Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass
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. Howe...
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Uppsala universitet, Institutionen för medicinsk cellbiologi
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ndltd-UPSALLA1-oai-DiVA.org-uu-2829532016-06-02T05:05:31ZEngraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell MassengEspes, DanielUppsala universitet, Institutionen för medicinsk cellbiologiUppsala2016Type 1 diabetesIslet transplantationAlternative implantation sitesExendin-4Positron Emission Tomography5-hydroxy tryptophanBeta-cell massIslet 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. Doctoral thesis, comprehensive summaryinfo:eu-repo/semantics/doctoralThesistexthttp://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-282953urn:isbn:978-91-554-9551-0Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 1211application/pdfinfo:eu-repo/semantics/openAccess |
collection |
NDLTD |
language |
English |
format |
Doctoral Thesis |
sources |
NDLTD |
topic |
Type 1 diabetes Islet transplantation Alternative implantation sites Exendin-4 Positron Emission Tomography 5-hydroxy tryptophan Beta-cell mass |
spellingShingle |
Type 1 diabetes Islet transplantation Alternative implantation sites Exendin-4 Positron Emission Tomography 5-hydroxy tryptophan Beta-cell mass Espes, Daniel Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass |
description |
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. |
author |
Espes, Daniel |
author_facet |
Espes, Daniel |
author_sort |
Espes, Daniel |
title |
Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass |
title_short |
Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass |
title_full |
Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass |
title_fullStr |
Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass |
title_full_unstemmed |
Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell Mass |
title_sort |
engraftment of pancreatic islets in alternative transplantation sites and the feasibility of in vivo monitoring of native and transplanted beta-cell mass |
publisher |
Uppsala universitet, Institutionen för medicinsk cellbiologi |
publishDate |
2016 |
url |
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-282953 http://nbn-resolving.de/urn:isbn:978-91-554-9551-0 |
work_keys_str_mv |
AT espesdaniel engraftmentofpancreaticisletsinalternativetransplantationsitesandthefeasibilityofinvivomonitoringofnativeandtransplantedbetacellmass |
_version_ |
1718292396748308480 |