Diabetes i 3D - från struktur till funktion

Vår forskargrupp drivs av ett starkt intresse för att förstå de cellulära och strukturella mekanismer som formar pankreasutvecklingen och bidrar till diabetes. Vi fokuserar på hur endokrina cellpopulationer är organiserade, upprätthålls och förändras vid hälsa och sjukdom, samt hur dessa rumsliga dynamiker påverkar β‑cellernas funktion och överlevnad.

En viktig av vårt arbete är att utveckla och tillämpa avancerade 3D‑avbildningstekniker - som optisk projektionstomografi (OPT) och light‑sheet fluorescence microscopy (LSFM) – för att kartlägga bukspottkörtelns anatomi hos mus och människa, på helorgansnivå och med cellulär upplösning. Genom att kombinera dessa avbildningsplattformar med klassisk cell‑ och molekylärbiologi strävar vi efter att avslöja tidigare okända aspekter av ö‑heterogenitet, endokrin cellplasticitet och sjukdomsassocierad vävnadsremodellering. Detta med det övrgripande syftet att generera nya mekanistiska insikter som kan bidra till strategier för att bevara eller återställa β‑cellfunktionen vid diabetes.

Insulinproducerande Langerhanska öar (röda) i en human bukspottkörtel visualiserade med optisk 3D teknik.

Utvalda publikationer

Optical 3D imaging of a whole pancreas identifies inversed proportions between extra-islet and islet-associated β-cells in late-onset type 1 diabetes. Joakim Lehrstrand, Max Hahn, Björn Morén, Wayne. I. L. Davies, Olle Korsgren, Tomas Alanentalo & Ulf Ahlgren. Science Advances, in press

Illuminating the complete ß-cell mass of the human pancreas - signifying a new view on the islets of Langerhans. Joakim Lehrstrand, Wayne I. L. Davies, Max Hahn, Olle Korsgren, Tomas Alanentalo, Ulf Ahlgren Nature Communications. April 18, 2024 DOI: 10.1038/s41467-024-47686-7 https://www.nature.com/articles/s41467-024-47686-7

An MR-based brain template and atlas for optical projection tomography and light sheet fluorescence microscopy in neuroscience. Stefanie M. A. WillekensFederico Morini , Tomas Mediavilla , Emma Nilsson , Greger Orädd , Max Hahn , Nunya Chotiwan, Montse Visa , Per-Olof Berggren , Erwin Ilegems , Anna K. Överby, Ulf Ahlgren and Daniel Marcellino. Frontiers in Neuroscience. 2024 Mar 27. https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1328815/full

Type I interferon shapes brain distribution and tropism of tick-borne flavivirus. Chotiwan N, Rosendal E, Willekens SMA, Schexnaydre E, Nilsson E, Lindqvist R, Hahn M, Mihai IS, Morini F, Zhang J, Ebel GD, Carlson LA, Henriksson J, Ahlgren U, Marcellino D, Överby AK. Nature Communications. 2023 Apr 10;14(1):2007. doi: 10.1038/s41467-023-37698-0. https://www.nature.com/articles/s41467-023-37698-0

Quantitative 3D OPT and LSFM datasets of pancreata from mice with streptozotocin-induced Diabetes.  Max Hah, Christoffer Nord, Pim P. van Krieken, Per-Olof Berggren, Erwin Ilegems & Ulf Ahlgren. Scientific Data, Sep 10, 2022 (9)558. https://doi.org/10.1038/s41597-022-01546-5 https://www.nature.com/articles/s41597-022-01546-5#citeas

Insulin-Binding Peptide Probes Provide a Novel Strategy for Pancreatic β-Cell Imaging. Eriksson M, Litwak SA, Yun Y, Stanley WJ, Thorn P, Ahlgren U, Gurzov EN. Mol Pharm. 2021, 18, 12, 4428–4436 doi: 10.1021/acs.molpharmaceut.1c00616. https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.1c00616

3D imaging of human organs with micrometer resolution - applied to the endocrine pancreas. Hahn M, Nord C, Eriksson M, Morini F, Alanentalo T, Korsgren O, Ahlgren U. Commun Biol. 2021 Sep 10;4(1):1063. doi:10.1038/s42003-021-02589-x. https://www.nature.com/articles/s42003-021-02589-x

Gsα-dependent signaling is required for postnatal establishment of a functional β-cell mass. Serra-Navarro B, Fernandez-Ruiz R, García-Alamán A, Pradas-Juni M, Fernandez-Rebollo E, Esteban Y, Mir-Coll J, Mathieu J, Dalle S, Hahn M, Ahlgren U, Weinstein LS, Vidal J, Gomis R, Gasa R. Mol Metab. 2021 Jun 4;53:101264. doi: 10.1016/j.molmet.2021.101264. 
https://www.sciencedirect.com/science/article/pii/S2212877821001095?via%3Dihub

Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease. Quilichini E, Fabre M, Nord C, Dirami T, Le Marec A, Cereghini S, Pasek RC, Gannon M, Ahlgren U, Haumaitre C. J Pathol. 2021 May;254(1):31-45. doi:10.1002/path.5629.
https://onlinelibrary.wiley.com/doi/10.1002/path.5629

Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes. Max Hahn, Pim P. van Krieken, Christoffer Nord, Tomas Alanentalo, Federico Morini, Yan Xiong, Maria Eriksson, Jüergn Mayer, Elena Kostromina, Jorge L. Ruas, James Sharpe, Teresa Pereira, Per-Olof Berggren, Erwin Ilegems & Ulf Ahlgren. Communications Biology. Volume 3, Article number: 541 (2020). https://www.nature.com/articles/s42003-020-01243-2

Mesoscopic 3D imaging of pancreatic cancer and Langerhans islets based on tissue autofluorescence. Max Hahn, Christoffer Nord, Oskar Franklin, Tomas Alanentalo, Martin Isaksson Mettävainio, Federico Morini, Maria Eriksson, Olle Korsgren, Malin Sund & Ulf Ahlgren. Scientific Reports (2020) Oct 26;10(1):18246. doi:10.1038/s41598-020-74616-6.
https://www.nature.com/articles/s41598-020-74616-6 

Early deficits in insulin secretion, beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats. Anya Medina, Saba Parween, Sara Ullsten, Neelanjan Vishnu, Yuk Ting Siu, My Quach, Hedvig Bennet, Alexander Balhuizen, Lina Åkesson, Nils Wierup, Per Ola Carlsson, Ulf Ahlgren, Åke Lernmark, Malin Fex. Diabetologia volume 61, pages896–905(2018).
https://link.springer.com/article/10.1007%2Fs00125-017-4512-z

The efect of hypergastrinemia following sleeve gastrectomy and pantoprazole on type 2 diabetes mellitus and beta‑cell mass in Goto‑Kakizaki rats E. Grong, C. Nord, I. B. Arbo, M. Eriksson, B. E. Kulseng,U. Ahlgren, R. Mårvik
Journal of Endocrinological Investigation volume 41, pages691–701(2018)
https://link.springer.com/article/10.1007/s40618-017-0793-9

Kinetics of functional beta cell mass decay in a diphtheria toxin receptor mouse model of diabetes. Pim P. van Krieken, Andrea Dicker, Maria Eriksson, Pedro L. Herrera, Ulf Ahlgren, Per-Olof Berggren & Erwin Ilegems.
Scientific Reports volume 7, Article number: 12440 (2017)
https://www.nature.com/articles/s41598-017-12124-w

Biochemical profiling of diabetes disease progression by multivariate vibrational microspectroscopy of the pancreas. Nord C, Eriksson M, Dicker A, Eriksson A, Grong E, Ilegems E, Mårvik R, Kulseng B, Berggren PO, Gorzsás A, Ahlgren U. Scientific Reports. 2017 Jul 27;7(1):6646. doi:10.1038/s41598-017-07015-z.
https://www.nature.com/articles/s41598-017-07015-z

Spatial and quantitative datasets of pancreatic β-cell mass in lean and obese mice. Parween S, Eriksson M, Nord C, Kostromina E, Ahlgren U. Scientific Data, 2017 Scientific Data 4, Article number: 170031.
http://www.nature.com/articles/sdata201731

Intra-islet lesions and lobular variations in β-cell mass expansion in ob/ob mice revealed by 3D imaging of intact pancreas. Parween S, Kostromina E, Nord C, Eriksson M, Lindström P, Ahlgren U. Scientific Reports. 2016 Oct 7;6:34885.
http://www.nature.com/articles/srep24576

Ex vivo SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for β-cell mass assessments. Eter WA, Parween S, Joosten L, Frielink C, Eriksson M, Brom M, Ahlgren U, Gotthardt M. Scientific Reports. 2016 Apr 15;6:24576. Co-senior authorship.
http://www.nature.com/articles/srep24576

Sleeve gastrectomy, but not duodenojejunostomy, preserves total beta-cell mass in Goto-Kakizaki rats evaluated by three-dimensional optical projection tomography. Grong E, Kulseng B, Arbo IB, Nord C, Eriksson M, Ahlgren U, Mårvik R. Surg Endosc. 2016 Feb;30(2):532-42. http://link.springer.com/article/10.1007%2Fs00464-015-4236-4

Light scattering as an intrinsic indicator for pancreatic islet cell mass and secretion. Ilegems E, van Krieken PP, Edlund PK, Dicker A, Alanentalo T, Eriksson M, Mandic S, Ahlgren U, Berggren PO. Scientific Reports. 2015 Jun 1;5:10740.
http://www.nature.com/articles/srep10740

