | title = Pancreatic islet blood flow and its measurement | journal = Upsala Journal of Medical Sciences | volume = 121 | issue = 2 | pages = 81–95 | date = May 2016 | pmid = 27124642 | pmc = 4900068 | doi = 10.3109/03009734.2016.1164769 }}

A large amount of blood flows through the islets, 5–6 mL/min per 1 g of islet. It is up to 15 times more than in exocrine tissue of the pancreas.

Islets can influence each other through paracrine and autocrine communication, and beta cells are coupled electrically to six to seven other beta cells, but not to other cell types.{{cite journal | vauthors = Kelly C, McClenaghan NH, Flatt PR | title = Role of islet structure and cellular interactions in the control of insulin secretion | journal = Islets | volume = 3 | issue = 2 | pages = 41–47 | year = 2011 | pmid = 21372635 | doi = 10.4161/isl.3.2.14805 | doi-access = free }} Pancreatic islets are characterized by rich innervation and vascularization, although there are notable differences between rodent and human islets. Research indicates that the vascular density in human islets is about five times lower than in rodent islets.{{cite journal | vauthors = Cohrs CM, Chen C, Jahn SR, Stertmann J, Chmelova H, Weitz J, Bähr A, Klymiuk N, Steffen A, Ludwig B, Kamvissi V, Wolf E, Bornstein SR, Solimena M, Speier S | title = Vessel Network Architecture of Adult Human Islets Promotes Distinct Cell-Cell Interactions In Situ and Is Altered After Transplantation | journal = Endocrinology | volume = 158 | issue = 5 | pages = 1373–1385 | date = May 2017 | pmid = 28324008 | doi = 10.1210/en.2016-1184 }}{{cite journal | vauthors = Brissova M, Shostak A, Fligner CL, Revetta FL, Washington MK, Powers AC, Hull RL | title = Human Islets Have Fewer Blood Vessels than Mouse Islets and the Density of Islet Vascular Structures Is Increased in Type 2 Diabetes | journal = The Journal of Histochemistry and Cytochemistry | volume = 63 | issue = 8 | pages = 637–645 | date = August 2015 | pmid = 26216139 | doi = 10.1369/0022155415573324 | pmc = 4530394 }} The vascular network within the islets resembles a glomeruli-like structure, consisting of highly fenestrated endothelial cells positioned closely to each endocrine cell.{{cite journal | vauthors = Bonner-Weir S, Orci L | title = New perspectives on the microvasculature of the islets of Langerhans in the rat | journal = Diabetes | volume = 31 | issue = 10 | pages = 883–889 | date = October 1982 | pmid = 6759221 | doi = 10.2337/diab.31.10.883 }}{{cite journal | vauthors = Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A | title = The unique cytoarchitecture of human pancreatic islets has implications for islet cell function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 7 | pages = 2334–2339 | date = February 2006 | pmid = 16461897 | pmc = 1413730 | doi = 10.1073/pnas.0510790103 | doi-access = free | bibcode = 2006PNAS..103.2334C }} Consequently, the oxygen tension within pancreatic islets is significantly higher than that in the surrounding exocrine tissue.{{cite journal | vauthors = Carlsson PO, Liss P, Andersson A, Jansson L | title = Measurements of oxygen tension in native and transplanted rat pancreatic islets | journal = Diabetes | volume = 47 | issue = 7 | pages = 1027–1032 | date = July 1998 | pmid = 9648824 | doi = 10.2337/diabetes.47.7.1027 }}

Human pancreatic islet.jpg|A pancreatic islet, stained.

Alfa-cells of islets of Langerhans.jpg|A pancreatic islet, showing alpha cells

Beta-cells of islets of Langerhans.jpg|A pancreatic islet, showing beta cells.

The paracrine feedback system of the pancreatic islets has the following structure:{{Cite book | vauthors = Wang MB, Bullock J, Boyle JR | title = Physiology | publisher = Lippincott Williams & Wilkins | location = Hagerstown, MD | year = 2001 | pages = 391 | isbn = 978-0-683-30603-3 }}

