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Ullsten, Sara
Publications (10 of 12) Show all publications
Ullsten, S., Lau, J. & Carlsson, P.-O. (2019). Decreased beta-Cell Proliferation and Vascular Density in a Subpopulation of Low-Oxygenated Male Rat Islets. Journal of the Endocrine Society, 3(8), 1608-1616
Open this publication in new window or tab >>Decreased beta-Cell Proliferation and Vascular Density in a Subpopulation of Low-Oxygenated Male Rat Islets
2019 (English)In: Journal of the Endocrine Society, E-ISSN 2472-1972, Vol. 3, no 8, p. 1608-1616Article in journal (Refereed) Published
Abstract [en]

Low-oxygenated and dormant islets with a capacity to become activated when neededmay play a crucial role in the complex machinery behind glucose homeostasis. We hypothesized that low-oxygenated islets, when not functionally challenged, do not rapidly cycle between activation and inactivation but are a stable population that remain low-oxygenated. As this was confirmed, we aimed to characterize these islets with regard to cell composition, vascular density, and endocrine cell proliferation. The 2-nitroimidazole low-oxygenation marker pimonidazole was administered as a single or repeated dose to Wistar Furth rats. The stability of oxygen status of islets was evaluated by immunohistochemistry as the number of islets with incorporated pimonidazole adducts after one or repeated pimonidazole injections. Adjacent sections were evaluated for islet cell composition, vascular density, and endocrine cell proliferation. Single and repeated pimonidazole injections over an 8-hour period yielded accumulation of pimonidazole adducts in the same islets. An average of 30% of all islets was in all cases positively stained for pimonidazole adducts. These islets showed a similar endocrine cell composition as other islets but had lower vascular density and beta-cell proliferation. In conclusion, low-oxygenated islets were found to be a stable subpopulation of islets for at least 8 hours. Although they have previously been observed to be less functionally active, their islet cell composition was similar to that of other islets. Consistent with their lower oxygenation, they had fewer blood vessels than other islets. Notably, beta-cell regeneration preferentially occurred in better-oxygenated islets.

Place, publisher, year, edition, pages
Endocrine Society, 2019
Keywords
islet vasculature, pancreatic islets, heterogeneity, beta-cell proliferation
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-330804 (URN)10.1210/js.2019-00101 (DOI)000484384400015 ()31404404 (PubMedID)
Funder
Swedish Research Council, 55X-15043Swedish Child Diabetes FoundationSwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in SwedenNovo Nordisk
Note

Title in thesis list of papers: Decreased beta cell proliferation and vascular density in a subpopulation of low-oxygenated rat islets

Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2019-10-17Bibliographically approved
Medina, A., Parween, S., Ullsten, S., Vishnu, N., Siu, Y. T., Quach, M., . . . Fex, M. (2018). Early deficits in insulin secretion, beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats. Diabetologia, 61(4), 896-905
Open this publication in new window or tab >>Early deficits in insulin secretion, beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats
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2018 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 4, p. 896-905Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available. Methods We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry. Additionally, measurements of intra-islet blood flow were performed using microsphere injections. We also assessed immune cell infiltration, cytokine expression in islets (by immunohistochemistry and qPCR), as well as islet Glut2 expression and ATP/ADP ratio to determine effects on glucose uptake and metabolism in beta cells. Results DRLyp/Lyp rats were normoglycaemic and without traces of immune cell infiltrates. However, IVGTTs revealed a significant decrease in the acute insulin response to glucose compared with control rats (1685.3 +/- 121.3 vs 633.3 +/- 148.7; p < 0.0001). In agreement, insulin secretion was severely perturbed in isolated islets, and both first- and second-phase insulin release were lowered compared with control rats, while glucagon secretion was similar in both groups. Interestingly, after 5-7 days of culture of islets from DRLyp/Lyp rats in normal media, glucose-stimulated insulin secretion (GSIS) was improved; although, a significant decrease in GSIS was still evident compared with islets from control rats at this time (7393.9 +/- 1593.7 vs 4416.8 +/- 1230.5 pg islet(-1) h(-1); p < 0.0001). Compared with controls, OPT of whole pancreas from DRLyp/Lyp rats revealed significant reductions in medium (4.1 x 10(9) +/- 9.5 x 10(7) vs 3.8 x 10(9) +/- 5.8 x 10(7) mu m(3); p = 0.044) and small sized islets (1.6 x 10(9) +/- 5.1 x 10(7) vs 1.4 x 10(9) +/- 4.5 x 10(7) mu m(3); p = 0.035). Finally, we found lower intra-islet blood perfusion in vivo (113.1 +/- 16.8 vs 76.9 +/- 11.8 mu l min(-1) [g pancreas](-1); p = 0.023) and alterations in the beta cell ATP/ADP ratio in DRLyp/Lyp rats vs control rats. Conclusions/interpretation The present study identifies a deterioration of beta cell function and mass, and intra-islet blood flow that precedes insulitis and diabetes development in animals prone to autoimmune type 1 diabetes. These underlying changes in islet function may be previously unrecognised factors of importance in type 1 diabetes development.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keywords
Beta cell dysfunction, Beta cell mass, Insulin secretion, Islet blood flow, Type 1 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-350274 (URN)10.1007/s00125-017-4512-z (DOI)000427049100017 ()29209740 (PubMedID)
Funder
Novo NordiskThe Crafoord FoundationSwedish Research Council, K2013-99X-22212-01-5, K2016-01495_3, K2011-54X-15312-07-6, K2013-55X-15043-10-5
Available from: 2018-05-14 Created: 2018-05-14 Last updated: 2018-05-14Bibliographically approved
Herrera Hidalgo, C., Ullsten, S., Vågesjö, E., Parv, K., Liu, H., Giraud, A., . . . Phillipson, M. (2018). Effect of neonatal infections on pancreatic macrophages, islet development and long-term glucose homeostasis. Paper presented at 52nd Annual Scientific Meeting of the European Society for Clinical Investigation “Precision medicine for healthy ageing”, 30th May – 1st June 2018, Barcelona, Spain.. European Journal of Clinical Investigation, 48(S1), 83-83
Open this publication in new window or tab >>Effect of neonatal infections on pancreatic macrophages, islet development and long-term glucose homeostasis
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2018 (English)In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 83-83Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-366628 (URN)10.1111/eci.12926 (DOI)000434100200185 ()
Conference
52nd Annual Scientific Meeting of the European Society for Clinical Investigation “Precision medicine for healthy ageing”, 30th May – 1st June 2018, Barcelona, Spain.
Note

