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The Microvasculature of Endogenous and Transplanted Pancreatic Islets: Blood Perfusion, Oxygenation and Islet Endocrine Function
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes mellitus affects millions of people worldwide. Islet transplantation is a minimal invasive surgical procedure that restores euglycemia and halts the progression of diabetic complications. However, despite transplantation of islets from multiple donors most patients reverse to hyperglycemia within five years. New strategies to improve long-term outcome of islet transplantation are indispensable. This thesis studied differences in the microvasculature between endogenous and transplanted pancreatic islets, and investigated means to improve islet graft revascularization and function. Islet graft microvessels were similar to endogenous islets responsive to adenosine, angiotensin II and nitric oxide (NO). Recipient hyperglycemia induced a higher basal islet graft blood flow, which also was less dependent on NO than in normoglycemic recipients. Transplantation of freshly isolated instead of cultured islets improved graft revascularization, oxygenation and function. Pretreatment of islets with vascular endothelial growth factor decreased their expression of matrix metalloproteinase-9 (MMP-9) and impaired graft revascularization. Moreover, MMP-9 pretreatment per se improved graft revascularization. In vivo, 20-25% of all endogenous rat islets was low oxygenated (pO2 <10 mmHg). Changes in the islet mass, by means of whole-pancreas transplantation, doubled the fraction of low oxygenated islets in the endogenous pancreas of transplanted animals, whereas this fraction almost completely disappeared after a 60% partial pancreatectomy. Interestingly, oxygenation was related to metabolism, since well oxygenated islets in vivo had 50% higher leucine-dependent protein biosynthesis, which includes (pro)insulin biosynthesis. In intraportally transplanted islets, the low oxygenated fraction of islets was markedly increased one day post-transplantation, and the oxygenation remained low following revascularization. In summary, these data suggest that a better revascularization of transplanted islets can improve graft function. Furthermore, the oxygenation and metabolism of endogenous islets is tightly regulated. This regulation seems to be disturbed following transplantation, which may contribute to long-term islet graft failure.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2006. , p. 83
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 167
Keywords [en]
Cell biology, diabetes mellitus, pancreatic islets, islet transplantation, vascular engraftment, islet microcirculation, oxygenation, blood flow, protein biosynthesis
Keywords [sv]
Cellbiologi
Identifiers
URN: urn:nbn:se:uu:diva-7107ISBN: 91-554-6633-8 (print)OAI: oai:DiVA.org:uu-7107DiVA, id: diva2:168749
Public defence
2006-09-30, B22, Biomedicum, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-09-08 Created: 2006-09-08Bibliographically approved
List of papers
1. Local blood flow regulation in transplanted rat pancreatic islets: Influence of adenosine, angiotensin II and nitric oxide inhibition
Open this publication in new window or tab >>Local blood flow regulation in transplanted rat pancreatic islets: Influence of adenosine, angiotensin II and nitric oxide inhibition
2000 In: Transplantation, Vol. 70, no 2, p. 280-287Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-94769 (URN)
Available from: 2006-09-08 Created: 2006-09-08Bibliographically approved
2. Better vascular engraftment and function in pancreatic islets transplanted without prior culture
Open this publication in new window or tab >>Better vascular engraftment and function in pancreatic islets transplanted without prior culture
2005 In: Diabetologia, Vol. 48, no 3, p. 469-476Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-94770 (URN)
Available from: 2006-09-08 Created: 2006-09-08Bibliographically approved
3. Revascularization of transplanted pancreatic islets following culture with stimulators of angiogenesis
Open this publication in new window or tab >>Revascularization of transplanted pancreatic islets following culture with stimulators of angiogenesis
2006 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 82, no 3, p. 340-347Article in journal (Refereed) Published
Abstract [en]

Background. Insufficient revascularization of transplanted islets may result in chronic hypoxia and loss of islet function. This study investigated whether simple culture of islets with angiogenic substances before transplantation could improve graft revascularization.

