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The Positron Emission Tomography ligand [11C]5-Hydroxy-Tryptophan can be used as a surrogate marker for the human endocrine pancreas
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
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2014 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 10, 3428-3437 p.Article in journal (Refereed) Published
Abstract [en]

In humans a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of beta cells, with healthy volunteers (HV).C-peptide negative (i.e. insulin-deficient) T1D subjects (n=10) and HV (n=9) underwent dynamic Positron Emission Tomography with the radiolabeled serotonin precursor [(11)C]5-Hydroxy-Tryptophan ([(11)C]5-HTP).A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HV, with large inter-individual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where beta-cells normally are the major constituent of the islets.[(11)C]5-HTP retention in the pancreas was reduced in T1D compared to non-diabetic subjects. Accumulation of [(11)C]5-HTP in the pancreas of both HV and subjects with T1D were in agreement with previously reported morphological observations on the beta cell volume implying that [(11)C]5-HTP retention is a useful non-invasive surrogate marker for the human endocrine pancreas.

Place, publisher, year, edition, pages
2014. Vol. 63, no 10, 3428-3437 p.
National Category
Other Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-224960DOI: 10.2337/db13-1877ISI: 000342527300029PubMedID: 24848067OAI: oai:DiVA.org:uu-224960DiVA: diva2:719445
Available from: 2014-05-25 Created: 2014-05-25 Last updated: 2018-01-11Bibliographically approved
In thesis
1. Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass
Open this publication in new window or tab >>Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Islet transplantation is a possible curative treatment for type 1 diabetes (T1D). Currently the liver dominates as implantation site, despite the many challenges encountered at this site.

Acute hypoxia in islets transplanted to muscle and omentum, two possible alternative sites, was prevailing. However, it was rapidly reversed at both implantation sites, in contrast to when islets were transplanted intraportally. At the intramuscular site hypoxia was further relieved by co-transplantation of an oxygen carrier, polymerized hemoglobin, which also improved the functional outcome. The complement system was activated after islet transplantation to muscle, but did not hamper graft function.

Both mouse and human islets transplanted to omentum become well re-vascularized and have a functional blood flow and oxygenation comparable with that of endogenous islets. Animals transplanted with islets to the omentum had a superior graft function compared with animals receiving intraportal islet grafts.

Alloxan-diabetic animals were cured with a low number of islets both when the islets were implanted in the omentum and muscle. The islet grafts responded adequately to both glucose and insulin and displayed a favorable mRNA gene expression profile.

A challenge in diabetes research and in islet transplantation is that there are no established techniques for quantifying beta-cell mass in vivo. By using radiolabeled Exendin-4, a GLP-1 receptor agonist, beta-cell mass after transplantation to muscle of mice was quantified. The results may well be translated to the clinical setting.

By comparing the pancreatic accumulation of [11C]5-hydroxy tryptophan ([11C]5-HTP) as detected by positron emission tomography (PET) in T1D patients with that of healthy controls, a 66% decrease was observed. This may in fact represent the loss of beta-cells, taking into account that other cells within the islets of Langerhans are largely unaffected in T1D. 

In conclusion, the data presented support the use of alternative implantation sites for islet transplantation. In addition to improving the functional outcome this may enable more transplantations since the number of transplanted islets may be reduced. The techniques investigated for quantifying transplanted and endogenous beta-cell mass may greatly improve our knowledge of the pathophysiology of T1D and become a valuable tool for evaluation of beta-cell mass.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 88 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1211
Keyword
Type 1 diabetes, Islet transplantation, Alternative implantation sites, Exendin-4, Positron Emission Tomography, 5-hydroxy tryptophan, Beta-cell mass
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-282953 (URN)978-91-554-9551-0 (ISBN)
Public defence
2016-06-01, Sal B22, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2016-05-11 Created: 2016-04-08 Last updated: 2018-01-10

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Eriksson, OlofEspes, DanielSelvaraju, Ram KJansson, EmmaAntoni, GunnarSörensen, JensLubberink, MarkBiglarnia, AlirezaEriksson, Jan WSundin, AndersAhlström, HåkanEriksson, BarbroJohansson, LarsCarlsson, Per-OlaKorsgren, Olle

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Eriksson, OlofEspes, DanielSelvaraju, Ram KJansson, EmmaAntoni, GunnarSörensen, JensLubberink, MarkBiglarnia, AlirezaEriksson, Jan WSundin, AndersAhlström, HåkanEriksson, BarbroJohansson, LarsCarlsson, Per-OlaKorsgren, Olle
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Preclinical PET PlatformDepartment of Medical Cell BiologyRadiologyOncologySection of Nuclear Medicine and PETTransplantation SurgeryClinical diabetology and metabolismEndocrine Tumor BiologyTransplantation and regenerative medicineClinical Immunology
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