• Glucose/Insulin: activates beta cells and inhibits alpha cells.
• Glycogen/Glucagon: activates alpha cells which activates beta cells and delta cells.
• Somatostatin: inhibits alpha cells and beta cells. Also inhibits the secretion of pancreatic polypeptide.{{cite journal | vauthors = Marques JM, Nunes R, Florindo H, Ferreira D, Sarmento B |title=A demanding path from iPSCs toward pancreatic β- and α-cells |journal=Recent Advances in IPSC-Derived Cell Types |series=Advances in Stem Cell Biology |date=2021 |volume=4 |pages=227–256 |doi=10.1016/B978-0-12-822230-0.00002-8 |isbn=9780128222300 |s2cid=234135648 |url=https://www.sciencedirect.com/science/article/pii/B9780128222300000028 |access-date=18 January 2023}}

A large number of G protein-coupled receptors (GPCRs) regulate the secretion of insulin, glucagon, and somatostatin from pancreatic islets,{{cite journal | vauthors = Amisten S, Salehi A, Rorsman P, Jones PM, Persaud SJ | title = An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans | journal = Pharmacology & Therapeutics | volume = 139 | issue = 3 | pages = 359–391 | date = September 2013 | pmid = 23694765 | doi = 10.1016/j.pharmthera.2013.05.004 }} and some of these GPCRs are the targets of drugs used to treat type-2 diabetes (ref GLP-1 receptor agonists, DPPIV inhibitors).

File:PancreaticPolypeptide.jpg | Mouse islet immunostained for pancreatic polypeptide

File:InsulinIHC.jpg | Mouse islet immunostained for insulin

File:Glucagon.jpg | Mouse islet immunostained for glucagon

Electrical activity of pancreatic islets has been studied using patch clamp techniques. It has turned out that the behavior of cells in intact islets differs significantly from the behavior of dispersed cells.{{cite journal | vauthors = Pérez-Armendariz M, Roy C, Spray DC, Bennett MV | title = Biophysical properties of gap junctions between freshly dispersed pairs of mouse pancreatic beta cells | journal = Biophysical Journal | volume = 59 | issue = 1 | pages = 76–92 | date = January 1991 | pmid = 2015391 | pmc = 1281120 | doi = 10.1016/S0006-3495(91)82200-7 | bibcode = 1991BpJ....59...76P }}

The beta cells of the pancreatic islets secrete insulin, and so play a significant role in diabetes. It is thought that they are destroyed by immune assaults.

Because the beta cells in the pancreatic islets are selectively destroyed by an autoimmune process in type 1 diabetes, clinicians and researchers are actively pursuing islet transplantation as a means of restoring physiological beta cell function, which would offer an alternative to a complete pancreas transplant or artificial pancreas.{{cite journal | vauthors = Meloche RM | title = Transplantation for the treatment of type 1 diabetes | journal = World Journal of Gastroenterology | volume = 13 | issue = 47 | pages = 6347–6355 | date = December 2007 | pmid = 18081223 | pmc = 4205453 | doi = 10.3748/wjg.13.6347 | doi-access = free }}{{cite journal | vauthors = Hogan A, Pileggi A, Ricordi C | title = Transplantation: current developments and future directions; the future of clinical islet transplantation as a cure for diabetes | journal = Frontiers in Bioscience | volume = 13 | issue = 13 | pages = 1192–1205 | date = January 2008 | pmid = 17981623 | doi = 10.2741/2755 | doi-access = free }} Islet transplantation emerged as a viable option for the treatment of insulin requiring diabetes in the early 1970s with steady progress over the following three decades.{{cite journal | vauthors = Piemonti L, Pileggi A | title = 25 Years of the Ricordi Automated Method for Islet Isolation | journal = CellR4-- Repair, Replacement, Regeneration, & Reprogramming | volume = 1 | issue = 1 | pages = 8–22 | year = 2013 | pmid = 30505878 | pmc = 6267808 | url = http://www.cellr4.org/article/128 }} Clinical trials {{asof|2008|lc=y}} have shown that insulin independence and improved metabolic control can be reproducibly obtained after transplantation of cadaveric donor islets into patients with unstable type 1 diabetes. Alternatively, daily insulin injections are an effective treatment for type 1 diabetes patients who are not candidates for islet transplantation.