Methods. Mouse islets were cultured with vascular endothelial growth factor (VEGF; 20 ng/ml), fibroblast growth factor 2 (FGF-2; 20 ng/ml) or matrix metalloproteinase 9 (MMP-9; 1 mu g/ml). Thereafter, 250 islets were implanted beneath the renal capsule of syngeneic C57Bl/6 mice. One month posttransplantation, blood flow (laser-Doppler flowmetry), oxygen tension (Clark microelectrodes), and vascular density were measured and correlated to graft function.

Results. Treatment of islets with VEGF during culture caused islet blood vessels to dilate, whereas FGF-2 treatment induced endothelial cell proliferation. However, the number of capillaries in both cases decreased during culture. When investigated one month posttransplantation, both VEGF and FGF-2 pretreated islets had similar or worse vascular engraftment when compared to transplanted control islets. MMP-9 pretreatment of islets increased vascular density, blood flow and oxygen tension within the grafts. Animals receiving MMP-9 pretreated islets returned, however, more slowly to normoglycemia than control animals, and performed worse than controls in a glucose tolerance test one month posttransplantation.

Conclusions. Treatment of islets during culture with VEGF or FGF-2 changed the islet vascular phenotype, but capillaries were still lost. Notably, the number of capillaries in the grafted islets one month posttransplantation was in all cases strikingly similar to that observed prior to transplantation. MMP-9 pretreatment of islets elicited an angiogenic response, which improved revascularization of the transplanted islets.

Keywords
islet transplantation, revascularization, vascular endothelial growth factor, fibroblast growth factor 2, matrix metalloproteinase 9
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-94771 (URN)10.1097/01.tp.0000229418.60236.87 (DOI)000239884800009 ()16906031 (PubMedID)
Available from: 2006-09-08 Created: 2006-09-08 Last updated: 2017-12-14Bibliographically approved
4. A low oxygenated subpopulation of pancreatic islets constitutes a functional reserve of endocrine cells
Open this publication in new window or tab >>A low oxygenated subpopulation of pancreatic islets constitutes a functional reserve of endocrine cells
2011 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 8, p. 2068-2075Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE The blood perfusion of pancreatic islets is highly variable and tightly regulated by the blood glucose concentration. Thus, oxygen levels are considered crucial for islet metabolism and function. Although islet oxygenation has been extensively studied in vitro, little is known about it in vivo. The current study aimed to investigate the oxygenation of the endocrine pancreas in vivo.

RESEARCH DESIGN AND METHODS The reductive metabolism of 2-nitroimidazoles, such as pimonidazole, has previously been extensively used in studies of oxygen metabolism both in vitro and in vivo. At tissue oxygen levels <10 mmHg, pimonidazole accumulates intracellularly and may thereafter be detected by means of immunohistochemistry. Islet oxygenation was investigated in normal, 60% partially pancreatectomized, as well as whole-pancreas–transplanted rats. Moreover, leucine-dependent protein biosynthesis was performed using autoradiography to correlate islet oxygenation with metabolic activity.

RESULTS In vivo, 20–25% of all islets in normal rats showed low oxygenation (pO2 <10 mmHg). Changes in the islet mass, by means of whole-pancreas transplantation, doubled the fraction of low-oxygenated islets in the endogenous pancreas of transplanted animals, whereas this fraction almost completely disappeared after a 60% partial pancreatectomy. Moreover, oxygenation was related to metabolism, since well-oxygenated islets in vivo had 50% higher leucine-dependent protein biosynthesis, which includes (pro)insulin biosynthesis.

CONCLUSIONS The current study suggests a novel subpopulation of dormant low-oxygenated islets, which seems to constitute a functional reserve of endocrine cells. This study establishes a novel perspective on the use of the endocrine pancreas in glucose homeostasis.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-94772 (URN)10.2337/db09-0877 (DOI)000293488100009 ()
Available from: 2006-09-08 Created: 2006-09-08 Last updated: 2017-12-14Bibliographically approved
5. Increased numbers of low oxygenated pancreatic islets after intraportal transplantation
Open this publication in new window or tab >>Increased numbers of low oxygenated pancreatic islets after intraportal transplantation
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-94773 (URN)
Available from: 2006-09-08 Created: 2006-09-08 Last updated: 2010-01-13Bibliographically approved

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