Improving signal detection in emission optical projection tomography via single source multi-exposure image fusion. Cheddad A, Nord C, Hörnblad A, Prunskaite-Hyyryläinen R, Eriksson M, Georgsson F, Vainio SJ, Ahlgren U. Opt Express. 2013 Jul 15;21(14):16584-604.
https://www.osapublishing.org/oe/fulltext.cfm?uri=oe-21-14-16584&id=258484

Neurogenin 3+ Cells Contribvute to Beta Cell Neogenesis and proliferation in in injured adult mouse pancreas. Neurogenin 3+ cells contribute to β-cell neogenesis and proliferation in injured adult mouse pancreas. Van de Casteele M, Leuckx G, Baeyens L, Cai Y, Yuchi Y, Coppens V, De Groef S, Eriksson M, Svensson C, Ahlgren U, Ahnfelt-Rønne J, Madsen OD, Waisman A, Dor Y, Jensen JN, Heimberg H. Cell Death and Disease, 2013 Mar 7;4:e523. 
https://www.nature.com/articles/cddis201352 

Near infrared optical projection tomography for assessments of b-cell mass distribution in diabetes research. A. U. Eriksson 1,5, C. Svensson1,5, A. Hörnblad1, A. Cheddad1, 6, E. Kostromina1, M. Eriksson1, N. Norlin1,7, A. Pileggi2, J. Sharpe3, F. Georgsson4, T. Alanentalo1,8 & U. Ahlgren1 ,* J Vis Exp, 2013 Jan 12;(71). Svensson C, Sharpe J, Georgsson F, Ahlgren U. Image Processing Assisted Algorithms for Optical Projection Tomography. IEEE Trans Med Imaging. 2012 Jan;31(1):1-15.
http://ieeexplore.ieee.org/document/5953523/

Hörnblad, A. Cheddad and U. Ahlgren. An improved protocol for optical projection tomography imaging reveals lobular heterogeneities in pancreatic islet and β-cell mass distribution. Islets, 2011, Jul-Aug;3(4):204-8. Epub 2011 Jul 1.
http://www.tandfonline.com/doi/full/10.4161/isl.3.4.16417 

Andreas Hörnblad, Anna U. Eriksson, Elisabeth Sock, Robert E. Hill and Ulf Ahlgren. Impaired spleen formation perturbs morphogenesis of the gastric lobe of the pancreas. PLoS One, 2011;6(6):e21753. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021753

Fredrik Wolfhagen Sand, Andreas Hörnblad Jenny K. Johansson, Christina Lorén, Josefina Edc sbagge, Anders Ståhlberg, Judith Magenheim, Ohad Ilovich, Eyal Mishani, Yuval Dor, Ulf Ahlgren and Henrik Semb. Growth-limiting role of endothelial cells in endoderm development. Developmental Biology, 2011, Apr 15;352(2):267-77.
http://www.sciencedirect.com/science/article/pii/S0012160611000595

Tomas Alanentalo, Andreas Hörnblad, Sofia Mayans, Anna Karin Nilsson, James Sharpe , Åsa Larefalk, Ulf Ahlgren., Dan Holmberg. Co-senior authorship. Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine Type 1 Diabetes. Diabetes, 2010 Jul;59(7):1756-64. http://diabetes.diabetesjournals.org/content/59/7/1756.long

Alanentalo T, Lorén C. E, Larefalk Å, Sharpe J, Holmberg D and Ahlgren U. High resolution 3D imaging of islet-infiltrate interactions based on optical projection tomography assessments of the intact adult mouse pancreas. J Biomed Opt, 2008 Sept/Oct; 13(5):054070-1-054070-4. http://biomedicaloptics.spiedigitallibrary.org/article.aspx?articleid=1102839

Alanentalo T, Asayesh A, Morrison H, Loren CE, Holmberg D, Sharpe J, Ahlgren U. Tomographic molecular imaging and 3D quantification within adult mouse organs. Nature Methods, 2007 Jan; 4(1):31-3.
http://www.nature.com/nmeth/journal/v4/n1/full/nmeth985.html

Amir Asayesh, James Sharpe, Robert P Watson, Jacob Hecksher-Sørensen, Nicholas D Hastie, Robert E Hill and Ulf Ahlgren. Spleen versus pancreas: strict control of organ interrelation-ship revealed by analyses of Bapx1-/- mice. Genes & Development, 2006 Aug 15;20(16):2208-13. http://genesdev.cshlp.org/content/20/16/2208.long

Norlin S., Ahlgren U and Edlund H. Nuclear Factor-KB Activity in b-Cells Is Required for Glucose-Stimulated Insulin Secretion. Diabetes, 2005, 54: 125-132. http://diabetes.diabetesjournals.org/content/54/1/125.long