Meeting Abstract: P032-T

Available from: 2018-11-23 Created: 2018-11-23 Last updated: 2018-12-11Bibliographically approved
Ullsten, S., Bohman, S., Oskarsson, M. E., Nilsson, K. P., Westermark, G. & Carlsson, P.-O. (2017). Islet amyloid deposits preferentially in the highly functional and most blood-perfused islets.. Endocrine Connections, 6(7), 458-468
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, p. 458-468Article 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.

Keywords
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)000411647000007 ()28790139 (PubMedID)
Funder
Swedish Research Council, 55X-15043Swedish Child Diabetes FoundationSwedish Diabetes AssociationNovo NordiskEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-12-18Bibliographically approved
Jansson, L., Barbu, A., Bodin, B., Drott, C. J., Espes, D., Gao, X., . . . Carlsson, P.-O. (2016). Pancreatic islet blood flow and its measurement. Upsala Journal of Medical Sciences, 121(2), 81-95
Open this publication in new window or tab >>Pancreatic islet blood flow and its measurement
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2016 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 2, p. 81-95Article, review/survey (Refereed) Published
Abstract [en]

Pancreatic islets are richly vascularized, and islet blood vessels are uniquely adapted to maintain and support the internal milieu of the islets favoring normal endocrine function. Islet blood flow is normally very high compared with that to the exocrine pancreas and is autonomously regulated through complex interactions between the nervous system, metabolites from insulin secreting beta-cells, endothelium derived mediators, and hormones. The islet blood flow is normally coupled to the needs for insulin release and is usually disturbed during glucose intolerance and overt diabetes. The present review provides a brief background on islet vascular function and especially focuses on available techniques to measure islet blood perfusion. The gold standard for islet blood flow measurements in experimental animals is the microsphere technique, and its advantages and disadvantages will be discussed. In humans there are still no methods to measure islet blood flow selectively, but new developments in radiological techniques hold great hopes for the future.

Keywords
Blood flow measurements, islet blood flow, microspheres, pancreatic islets
National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-299775 (URN)10.3109/03009734.2016.1164769 (DOI)000376695600004 ()27124642 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Childhood Cancer FoundationNovo Nordisk
Available from: 2016-07-27 Created: 2016-07-27 Last updated: 2018-01-10Bibliographically approved
Espes, D., Lau, J., Quach, M., Ullsten, S., Christoffersson, G. & Carlsson, P.-O. (2016). Rapid Restoration of Vascularity and Oxygenation in Mouse and Human Islets Transplanted to Omentum May Contribute to Their Superior Function Compared to Intraportally Transplanted Islets. American Journal of Transplantation, 16(11), 3246-3254
Open this publication in new window or tab >>Rapid Restoration of Vascularity and Oxygenation in Mouse and Human Islets Transplanted to Omentum May Contribute to Their Superior Function Compared to Intraportally Transplanted Islets
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2016 (English)In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 16, no 11, p. 3246-3254Article in journal (Refereed) Published
Abstract [en]

