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Blood Flow Regulation and Inflammatory Response in Experimental Models of Diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 733
Keyword [en]
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
Identifiers
URN: urn:nbn:se:uu:diva-161807ISBN: 978-91-554-8247-3 (print)OAI: oai:DiVA.org:uu-161807DiVA: diva2:467835
Public defence
2012-02-10, B41, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2012-01-20 Created: 2011-11-17 Last updated: 2012-01-24Bibliographically approved
List of papers
1. Reversal of high pancreatic islet and white adipose tissue blood flow in type 2 diabetic GK rats by administration of the beta(3)-adrenoceptor inhibitor SR-59230A
Open this publication in new window or tab >>Reversal of high pancreatic islet and white adipose tissue blood flow in type 2 diabetic GK rats by administration of the beta(3)-adrenoceptor inhibitor SR-59230A
2009 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 297, no 2, E490-E494 p.Article in journal (Refereed) Published
Abstract [en]

Pettersson US, Henriksnas J, Jansson L. Reversal of high pancreatic islet and white adipose tissue blood flow in type 2 diabetic GK rats by administration of the beta(3)-adrenoceptor inhibitor SR-59230A. Am J Physiol Endocrinol Metab 297: E490-E494, 2009. First published June 2, 2009; doi: 10.1152/ajpendo.00140.2009.-Previous studies have shown that the Goto-Kakizaki (GK) rat, a nonobese type 2 diabetes model, has an increased white adipose tissue (WAT) and islet blood flow when compared with control rats. The aim of the study was to examine if these increased blood flow values in GK rats could be affected by the beta(3)-adrenoceptor antagonist SR-59230A. We measured organ blood flow with a microsphere technique 10 min after administration of SR-59230A (1 mg/kg body wt), or the corresponding volume of 0.9% NaCl solution (1 ml/kg body wt) in rats anaesthetized with thiobutabarbital. The GK rat had an increased blood flow in all intra-abdominal adipose tissue depots except for the sternal fat pad compared with Wistar-Furth (WF) rats. However, no differences were seen in the blood perfusion of subcutaneous white or brown adipose tissue. The blood flow was also increased in both the pancreas and in the islets in the GK rat compared with WF rats. SR-59230A treatment affected neither WAT nor pancreatic blood flow in WF rats. In GK rats, on the other hand, SR-59230A decreased both WAT and islet blood flow values to values similar to those seen in control WF rats. The whole pancreatic blood flow was not affected by SR-59230A administration in GK rats. Interestingly, the brown adipose tissue blood flow in GK rats increased after SR-59230A administration. These results suggest that beta(3)-adrenoceptors are involved in regulation of blood flow both in islet and in adipose tissue.

Keyword
microsphere, in vivo, Goto-Kakizaki
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-128366 (URN)10.1152/ajpendo.00140.2009 (DOI)000268252700024 ()
Available from: 2010-07-22 Created: 2010-07-20 Last updated: 2017-12-12Bibliographically approved
2. Two-week treatment with the β3-adrenoceptor antagonist SR59230A normalizes the increased pancreatic islet blood flow in type 2 diabetic GK rats
Open this publication in new window or tab >>Two-week treatment with the β3-adrenoceptor antagonist SR59230A normalizes the increased pancreatic islet blood flow in type 2 diabetic GK rats
2012 (English)In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 14, no 10, 960-962 p.Article in journal (Refereed) Published
Abstract [en]

The Goto-Kakizaki (GK) rat, a type 2 diabetes model, has increased pancreatic islet and white adipose tissue (WAT) blood flow, and this can be normalized by acute administration of SR59230A, a beta(3)-adrenoceptor antagonist. We now implanted osmotic pumps which allowed a constant release of saline or SR59230A (0.6 mg/kg x day) for 2 weeks. A decrease in islet blood flow was seen also after 2 weeks of continuous SR59230A treatment in the GK rat. However, no improvement in glucose tolerance was seen in the GK rats. Neither did SR59230A affect insulin secretion from isolated islets in vitro. WAT blood flow was not affected by the 2-week SR59230A treatment. Thus, the increased islet blood flow seen in the GK rat can be normalized for up to 2 weeks, which opens the possibilities for further studies on the long-term functional role on the islet blood flow increase in this type 2 diabetes model.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-161804 (URN)10.1111/j.1463-1326.2012.01616.x (DOI)000309453700011 ()22564532 (PubMedID)
Available from: 2011-12-19 Created: 2011-11-17 Last updated: 2017-12-08Bibliographically approved
3. Increased Recruitment but Impaired Function of Leukocytes during Inflammation in Mouse Models of Type 1 and Type 2 Diabetes
Open this publication in new window or tab >>Increased Recruitment but Impaired Function of Leukocytes during Inflammation in Mouse Models of Type 1 and Type 2 Diabetes
Show others...
2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, e22480- p.Article in journal (Refereed) Published
Abstract [en]

Background

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.

Conclusions/Significance

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-157036 (URN)10.1371/journal.pone.0022480 (DOI)000293172900037 ()
Available from: 2011-08-15 Created: 2011-08-15 Last updated: 2017-12-08Bibliographically approved
4. Female Mice are Protected against High-Fat Diet Induced Metabolic Syndrome and Increase the Regulatory T Cell Population in Adipose Tissue
Open this publication in new window or tab >>Female Mice are Protected against High-Fat Diet Induced Metabolic Syndrome and Increase the Regulatory T Cell Population in Adipose Tissue
Show others...
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, e46057- p.Article in journal (Refereed) Published
Abstract [en]

Sex differences in obesity-induced complications such as type 2 diabetes have been reported. The aim of the study was to pinpoint the mechanisms resulting in different outcome of female and male mice on a high-fat diet (HFD). Mice fed control or HFD were monitored for weight, blood glucose, and insulin for 14 weeks. Circulating chemokines, islet endocrine function and blood flow, as well as adipose tissue populations of macrophages and regulatory T-lymphocytes (T-reg) were thereafter assessed. Despite similar weight (43.8 +/- 1.0 and 40.2 +/- 1.5 g, respectively), male but not female mice developed hyperinsulinemia on HFD as previously described (2.5 +/- 0.7 and 0.5 +/- 0.1 pmol/l, respectively) consistent with glucose intolerance. Male mice also exhibited hypertrophic islets with intact function in terms of insulin release and blood perfusion. Low-grade, systemic inflammation was absent in obese female but present in obese male mice (IL-6 and mKC, males: 77.4 +/- 17 and 1795 +/- 563; females: 14.6 +/- 4.9 and 240 +/- 22 pg/ml), and the population of inflammatory macrophages was increased in intra-abdominal adipose tissues of high-fat-fed male but not female mice. In contrast, the anti-inflammatory T-reg cell population increased in the adipose tissue of female mice in response to weight gain, while the number decreased in high-fat-fed male mice. In conclusion, female mice are protected against HFD-induced metabolic changes while maintaining an anti-inflammatory environment in the intra-abdominal adipose tissue with expanded T-reg cell population, whereas HFD-fed male mice develop adipose tissue inflammation, glucose intolerance, hyperinsulinemia, and islet hypertrophy.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-161805 (URN)10.1371/journal.pone.0046057 (DOI)000309556100125 ()
Available from: 2011-12-19 Created: 2011-11-17 Last updated: 2017-12-08Bibliographically approved

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