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The bank vole (Myodes glareolus) – a novel animal model for the study of diabetes mellitus
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Stellan Sandler)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The bank vole (Microtus arvalis) develops glucose intolerance both when kept in captivity and in the wild state. Glucose intolerant bank voles kept in captivity exhibited polydipsia, polyuria, hyperglycemia, hyperinsulinemia, islet autoantibodies and a markedly changed islet structure resembling so–called hydropic degeneration. Islets showing hydropic degeneration have reduced β–cell mass. However, the relative islet size to total pancreas area was not changed.

Pancreatic islet isolated from glucose intolerant bank voles had an altered islet function showing signs of being exposed to an increased functional demand on their β–cells. Also, islets from male bank voles seem more affected than the islets from females. Islets isolated from glucose tolerant male bank voles cultured for 5 days at 28 mM glucose did not reveal any change in insulin gene expression or insulin biosynthesis rate. However, islets from female bank voles displayed a glucose concentration dependent response. This suggests that there is gender difference in that, islets of female more easily than islets of males adapt to elevated glucose concentration. Furthermore, islets isolated from glucose tolerant males had reduced insulin gene expression after exposure to proinflammatory cytokines for 48 hrs. This effect seemed to be NO-independent since only a minor elevation of nitrite accumulation in the medium was seen, and the use of iNOS inhibitor could not counteract the cytokine effect. The observed response seen in bank vole islets upon exposure to various glucose concentrations or proinflammatory cytokines is similar to those seen in studies of human islets. The bank vole may therefore represent a novel animal model for the study of diabetes. An unresolved issue is the role of the Ljungan virus which is found in the bank vole colony.

Bank voles developing glucose intolerance display features of both human type 1 and type 2 diabetes, where environmental factors seems to play an important role as determinant. Our findings suggest that bank voles bred in the laboratory may develop more of a type 2 diabetes. However, bank voles caught in nature instead may rather develop a type 1 form of the disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2010. , p. 49
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 559
Keywords [en]
Bank vole, pancreatic islets, diabetes mellitus, hydropic degeneration, proinflammatory cytokine
National Category
Endocrinology and Diabetes Endocrinology and Diabetes
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-122715ISBN: 978-91-554-7806-3 (print)OAI: oai:DiVA.org:uu-122715DiVA, id: diva2:311167
Public defence
2010-06-03, MCB, B7:101a, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2010-05-11 Created: 2010-04-16 Last updated: 2010-05-24
List of papers
1. Characterization of β-cell function of pancreatic islets isolated from bank voles developing glucose intolerance/diabetes: an animal model showing features of both type 1 and type 2 diabetes mellitus, and a possible role of the Ljungan virus
Open this publication in new window or tab >>Characterization of β-cell function of pancreatic islets isolated from bank voles developing glucose intolerance/diabetes: an animal model showing features of both type 1 and type 2 diabetes mellitus, and a possible role of the Ljungan virus
2007 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 154, no 1-3, p. 41-47Article in journal (Refereed) Published
Abstract [en]

Bank voles (Clethrionomys glareolus) kept in captivity develop diabetes mellitus to a significant extent. Also in wild bank voles, elevated blood glucose has been observed. A newly isolated picornavirus named Ljungan virus (LV) has been found in the pancreas of these bank voles. Moreover, LV infection in combination with environmental factors may cause glucose intolerance/diabetes (GINT/D) in normal mice. The aim of the present study was to investigate the functional characteristics of pancreatic islets, isolated from bank voles, bred in the laboratory but considered LV infected. About 20% of all males and females were classified as GINT/D following a glucose tolerance test. Of these animals the majority had become diabetic by 20 weeks of age, with a tendency towards an earlier onset in the males. GINT/D animals had increased serum insulin levels. Islets were tested on the day of isolation (day 0) and after 1 week of culture for their insulin content and their capacity to synthesize (pro)insulin, secrete insulin and metabolize glucose. Functional differences could be observed between normal and GINT/D animals as well as between genders. An elevated basal insulin secretion was observed on day 0 indicating β-cell dysfunction among islets isolated from diabetic males. In vitro culture could reverse some functional changes. The increased serum insulin level and the increased basal islet insulin secretion may suggest that the animals had developed a type 2 diabetes-like condition. It is likely that the putative stress imposed in the laboratory, maybe in combination with LV infection, can lead to an increased functional demand on the β-cells.

