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Increased Recruitment but Impaired Function of Leukocytes during Inflammation in Mouse Models of Type 1 and Type 2 Diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2011 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 6, no 7, e22480- p.Article in journal (Refereed) Published
Abstract [en]


Patients suffering from diabetes show defective bacterial clearance. This study investigates the effects of elevated plasma glucose levels during diabetes on leukocyte recruitment and function in established models of inflammation.

Methodology/Principal Findings

Diabetes was induced in C57Bl/6 mice by intravenous alloxan (causing severe hyperglycemia), or by high fat diet (moderate hyperglycemia). Leukocyte recruitment was studied in anaesthetized mice using intravital microscopy of exposed cremaster muscles, where numbers of rolling, adherent and emigrated leukocytes were quantified before and during exposure to the inflammatory chemokine MIP-2 (0.5 nM). During basal conditions, prior to addition of chemokine, the adherent and emigrated leukocytes were increased in both alloxan- (62±18% and 85±21%, respectively) and high fat diet-induced (77±25% and 86±17%, respectively) diabetes compared to control mice. MIP-2 induced leukocyte emigration in all groups, albeit significantly more cells emigrated in alloxan-treated mice (15.3±1.0) compared to control (8.0±1.1) mice. Bacterial clearance was followed for 10 days after subcutaneous injection of bioluminescent S. aureus using non-invasive IVIS imaging, and the inflammatory response was assessed by Myeloperoxidase-ELISA and confocal imaging. The phagocytic ability of leukocytes was assessed using LPS-coated fluorescent beads and flow cytometry. Despite efficient leukocyte recruitment, alloxan-treated mice demonstrated an impaired ability to clear bacterial infection, which we found correlated to a 50% decreased phagocytic ability of leukocytes in diabetic mice.


These results indicate that reduced ability to clear bacterial infections observed during experimentally induced diabetes is not due to reduced leukocyte recruitment since sustained hyperglycemia results in increased levels of adherent and emigrated leukocytes in mouse models of type 1 and type 2 diabetes. Instead, decreased phagocytic ability observed for leukocytes isolated from diabetic mice might account for the impaired bacterial clearance.

Place, publisher, year, edition, pages
2011. Vol. 6, no 7, e22480- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-157036DOI: 10.1371/journal.pone.0022480ISI: 000293172900037OAI: oai:DiVA.org:uu-157036DiVA: diva2:434479
Available from: 2011-08-15 Created: 2011-08-15 Last updated: 2014-10-29Bibliographically approved
In thesis
1. Blood Flow Regulation and Inflammatory Response in Experimental Models of Diabetes
Open this publication in new window or tab >>Blood Flow Regulation and Inflammatory Response in Experimental Models of Diabetes
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 2 diabetes is caused by defect pancreatic islet β-cells together with peripheral insulin resistance. The disease is often accompanied by obesity with associated low-grade visceral adipose tissue inflammation, which contributes to insulin resistance. As a consequence of, and a possible compensation for the increased insulin demand, blood flow to the pancreatic islets is increased in animal models of diabetes. This increased blood perfusion might with time affect the vascular network as well as β-cells within the islets.

This thesis investigates the role of changes of blood perfusion in pancreatic islets and adipose tissues, as well as the recruitment to and composition of leukocyte subpopulations in insulin-sensitive tissues in experimental models of diabetes.

Blood flow measurements in islets and adipose tissues of rats and mice were performed using the microsphere technique, while leukocyte recruitment was studied in the mouse cremaster muscle using intravital microscopy. Increased islet blood flow was observed in the GK rat model of type 2 diabetes, which was decreased by acute as well as continuous 2-week inhibition of β3-adrenoceptors without affecting plasma insulin concentrations. Increased inflammatory leukocyte recruitment was observed in both alloxan-induced and high-fat diet-induced diabetes. However, an impaired bacterial clearance was observed in diabetic mice, which was due to impaired phagocytosis. A gender difference was detected in mice fed a high-fat diet, since obese female mice did not show increased levels of pro-inflammatory circulatory markers or inflammatory leukocytes in the adipose tissue. The main effector cell in the adipose tissue inflammation in high-fat-fed male mice seemed to be the pro-inflammatory macrophage. The Treg population in adipose tissue was increased in female mice, but remained unchanged in male mice on high-fat diet.

In conclusion, increased islet blood flow in type 2 diabetes could be reversed by β3-adrenoceptor inhibition, which may maintain islet function. The diabetes-associated hyperglycemia activated leukocytes but impaired their phagocytic ability. High-fat-fed female mice showed less peripheral inflammation due to a smaller number of recruited inflammatory macrophages and a high-fat diet-induced Treg population in intra-abdominal adipose tissues.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 60 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 733
Islets, beta-cells, pancreas, inflammation, obesity, adipose tissue, rats, mice, leukocytes, beta3-adrenoceptors
National Category
Physiology Cell and Molecular Biology
Research subject
Medical Cell Biology
urn:nbn:se:uu:diva-161807 (URN)978-91-554-8247-3 (ISBN)
Public defence
2012-02-10, B41, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Available from: 2012-01-20 Created: 2011-11-17 Last updated: 2012-01-24Bibliographically approved

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Pettersson, Ulrika SofiaChristoffersson, GustafMassena, SaraAhl, DavidJansson, LeifPhillipson, Mia
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