Hecksher-Sorensen J, Watson RP, Lettice LA, Serup P, Eley L, De Angelis C, Ahlgren U, Hill RE. The splanchnic mesodermal plate directs spleen and pancreatic laterality, and is regulated by Bapx1/Nkx3.2. Development. 2004 Oct;131(19):4665-75.
http://dev.biologists.org/content/131/19/4665.long

Sharpe J, Ahlgren U, Perry P, Hill B, Ross A, Hecksher-Sorensen J, Baldock R, Davidson D. Optical projection tomography as a tool for 3D microscopy and gene expression studies. Science. 2002 Apr 19;296(5567):541-5.
http://dev.biologists.org/content/131/19/4665.long

Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H. beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes & Development 1998 Jun 15;12(12):1763-8.
http://genesdev.cshlp.org/content/12/12/1763.long

Ahlgren U, Pfaff SL, Jessell TM, Edlund T, Edlund H. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature. 1997 Jan 16;385(6613):257-60.
http://www.nature.com/nature/journal/v385/n6613/abs/385257a0.html

Apelqvist A, Ahlgren U, Edlund H. Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Current Biology, 1997 Oct 1;7(10):801-4.
http://www.sciencedirect.com/science/article/pii/S096098220600340X

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 May;122(5):1409-16.
http://dev.biologists.org/content/122/5/1409.long

Reviews and book chapters:

Development of the Pancreas. Wayne I. L. Davies, Andreas Hönblad, Max Hahn, Joakim Lehrstrand, Jonas-Ahnfeldt Rønne, Tomas Alanentalo and Ulf Ahlgren.  Kaufman’s Atlas of Mouse Development Supplement: With Coronal Sections, Second Edition. Edited by: G. Morriss-Kay & S. Srinivas, Elsevier. 2025,  DOI: 10.1016/B978-0-443-23739-3.00014-6   

3D Optical Molecular Imaging of the Rodent Pancreas by OPT and LSFM. Hahn M & Ahlgren U. In the book “Type-1 Diabetes” Methods Mol Biol. 2023;2592:1-19. doi: 10.1007/978-1-0716-2807-2_1. https://link.springer.com/protocol/10.1007/978-1-0716-2807-2_1.

Mesoscopic Optical Imaging of the Pancreas-Revisiting Pancreatic Anatomy and Pathophysiology. Alanentalo T, Hahn M, Willekens SMA, Ahlgren U. Front Endocrinol (Lausanne). 2021 Mar 4;12:633063. doi:10.3389/fendo.2021.633063. (Review)
https://www.frontiersin.org/articles/10.3389/fendo.2021.633063/full

Novel strategies to protect and visualize pancreatic β-cells in diabetes. Esteban N. Gurzov, Pu Chun Ke, Ulf Ahlgren, Rita S. Garcia Ribeiro, Martin Gotthardt. Trends Endocrinol Metab. 2020 Dec;31(12):905-917. doi: 10.1016/j.tem.2020.10.002.

A. Hörnblad, C. Nord, S. Parween, J. Ahnfelt-Rønne & U. Ahlgren, The Pancreas. Kaufman's Atlas of Mouse Development, Supplement, 1st Edition With Coronal Sections Edited by: R. Baldock, M. Kaufman, J. Bard, D.R. Davidson and G. Morriss-Kay, Elsevier. 2016, ISBN : 9780128000434 (Review)

Ulf Ahlgren, Exploring the pancreas with optical projection tomography, Imaging Med. Feb 2012, Vol. 4, No. 1, Pages 5-7 (editorial)

Junghyo Jo, Manami Hara, Ulf Ahlgren, Robert L. Sorenson, and Vipul Periwal. Mathematical models of pancreatic islet size distributions. Islets, 4:1, 1–10; January/February, 2012. (Review)

U. Ahlgren and E. Kostromina. Imaging the pancreatic ß-cell. In "Type 1 diabetes" Intech publishers 2011, ISBN: 987-953-307-362-0.

Gotthardt M and Ahlgren U. Approaches for imaging of islets: recent advances and future prospects, in The Islets of Langerhans. Editor Shahidul Islam, Adv Exp Med Biol. 2010, 654:39-57.

Holmberg D and Ahlgren U. Imaging the pancreas: From ex vivo to non-invasive technology. Diabetologia, 2008 Dec;51(12):2148-54.

Ahlgren U and Edlund H. Homeodomain Proteins in Pancreas Development in Molecular Basis of Pancreas Development and Function, in Molecular Basis of Pancreas Development and Function. Editors: Joel F. Habener, Mehboob Hussain  ISBN 0-7923-7271-9 January 2001