Keywords
Bank vole, Clethrionomys glareolus, Diabetes mellitus, Insulin release, Ljungan virus, Pancreatic islets
National Category
Medical and Health Sciences
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-17170 (URN)10.1016/j.ygcen.2007.06.019 (DOI)000249641100006 ()17686482 (PubMedID)
Available from: 2008-06-17 Created: 2008-06-17 Last updated: 2017-12-08Bibliographically approved
2. Suppression of bank vole pancreatic islet function by proinflammatory cytokines
Open this publication in new window or tab >>Suppression of bank vole pancreatic islet function by proinflammatory cytokines
2009 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 305, no 1-2, p. 1-5Article in journal (Refereed) Published
Abstract [en]

Bank voles kept in captivity may develop diabetes. We recently characterized beta-cell function of pancreatic islets from normal and glucose intolerant/diabetic bank voles. These animals had features of both human type 1 and type 2 diabetes. Cytokines may impair β-cell function in both types of diabetes. Presently, we studied how pancreatic islets isolated from normal, i.e. glucose tolerant bank voles are affected by proinflammatory cytokines in vitro. Islets were exposed to hIL-1β (25U/ml) alone or in combination with hTNF-α (1000U/ml)+mIFN-γ (1000U/ml) for 48h, whereupon islet functions were assessed. Cytokines markedly reduced insulin gene expression and the (pro)insulin biosynthesis rate, which was accompanied by a profound depletion of the islet insulin content. The cytokines did not affect the culture medium insulin accumulation and the glucose oxidation rate, but caused a modest increase in medium nitrite, an indicator of nitric oxide (NO) generation. Cytokine-induced decrease in islet insulin content was not prevented by the preferential inducible NO synthase inhibitor aminoguanidine. These findings suggest that the reduction in islet insulin content is not attributed to enhanced exocytosis or related to altered glucose metabolism, but is rather due to a decline in insulin production. The suppressive effects of islet functions elicited by cytokines seem to be mediated by an NO-independent mechanism. In relation to previous studies on cytokine effects on islets from various species, the bank vole islets show a pattern which more resembles human islets than rat or murine islets.

Keywords
Bank vole, pancreatic islet, proinflammatory cytokines, interleukin-1β, tumor necrosis factor-α, interferon-γ
National Category
Medical and Health Sciences
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-122700 (URN)10.1016/j.mce.2009.02.010 (DOI)000266750200001 ()19433255 (PubMedID)
Available from: 2010-04-16 Created: 2010-04-16 Last updated: 2017-12-12Bibliographically approved
3. Pancreatic islets of bank vole show signs of dysfunction after prolonged exposure to high glucose in vitro.
Open this publication in new window or tab >>Pancreatic islets of bank vole show signs of dysfunction after prolonged exposure to high glucose in vitro.
(English)Manuscript (preprint) (Other academic)
Keywords
Bank vole, pancreatic islet, glucose culture, diabetes mellitus
National Category
Endocrinology and Diabetes Endocrinology and Diabetes
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-122713 (URN)
Available from: 2010-04-16 Created: 2010-04-16 Last updated: 2010-05-12
4. Morphologic investigation of the endocrine pancreas in diabetic bank voles indicates a type 2 diabetes profile.
Open this publication in new window or tab >>Morphologic investigation of the endocrine pancreas in diabetic bank voles indicates a type 2 diabetes profile.
(English)Manuscript (preprint) (Other academic)
Keywords
Bank vole, hydropic degeneration, pancreatic islet, hyperinsulinemia, diabetes mellitus
National Category
Endocrinology and Diabetes Endocrinology and Diabetes
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-122714 (URN)
Available from: 2010-04-16 Created: 2010-04-16 Last updated: 2010-05-12

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