People with high body mass index (BMI) are unsuitable pancreatic donors due to greater technical complications during transplantation. However, it is possible to isolate a larger number of islets because of their larger pancreas, and therefore they are more suitable donors of islets.{{cite journal | vauthors = Niclauss N, Meier R, Bédat B, Berishvili E, Berney T | title = Beta-Cell Replacement: Pancreas and Islet Cell Transplantation | journal = Endocrine Development | volume = 31 | pages = 146–162 | date = 2016-01-27 | pmid = 26824893 | doi = 10.1159/000439412 | publisher = S. Karger AG | isbn = 978-3-318-05638-9 | veditors = Stettler C, Christ E, Diem P }}

Islet transplantation only involves the transfer of tissue consisting of beta cells that are necessary as a treatment of this disease. It thus represents an advantage over whole pancreas transplantation, which is more technically demanding and poses a risk of, for example, pancreatitis leading to organ loss. Another advantage is that patients do not require general anesthesia.{{cite journal | vauthors = Gamble A, Pepper AR, Bruni A, Shapiro AM | title = The journey of islet cell transplantation and future development | journal = Islets | volume = 10 | issue = 2 | pages = 80–94 | date = March 2018 | pmid = 29394145 | pmc = 5895174 | doi = 10.1080/19382014.2018.1428511 }}

Islet transplantation for type 1 diabetes ({{asof|2008|lc=y}}) requires potent immunosuppression to prevent host rejection of donor islets.{{cite journal | vauthors = Chatenoud L | title = Chemical immunosuppression in islet transplantation--friend or foe? | journal = The New England Journal of Medicine | volume = 358 | issue = 11 | pages = 1192–1193 | date = March 2008 | pmid = 18337609 | doi = 10.1056/NEJMcibr0708067 }}

The islets are transplanted into a portal vein, which is then implanted in the liver. There is a risk of portal venous branch thrombosis and the low value of islet survival a few minutes after transplantation, because the vascular density at this site is after the surgery several months lower than in endogenous islets. Thus, neovascularization is key to islet survival, that is supported, for example, by VEGF produced by islets and vascular endothelial cells. However, intraportal transplantation has some other shortcomings, and so other alternative sites that would provide better microenvironment for islets implantation are being examined. Islet transplant research also focuses on islet encapsulation, CNI-free (calcineurin-inhibitor) immunosuppression, biomarkers of islet damage or islet donor shortage.{{cite journal | vauthors = Chang CA, Lawrence MC, Naziruddin B | title = Current issues in allogeneic islet transplantation | journal = Current Opinion in Organ Transplantation | volume = 22 | issue = 5 | pages = 437–443 | date = October 2017 | pmid = 28692442 | doi = 10.1097/MOT.0000000000000448 | s2cid = 37483032 }}

An alternative source of beta cells, such insulin-producing cells derived from adult stem cells or progenitor cells would contribute to overcoming the shortage of donor organs for transplantation. The field of regenerative medicine is rapidly evolving and offers great hope for the nearest future. However, type 1 diabetes is the result of the autoimmune destruction of beta cells in the pancreas. Therefore, an effective cure will require a sequential, integrated approach that combines adequate and safe immune interventions with beta cell regenerative approaches.{{cite journal | vauthors = Pileggi A, Cobianchi L, Inverardi L, Ricordi C | title = Overcoming the challenges now limiting islet transplantation: a sequential, integrated approach | journal = Annals of the New York Academy of Sciences | volume = 1079 | issue = 1 | pages = 383–398 | date = October 2006 | pmid = 17130583 | doi = 10.1196/annals.1375.059 | s2cid = 33009393 | bibcode = 2006NYASA1079..383P }} It has also been demonstrated that alpha cells can spontaneously switch fate and transdifferentiate into beta cells in both healthy and diabetic human and mouse pancreatic islets, a possible future source for beta cell regeneration.{{cite journal | vauthors = van der Meulen T, Mawla AM, DiGruccio MR, Adams MW, Nies V, Dólleman S, Liu S, Ackermann AM, Cáceres E, Hunter AE, Kaestner KH, Donaldson CJ, Huising MO | title = Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets | journal = Cell Metabolism | volume = 25 | issue = 4 | pages = 911–926.e6 | date = April 2017 | pmid = 28380380 | pmc = 8586897 | doi = 10.1016/j.cmet.2017.03.017 | doi-access = free }} In fact, it has been found that islet morphology and endocrine differentiation are directly related.{{cite journal | vauthors = Sharon N, Chawla R, Mueller J, Vanderhooft J, Whitehorn LJ, Rosenthal B, Gürtler M, Estanboulieh RR, Shvartsman D, Gifford DK, Trapnell C, Melton D | title = A Peninsular Structure Coordinates Asynchronous Differentiation with Morphogenesis to Generate Pancreatic Islets | journal = Cell | volume = 176 | issue = 4 | pages = 790–804.e13 | date = February 2019 | pmid = 30661759 | pmc = 6705176 | doi = 10.1016/j.cell.2018.12.003 | publication-date = 2019 }} Endocrine progenitor cells differentiate by migrating in cohesion and forming bud-like islet precursors, or "peninsulas", in which alpha cells constitute the peninsular outer layer and beta cells form later beneath them. Cryopreservation has shown promise to improve the supply chain of pancreatic islets for better transplantation outcomes. {{cite journal | vauthors = Zhan L, Rao JS, Sethia N, Slama MQ, Han Z, Tobolt D, Etheridge M, Peterson QP, Dutcher CS, Bischof JC, Finger EB | title = Pancreatic islet cryopreservation by vitrification achieves high viability, function, recovery and clinical scalability for transplantation | journal = Nature Medicine | volume = 28 | issue = 4 | pages = 798–808 | date = April 2022 | pmid = 35288694 | pmc = 9018423 | doi = 10.1038/s41591-022-01718-1 }}

