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Quantification of Beta-Cell Mass in Intramuscular Islet Grafts using Radiolabeled Exendin-4
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 Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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2016 (English)In: Transplantation Direct, ISSN 2373-8731, Vol. 2, no 8, e93Article in journal (Refereed) Published
Abstract [en]

Background: There is an increasing interest in alternative implantation sites to the liver for islet transplantation. Intramuscular implantation has even been tested clinically. Possibilities to monitor [beta]-cell mass would be of huge importance not only for the understanding of islet engraftment but also for the decision of changing the immunosuppressive regime. We have therefore evaluated the feasibility of quantifying intramuscular [beta]-cell mass using the radiolabeled glucagon like peptide-1 receptor agonist DO3A-VS-Cys40-Exendin-4.

Methods: One hundred to 400 islets were transplanted to the abdominal muscle of nondiabetic mice. After 3 to 4 weeks, 0.2 to 0.5 MBq [177Lu]DO3A-VS-Cys40-Exendin-4 was administered intravenously. Sixty minutes postinjection abdominal organs and graft bearing muscle were retrieved, and the radioactive uptake measured in a well counter within 10 minutes. The specific uptake in native and transplanted islets was assessed by autoradiography. The total insulin-positive area of the islet grafts was determined by immunohistochemistry.

Results: Intramuscular islet grafts could easily be visualized by this tracer, and the background uptake was very low. There was a linear correlation between the radioactivity uptake and the number of transplanted islets, both for standardized uptake values and the total radiotracer uptake in each graft (percentage of injected dose). The quantified total insulin area of surviving [beta] cells showed an even stronger correlation to both standardized uptake values (R = 0.96, P = 0.0002) and percentage of injected dose (R = 0.88, P = 0.0095). There was no correlation to estimated [alpha] cell mass.

Conclusions: [177Lu]DO3A-VS-Cys40-Exendin-4 could be used to quantify [beta]-cell mass after experimental intramuscular islet transplantation. This technique may well be transferred to the clinical setting by exchanging Lutetium-177 radionuclide to a positron emitting Gallium-68.

Place, publisher, year, edition, pages
2016. Vol. 2, no 8, e93
Keyword [en]
Islet transplantation, beta-cell mass, exendin-4, Lutetium-177
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-282942DOI: 10.1097/TXD.0000000000000598ISI: 000390130200004PubMedID: 27819034OAI: oai:DiVA.org:uu-282942DiVA: diva2:917900
Funder
Swedish Research Council, 55X-15043
Available from: 2016-04-08 Created: 2016-04-08 Last updated: 2017-01-30Bibliographically 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: 2016-06-01

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Espes, DanielSelvaraju, RamkumarVelikyan, IrinaCarlsson, Per-OlaEriksson, Olof

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