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A low oxygenated subpopulation of pancreatic islets constitutes a functional reserve of endocrine cells
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
2011 (engelsk)Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, nr 8, s. 2068-2075Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2011. Vol. 60, nr 8, s. 2068-2075
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-94772DOI: 10.2337/db09-0877ISI: 000293488100009OAI: oai:DiVA.org:uu-94772DiVA, id: diva2:168747
Tilgjengelig fra: 2006-09-08 Laget: 2006-09-08 Sist oppdatert: 2017-12-14bibliografisk kontrollert
Inngår i avhandling
1. The Microvasculature of Endogenous and Transplanted Pancreatic Islets: Blood Perfusion, Oxygenation and Islet Endocrine Function
Åpne denne publikasjonen i ny fane eller vindu >>The Microvasculature of Endogenous and Transplanted Pancreatic Islets: Blood Perfusion, Oxygenation and Islet Endocrine Function
2006 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2006. s. 83
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 167
Emneord
Cell biology, diabetes mellitus, pancreatic islets, islet transplantation, vascular engraftment, islet microcirculation, oxygenation, blood flow, protein biosynthesis, Cellbiologi
Identifikatorer
urn:nbn:se:uu:diva-7107 (URN)91-554-6633-8 (ISBN)
Disputas
2006-09-30, B22, Biomedicum, Husargatan 3, Uppsala, 09:15
Opponent
Veileder
Tilgjengelig fra: 2006-09-08 Laget: 2006-09-08bibliografisk kontrollert

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