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Diabetes in 3D: β-cell mass assessments in disease models & evaluation of SPECT based imaging
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). (Ulf Ahlgren)ORCID iD: 0000-0002-7437-1870
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes is a rapidly growing disease with 415 million affected adults worldwide. The pancreatic endocrine cells, most importantly the insulin producing β-cells, play an important role in regulating blood glucose homeostasis. Type 1 diabetes (T1D) is characterized by the inability of the pancreas to secrete sufficient amounts of insulin due to autoimmune destruction of insulin producing β-cells. Type 2 diabetes (T2D) on the other hand is characterized by defects in insulin secretion and insulin sensitivity. Alterations in the β-cell mass (BCM) and/or function play a major role in the development and progression of the disease. Understanding BCM dynamics in disease models is therefore a key aspect for better interpretation of research results. In this thesis, we have used optical projection tomography (OPT) as a tool to evaluate a non-invasive imaging modality for β-cell scoring and to study disease dynamics in frequently used animal models for T1D and T2D.

The possibility to monitor BCM in vivo would radically improve our competence in studying the pathogenesis of diabetes and in therapeutic interventions. Single photon emission computed tomography (SPECT) is a widely used technique that has become a promising approach to monitor changes in BCM in vivo. A key issue for using this approach is to evaluate the β-cell specificity and read out of the utilized radiotracers. This is most commonly performed by conventional stereological approaches, which rely on the extrapolation of 2D data. We developed a protocol for SPECT-OPT multimodal imaging that enables rapid and accurate cross evaluation of SPECT based assessments of BCM. While histological determination of islet spatial distribution was challenging, SPECT and OPT revealed similar distribution patterns of the radiotracer 111In-exendin-3 and insulin positive β-cell volumes respectively between different pancreatic lobes, both visually and quantitatively. We propose SPECT-OPT multimodal imaging as an accurate and better approach for validating the performance of β-cell radiotracers.

The leptin deficient ob/ob mouse is a widely used model for studies of metabolic disturbances leading to T2D, including obesity and insulin resistance. By OPT imaging we created the first 3D-spatial and quantitative account of BCM distribution in this model. We observed a previously unreported degree of cystic lesions in hypertrophic islets, that were occupied by red blood cells (RBCs) and/or fibrin mesh. We propose that these lesions are formed by a mechanism involving the extravasation of RBCs/plasma due to increased blood flow and islet vessel instability. Further, our data indicate that the primary lobular compartments of the ob/ob pancreas have different potentials for expanding their β-cell population. Unawareness of these characteristics of β-cell expansion in ob/ob mice presented in this study may significantly influence ex vivo and in vivo assessments of this model in studies of β-cell adaptation and function. The tomographic data, on which this study was based, will be made publically available as a resource to the research community for the planning and interpretation of research involving this model.

There are limited studies on early metabolic and functional changes of BCM in the settings of T1D. In order to assess initial metabolic alterations in BCM before the onset of diabetes, we characterized congenic diabetes prone Bio-breeding (BB) DR.lyp/lyp rats, a widely used model for T1D diabetes. We observed lower acute insulin response, reduced islet blood flow and a significant reduction in the BCM of small and medium sized islets at a very early stage (40 days), i.e. before insulitis and development of diabetes. Underlying changes in islet function may be a previously unrecognized factor of importance in the development of T1D.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2016. , 52 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1852
Keyword [en]
Optical projection tomography, Diabetes, β-cell mass, disease etiology, 3D imaging, radiotracers, Single photon emission computed tomography
National Category
Cell and Molecular Biology
Research subject
Molecular Medicine
Identifiers
URN: urn:nbn:se:umu:diva-127550ISBN: 978-91-7601-584-1OAI: oai:DiVA.org:umu-127550DiVA: diva2:1046824
Public defence
2016-12-15, Hörsal B Unod T9, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
EU, FP7, Seventh Framework Programme, 289932Swedish Research Council
Available from: 2016-11-18 Created: 2016-11-15 Last updated: 2016-11-18Bibliographically approved
List of papers
1. SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for beta-cell mass assessments
Open this publication in new window or tab >>SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for beta-cell mass assessments
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 24576Article in journal (Refereed) Published
Abstract [en]