Langerhanssche Insel.jpg|Pancreatic islets, the lighter tissue among the darker, acinar pancreatic tissue, hemalum-eosin stain.

File:Gray1105.png | Illustration of dog pancreas. 250x.

File:Suckale08 fig2 islet structure.jpg | Structural differences between rat islets (top) and humans islets (bottom) as well as the ventral part (left) and the dorsal part (right) of the pancreas. Different cell types are colour-coded. Rodent islets, unlike the human ones, show the characteristic insulin core.

Cannabinoid receptors are found widely expressed in islets of Langerhans, and several studies have investigated specific distribution and mechanisms of CB1 versus CB2 receptors in relation to pancreatic endocrine functions, where they play an important homeostatic role, as endocannabinoids modulate pancreatic β-cells function, proliferation, and survival, as well as insulin production, secretion, and resistance.{{cite journal | vauthors = Bermúdez-Silva FJ, Suárez J, Baixeras E, Cobo N, Bautista D, Cuesta-Muñoz AL, Fuentes E, Juan-Pico P, Castro MJ, Milman G, Mechoulam R, Nadal A, Rodríguez de Fonseca F | title = Presence of functional cannabinoid receptors in human endocrine pancreas | journal = Diabetologia | volume = 51 | issue = 3 | pages = 476–487 | date = March 2008 | pmid = 18092149 | doi = 10.1007/s00125-007-0890-y | doi-access = free }}{{cite journal | vauthors = Flores LE, Alzugaray ME, Cubilla MA, Raschia MA, Del Zotto HH, Román CL, Suburo AM, Gagliardino JJ | title = Islet cannabinoid receptors: cellular distribution and biological function | language = en-US | journal = Pancreas | volume = 42 | issue = 7 | pages = 1085–1092 | date = October 2013 | pmid = 24005231 | doi = 10.1097/MPA.0b013e31828fd32d | s2cid = 36905885 }}{{cite journal | vauthors = Juan-Picó P, Fuentes E, Bermúdez-Silva FJ, Javier Díaz-Molina F, Ripoll C, Rodríguez de Fonseca F, Nadal A | title = Cannabinoid receptors regulate Ca(2+) signals and insulin secretion in pancreatic beta-cell | journal = Cell Calcium | volume = 39 | issue = 2 | pages = 155–162 | date = February 2006 | pmid = 16321437 | doi = 10.1016/j.ceca.2005.10.005 }}{{cite journal | vauthors = Farokhnia M, McDiarmid GR, Newmeyer MN, Munjal V, Abulseoud OA, Huestis MA, Leggio L | title = Effects of oral, smoked, and vaporized cannabis on endocrine pathways related to appetite and metabolism: a randomized, double-blind, placebo-controlled, human laboratory study | journal = Translational Psychiatry | volume = 10 | issue = 1 | pages = 71 | date = February 2020 | pmid = 32075958 | pmc = 7031261 | doi = 10.1038/s41398-020-0756-3 }}

• Betatrophin
• Neuroendocrine tumor
• Pancreatic neuroendocrine tumor
• Adrift Just Off the Islets of Langerhans, a novelette by Harlan Ellison

{{Reflist|2}}

• [https://www.proteinatlas.org/humanproteome/pancreas Pancreas] at the Human Protein Atlas

{{Digestive glands}}

{{Endocrine system}}

{{Authority control}}

{{DEFAULTSORT:Islets Of Langerhans}}

Category:Pancreas anatomy