Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes

Hahn, Max; van Krieken, Pim P.; Nord, Christoffer; Alanentalo, Tomas; Morini, Federico; Xiong, Yan; Eriksson, Maria; Mayer, Jürgen, 1977-; Kostromina, Elena; Ruas, Jorge L.; Sharpe, James; Pereira, Teresa; Berggren, Per-Olof; Ilegems, Erwin; Ahlgren, Ulf

Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes

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dc.contributor.author Hahn, Max
dc.contributor.author van Krieken, Pim P.
dc.contributor.author Nord, Christoffer
dc.contributor.author Alanentalo, Tomas
dc.contributor.author Morini, Federico
dc.contributor.author Xiong, Yan
dc.contributor.author Eriksson, Maria
dc.contributor.author Mayer, Jürgen, 1977-
dc.contributor.author Kostromina, Elena
dc.contributor.author Ruas, Jorge L.
dc.contributor.author Sharpe, James
dc.contributor.author Pereira, Teresa
dc.contributor.author Berggren, Per-Olof
dc.contributor.author Ilegems, Erwin
dc.contributor.author Ahlgren, Ulf
dc.date.accessioned 2020-11-10T07:05:43Z
dc.date.available 2020-11-10T07:05:43Z
dc.date.issued 2020
dc.description.abstract Mouse models of Streptozotocin (STZ) induced diabetes represent the most widely used preclinical diabetes research systems. We applied state of the art optical imaging schemes, spanning from single islet resolution to the whole organ, providing a first longitudinal, 3D-spatial and quantitative account of β-cell mass (BCM) dynamics and islet longevity in STZ-treated mice. We demonstrate that STZ-induced β-cell destruction predominantly affects large islets in the pancreatic core. Further, we show that hyperglycemic STZ-treated mice still harbor a large pool of remaining β-cells but display pancreas-wide downregulation of glucose transporter type 2 (GLUT2). Islet gene expression studies confirmed this downregulation and revealed impaired β-cell maturity. Reversing hyperglycemia by islet transplantation partially restored the expression of markers for islet function, but not BCM. Jointly our results indicate that STZ-induced hyperglycemia results from β-cell dysfunction rather than β-cell ablation and that hyperglycemia in itself sustains a negative feedback loop restraining islet function recovery.
dc.description.sponsorship The authors thank Lars Haag and Lisa Sjöwall at Karolinska Institutet’s electron microscopy shared facility for providing TEM images. Dr. S. Willekens is acknowledged for help with editing of the manuscript. This project was funded by the Swedish Research Council, the Kempe foundations, Umeå University, Lenanders stiftelse, The strategic Research program in Diabetes at Karolinska Institutet, the Novo Nordisk Foundation, the Swedish Diabetes Association, the Family Knut and Alice Wallenberg Foundation, Diabetes Research and Wellness Foundation, the Stichting af Jochnick Foundation, the Family Erling-Persson Foundation, Berth von Kantzow’s Foundation, the Skandia Insurance Company, Ltd., ERC-2013-AdG 338936-BetaImage, the European Union’s Seventh Framework Program under grant agreements nos. 289932 and 613879.
dc.format.mimetype application/pdf
dc.identifier.citation Hahn M, van Krieken PP, Nord C, Alanentalo T, Morini F, Xiong Y, Eriksson M, Mayer J, Kostromina E, Ruas JL, Sharpe J, Pereira T, Berggren PO, Ilegems E, Ahlgren U. Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes. Commun Biol. 2020; 3(1):541. DOI: 10.1038/s42003-020-01243-2
dc.identifier.doi http://dx.doi.org/10.1038/s42003-020-01243-2
dc.identifier.issn 2399-3642
dc.identifier.uri http://hdl.handle.net/10230/45694
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Commun Biol. 2020; 3(1):541
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/338936
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/289932
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/613879
dc.rights © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword 3-D reconstruction
dc.subject.keyword Diabetes
dc.subject.keyword Experimental models of disease
dc.subject.keyword Mechanisms of disease
dc.subject.keyword Optical imaging
dc.title Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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