Single Photon Emission Computed Tomography (SPECT) has become a promising experimental approach to monitor changes in beta-cell mass (BCM) during diabetes progression. SPECT imaging of pancreatic islets is most commonly cross-validated by stereological analysis of histological pancreatic sections after insulin staining. Typically, stereological methods do not accurately determine the total beta-cell volume, which is inconvenient when correlating total pancreatic tracer uptake with BCM. Alternative methods are therefore warranted to cross-validate beta-cell imaging using radiotracers. In this study, we introduce multimodal SPECT - optical projection tomography (OPT) imaging as an accurate approach to cross-validate radionuclide-based imaging of beta-cells. Uptake of a promising radiotracer for beta-cell imaging by SPECT, In-111-exendin-3, was measured by ex vivo-SPECT and cross evaluated by 3D quantitative OPT imaging as well as with histology within healthy and alloxan-treated Brown Norway rat pancreata. SPECT signal was in excellent linear correlation with OPT data as compared to histology. While histological determination of islet spatial distribution was challenging, SPECT and OPT revealed similar distribution patterns of In-111-exendin-3 and insulin positive beta-cell volumes between different pancreatic lobes, both visually and quantitatively. We propose ex vivo SPECT-OPT multimodal imaging as a highly accurate strategy for validating the performance of beta-cell radiotracers.

Keyword
Diabetes Mellitus, Pancreas, Radioisotopes, SPECT
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-120360 (URN)10.1038/srep24576 (DOI)000374221700001 ()27080529 (PubMedID)
Available from: 2016-05-23 Created: 2016-05-16 Last updated: 2016-11-17Bibliographically approved
2. Intra-islet lesions and lobular variations in β-cell mass expansion in  ob/ob  mice revealed by 3D imaging of intact pancreas
Open this publication in new window or tab >>Intra-islet lesions and lobular variations in β-cell mass expansion in  ob/ob  mice revealed by 3D imaging of intact pancreas
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 34885Article in journal (Refereed) Published
Abstract [en]

The leptin deficient ob/ob mouse is a widely used model for studies on initial aspects of metabolic disturbances leading to type 2 diabetes, including insulin resistance and obesity. Although it is generally accepted that ob/ob mice display a dramatic increase in β-cell mass to compensate for increased insulin demand, the spatial and quantitative dynamics of β-cell mass distribution in this model has not been assessed by modern optical 3D imaging techniques. We applied optical projection tomography and ultramicroscopy imaging to extract information about individual islet β-cell volumes throughout the volume of ob/ob pancreas between 4 and 52 weeks of age. Our data show that cystic lesions constitute a significant volume of the hyperplastic ob/ob islets. We propose that these lesions are formed by a mechanism involving extravasation of red blood cells/plasma due to increased islet vessel blood flow and vessel instability. Further, our data indicate that the primary lobular compartments of the ob/ob pancreas have different potentials for expanding their β-cell population. Unawareness of the characteristics of β-cell expansion in ob/ob mice presented in this report may significantly influence ex vivo and in vivo assessments of this model in studies of β-cell adaptation and function.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-127539 (URN)10.1038/srep34885 (DOI)2-s2.0-84990210699 (ScopusID)
Funder
EU, FP7, Seventh Framework Programme, 289932Swedish Research Council
Available from: 2016-11-15 Created: 2016-11-15 Last updated: 2016-11-17Bibliographically approved
3. Spatial and quantitative datasets of the pancreatic β-cell mass distribution in lean and obese (ob/ob) mice
Open this publication in new window or tab >>Spatial and quantitative datasets of the pancreatic β-cell mass distribution in lean and obese (ob/ob) mice
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-127547 (URN)
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme, 289932
Available from: 2016-11-15 Created: 2016-11-15 Last updated: 2016-11-17
4. Early deficits in insulin secretion, β−cell mass and islet blood perfusion precedes onset of autoimmune Type 1 Diabetes in diabetes prone Bio-Breeding (BB) rats
Open this publication in new window or tab >>Early deficits in insulin secretion, β−cell mass and islet blood perfusion precedes onset of autoimmune Type 1 Diabetes in diabetes prone Bio-Breeding (BB) rats
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(English)Manuscript (preprint) (Other academic)
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-127548 (URN)
Funder
Swedish Research CouncilNovo Nordisk
Available from: 2016-11-15 Created: 2016-11-15 Last updated: 2016-11-17

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