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The Impact of Pancreatic Islet Vascular Heterogeneity on Beta Cell Function and Disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes Mellitus is a group of complex and heterogeneous metabolic disorders characterized by hyperglycemia. Even though the condition has been extensively studied, its causes and complex pathologies are still not fully understood. The occurring damage to the pancreatic islets is strikingly heterogeneous. In type 1 diabetes, the insulin producing beta cells are all destroyed within some islets, and similarly in type 2 diabetes, some islets may be severely affected by amyloid. At the same time other islets, in the near vicinity of the ones that are affected by disease, may appear fully normal in both diseases. Little is known about this heterogeneity in susceptibility to disease between pancreatic islets. This thesis examines the physiological and pathophysiological characteristics of islet subpopulations.

Two subpopulations of islets were studied; one constituting highly vascularized islets with superior beta cell functionality, and one of low-oxygenated islets with low metabolic activity. The highly functional islets were found to be more susceptible to cellular stress both in vitro and in vivo, and developed more islet amyloid when metabolically challenged. Highly functional islets preferentially had a direct venous drainage, facilitating the distribution of islet hormones to the peripheral tissues. Further, these islets had an increased capacity for insulin secretion at low glucose levels, a response that was observed abolished in patients with recent onset type 1 diabetes.  The second investigated islet subpopulation, low-oxygenated islets, was found to be an over time stable subpopulation of islets with low vascular density and beta cell proliferation.

In summary, two subpopulations of islets can be identified in the pancreas based on dissimilarities in vascular support and blood flow. These subpopulations appear to have different physiological functions of importance for the maintenance of glucose homeostasis. However, they also seem to differ in vulnerability, and a preferential death of the highly functional islets may accelerate the progression of both type 1 and type 2 diabetes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1374
Keyword [en]
Pancreatic islets, heterogeneity, islet vascularity, blood flow, islet transplantation, islet amyloid, insulitis, type 1 diabetes, beta cell proliferation
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-330805ISBN: 978-91-513-0089-4 (print)OAI: oai:DiVA.org:uu-330805DiVA: diva2:1146925
Public defence
2017-11-23, A1:107a, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2017-10-31 Created: 2017-10-04 Last updated: 2017-11-15
List of papers
1. Vascular heterogeneity between native rat pancreatic islets is responsible for differences in survival and revascularisation post transplantation
Open this publication in new window or tab >>Vascular heterogeneity between native rat pancreatic islets is responsible for differences in survival and revascularisation post transplantation
2015 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 1, 132-139 p.Article in journal (Refereed) Published
Abstract [en]

AIMS/HYPOTHESIS: Highly blood-perfused islets have been observed to be the most functional islets in the native pancreas. We hypothesised that differences in vascular support of islets in donor pancreases influence their susceptibility to cellular stress and capacity for vascular engraftment after transplantation. METHODS: Highly blood-perfused islets in rats were identified by injection of microspheres into the ascending aorta before islet isolation. Cell death was evaluated after in vitro cytokine or hypoxia exposure, and 2days post transplantation. One month post transplantation, islet engraftment, including vascular density, blood perfusion and oxygen tension (pO2) in the tissue, was evaluated. RESULTS: Microsphere-containing islets had a similar frequency of cell death during standard culture conditions but increased cell death after exposure to cytokines and hypoxia in comparison with other islets. Two days after transplantation the percentage of apoptotic or necrotic cells was also higher in grafts of such islets and 1month post transplantation these grafts were composed of substantially more connective tissue. Grafts of highly blood-perfused islets in the native pancreas regained a higher vascular density, blood perfusion and pO2 in comparison with grafts of other islets. CONCLUSIONS/INTERPRETATION: Native islets that are highly blood-perfused regained this feature after transplantation, indicating a superior capacity for revascularisation and post-transplant function. However, the same group of islets was more vulnerable to different kinds of cellular stress, which limited their early survival post transplantation. Preferential death of these most active islets may contribute to the high number of islets needed to provide cure with islet transplantation.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-239079 (URN)10.1007/s00125-014-3385-7 (DOI)000346022300018 ()25257098 (PubMedID)
Funder
Swedish Research Council, 5XX-15043
Available from: 2015-01-06 Created: 2014-12-18 Last updated: 2017-10-04Bibliographically approved
2. Islet amyloid deposits preferentially in the highly functional and most blood-perfused islets.
Open this publication in new window or tab >>Islet amyloid deposits preferentially in the highly functional and most blood-perfused islets.
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2017 (English)In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 6, no 7, 458-468 p.Article in journal (Refereed) Published
Abstract [en]

Islet amyloid and beta cell death in type 2 diabetes are heterogeneous events, where some islets are affected early in the disease process, whereas others remain visibly unaffected. This study investigated the possibility that inter-islet functional and vascular differences may explain the propensity for amyloid accumulation in certain islets. Highly blood-perfused islets were identified by microspheres in human islet amyloid polypeptide expressing mice fed a high-fat diet for three or 10 months. These highly blood-perfused islets had better glucose-stimulated insulin secretion capacity than other islets and developed more amyloid deposits after 10 months of high-fat diet. Similarly, human islets with a superior release capacity formed more amyloid in high glucose culture than islets with a lower release capacity. The amyloid formation in mouse islets was associated with a higher amount of prohormone convertase 1/3 and with a decreased expression of its inhibitor proSAAS when compared to islets with less amyloid. In contrast, levels of prohormone convertase 2 and expression of its inhibitor neuroendocrine protein 7B2 were unaltered. A misbalance in prohormone convertase levels may interrupt the normal processing of islet amyloid polypeptide and induce amyloid formation. Preferential amyloid load in the most blood-perfused and functional islets may accelerate the progression of type 2 diabetes.

Keyword
blood flow, heterogeneity, islet amyloid, pancreatic islets
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-330801 (URN)10.1530/EC-17-0148 (DOI)28790139 (PubMedID)
Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-04
3. Heterogeneities in vascularity and function between pancreatic islets may explain dissimilar propensities for disease development in type 1 diabetes
Open this publication in new window or tab >>Heterogeneities in vascularity and function between pancreatic islets may explain dissimilar propensities for disease development in type 1 diabetes
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-330803 (URN)
Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-04
4. Decreased beta cell proliferation and vascular density in a subpopulation of low-oxygenated rat islets
Open this publication in new window or tab >>Decreased beta cell proliferation and vascular density in a subpopulation of low-oxygenated rat islets
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-330804 (URN)
Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-04

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