Transplantation of islets into the liver confers several site-specific challenges, including a delayed vascularization and prevailing hypoxia. The greater omentum has in several experimental studies been suggested as an alternative implantation site for clinical use, but there has been no direct functional comparison to the liver. In this experimental study in mice, we characterized the engraftment of mouse and human islets in the omentum and compared engraftment and functional outcome with those in the intraportal site. The vascularization and innervation of the islets transplanted into the omentum were restored within the first month by paralleled ingrowth of capillaries and nerves. The hypoxic conditions in the islets early posttransplantation were transient and restricted to the first days. Newly formed blood vessels were fully functional, and the blood perfusion and oxygenation of the islets became similar to that of endogenous islets. Furthermore, islet grafts in the omentum showed at 1 month posttransplantation functional superiority to intraportally transplanted grafts. We conclude that in contrast to the liver the omentum provides excellent engraftment conditions for transplanted islets. Future studies in humans will be of great interest to investigate the capability of this site to also harbor larger grafts without interfering with islet functionality.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-311198 (URN)10.1111/ajt.13927 (DOI)000388204600023 ()27321369 (PubMedID)
Funder
Swedish Research Council, 55X-15043Swedish Child Diabetes FoundationSwedish Diabetes AssociationNovo Nordisk
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2017-11-29Bibliographically approved
Ullsten, S., Grapensparr, L., Sandberg, M. & Carlsson, P.-O. (2015). Schwann cells regulate angiogenesis and blood vessel structure in native and transplanted pancreatic. Paper presented at IPITA/IXA/CTS Joint Congress, NOV 15-19, 2015, Melbourne, AUSTRALIA. Xenotransplantation, 22, S46-S46
Open this publication in new window or tab >>Schwann cells regulate angiogenesis and blood vessel structure in native and transplanted pancreatic
2015 (English)In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 22, p. S46-S46Article in journal, Meeting abstract (Other academic) Published
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-276047 (URN)000364594100109 ()
Conference
IPITA/IXA/CTS Joint Congress, NOV 15-19, 2015, Melbourne, AUSTRALIA
Available from: 2016-02-09 Created: 2016-02-09 Last updated: 2017-11-30Bibliographically approved
Ullsten, S., Grapensparr, L., Sandberg, M. & Carlsson, P.-O. (2015). Schwann Cells Regulate Angiogenesis And Blood Vessel Structure In Native And Transplanted Pancreatic Islets. Paper presented at Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society, NOV 15-19, 2015, Melbourne, AUSTRALIA. Transplantation, 99(11), S75-S75
Open this publication in new window or tab >>Schwann Cells Regulate Angiogenesis And Blood Vessel Structure In Native And Transplanted Pancreatic Islets
2015 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 11, p. S75-S75Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-281554 (URN)000368625700106 ()
Conference
Joint Congress of the International-Pancreas-and-Islet-Transplantation-Association, International-Xenotransplantation-Association and Cell-Transplant-Society, NOV 15-19, 2015, Melbourne, AUSTRALIA
Available from: 2016-04-05 Created: 2016-03-24 Last updated: 2018-01-10Bibliographically approved
Ullsten, S., Lau, J. & Carlsson, P.-O. (2015). Vascular heterogeneity between native rat pancreatic islets is responsible for differences in survival and revascularisation post transplantation. Diabetologia, 58(1), 132-139
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, p. 132-139Article 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: 2018-01-11Bibliographically approved
Ullsten, S., Lau, J., Welsh, N. & Carlsson, P.-O. (2013). Vascular Heterogeneity Between Native Pancreatic Islets Determines Their Fate of Survival and Revascularization Posttransplantation. Paper presented at 14th World Congress of the International-Pancreas-and-Islet-Transplant-Association (IPITA), SEP 24-27, 2013, Monterey, CA. Transplantation, 96(6), S21-S21
Open this publication in new window or tab >>Vascular Heterogeneity Between Native Pancreatic Islets Determines Their Fate of Survival and Revascularization Posttransplantation
2013 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S21-S21Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-220761 (URN)000330443500040 ()
Conference
14th World Congress of the International-Pancreas-and-Islet-Transplant-Association (IPITA), SEP 24-27, 2013, Monterey, CA
Available from: 2014-03-20 Created: 2014-03-20 Last updated: 2017-12-05Bibliographically approved
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