Kronologi:
August 2011
Fundamentale karakteritika vedrørende diabetes hos danske rødmus bliver langt om længe præsenteret (en ekseptionel evne til at overleve en ubehandlet diabetes, samt at diabetiske rødmus vejer det samme som ikke-diabetiske - i det mindste det første halve år med sygdommen). Derudover kvantificeres den diagnostiske værdi af en simpel - ikke-invasiv - metode til at udpege individer med en høj risiko for at være diabetiske (eller modsat raske).
Schønecker B, Freimanis T, Sørensen IV.Diabetes in Danish Bank Voles (M. glareolus): Survivorship, Influence on Weight, and Evaluation of Polydipsia as a Screening Tool for Hyperglycaemia. PLoS One. 2011;6(8):e22893.
Abstract from PLoS One (Free text):
Background
Previous studies have concluded that the development of polydipsia (PD, a daily water intake ≥21 ml) among captive Danish bank voles, is associated with the development of a type 1 diabetes (T1D), based on findings of hyperglycaemia, glucosuria, ketonuria/-emia, lipemia, destroyed beta cells, and presence of autoantibodies against GAD65, IA-2, and insulin.
Aim and Methods
We retrospectively analysed data from two separate colonies of Danish bank voles in order to 1) estimate survivorship after onset of PD, 2) evaluate whether the weight of PD voles differed from non-PD voles, and, 3), evaluate a state of PD as a practical and non-invasive tool to screen for voles with a high probability of hypeglycaemia. In addition, we discuss regional differences related to the development of diabetes in Scandinavian bank voles and the relevance of the Ljungan virus as proposed etiological agent.
Results
We found that median survival after onset of PD is at least 91 days (lower/upper quartiles = 57/134 days) with a maximum recording of at least 404 days survivorship. The development of PD did not influence the weight of Danish bank voles. The measures of accuracy when using PD as predictor of hyperglycaemia, i.e. sensitivity, specificity, positive predictive value, and negative predictive value, equalled 69%, 97%, 89%, and 89%, respectively.
Conclusion
The relatively long survival of Danish PD bank voles suggests potentials for this model in future studies of the long-term complications of diabetes, of which some observations are mentioned. Data also indicates that diabetes in Danish bank is not associated with a higher body weight. Finally, the method of using measurements of daily water intake to screen for voles with a high probability of hyperglycaemia constitutes a considerable refinement when compared to the usual, invasive, methods.
May 2010
Isolerede ø-celler fra ikke-diabetiske svenske hun-rødmus ser ud til at være bedre end ø-celler fra hanner til at tilpasse deres (pro)insulin syntese til det omgivende niveau af glucose.
Blixt M, Niklasson B, Sandler S. Pancreatic islets of bank vole show signs of dysfunction after prolonged exposure to high glucose concentrations in vitro. J Endocrinol. 206(1), 47-54.
Abstract from PubMed:
Bank voles develop glucose intolerance/diabetes mellitus when kept in captivity. We have characterized beta-cell function of glucose intolerant/diabetic animals, and found that this animal model has features of both human type 1 and type 2 diabetes. The aim of this study was to study the functional alterations of islets isolated from glucose tolerant bank voles after a prolonged exposure to various glucose concentrations in vitro. For this purpose, pancreatic islets from normal (glucose tolerant) male and female bank voles were cultured at different glucose concentrations (5.6, 11.1 (control), or 28 mM) whereupon islet functions were examined. Overall, islet insulin output was lowered at 5.6 mM glucose, and similar to control, or enhanced after culture in 28 mM glucose. High glucose culture led to decreased insulin contents, but there was no change in islet DNA content and in morphological assessments of cell death, with the latter findings suggesting that the so-called glucotoxicity had not evolved. A slight gender difference was observed in that islets isolated from females exhibited a glucose-regulated (pro)insulin biosynthesis rate and insulin gene expression. In conclusion, we have found that islets isolated from female and male bank voles are affected by glucose concentrations in vitro in that some signs of dysfunction were observed upon high glucose exposure. A minor gender difference was observed suggesting that the islets of the females may more readily adapt to the elevated glucose concentration than islets of the male bank voles. It could be that these in vitro gender differences observed may represent a mechanism underlying the gender difference in diabetes development observed among bank voles.
June 2009
Isolerede betaceller fra svenske rødmus minder mere om isolerede humane betaceller i deres respons til cytokiner end de gør om isolerede betaceller fra rotter og mus´respons..
Blixt M, Niklasson B, Sandler S. Suppression of bank vole pancreatic islet function by proinflammatory cytokines. Mol Cell Endocrinol, 305 (2009), 1-5.
Abstract from PubMed:
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 beta-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-1beta (25U/ml) alone or in combination with hTNF-alpha (1000U/ml)+mIFN-gamma (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.
Marts 2009
Epilepsi-lignende anfald (seizures) bliver beskrevet hos danske rødmus, for så vidt de er fødte i fangenskab. Med andre ord, nok en ny potentiel dyremodel baseret på rødmus.
Schønecker B. Handling-induced tonic(clonic seizures in captive born bank voles (Clethrionomys glareolus). Applied Animal Behaviour Science 118 (2009) pp. 84-90
Abstract from Applied Animal Behaviour Science:
Handling-induced seizures observed among 23 of 333 captive born bank voles was characterized by tonic/clonic convulsions, occasionally accompanied by an apparent loss of consciousness. Seizures were never observed among wild caught voles (N = 71). Median age for first observation of seizures was 157 days. Median latency to onset following mild handling was 12.6 s and median time to resumption of normal behaviour after arrest of convulsions was 28.05 s. Consecutive daily tests to provoke seizures indicated that more seizures were elicitated on the first day of testing (25.6%) compared to the following 4 test-days (8.7%). Incidence of seizure prone (SP) voles declined from 10.2% in F1 to 5.1% in F2 with no sex bias. A possible explanation for this decline could be that all F1 voles (N = 118) descended from non-stereotyping (N-Ster) parents where the majority of F2 voles (n = 138) descended from two stereotyping (Ster) parents: incidence of SP voles were five times higher among offspring from N-Ster parents than Ster parents (10–11% vs. 2.2%; p < 0.0001). However, the development of stereotypic behaviours did not affect seizure proneness. Roughly one-third of the captive born voles developed diabetes. However, the disease did not affect seizure proneness. SP voles were distributed among the litters (n = 60) in accordance with the negative binomial distribution, which indicate a “lumped” distribution. The proportion of SP voles which had SP full siblings, was significantly higher than the proportion of non-SP voles having SP full siblings (15/23 vs. 30/310, p = 0.0001), which, taken together, suggest the possibility for future establishment of lines differing in seizure proneness.
Juli 2007
Isolerede Betaceller fra Svenske rødmus i fangenskab antyder udvikling af en type 2 lignende diabetes. Frekvensen af diabetes blandt Svenske rødmus holdt i fangenskab ser tillige ud til at være cirka det halve af hvad der normalt observeres blandt Danske rødmus.
Blixt M, Niklasson B, Sandler S. Characterization of beta-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. Gen Comp Endocrinol. 2007 Oct-Dec;154(1-3):41-7
Abstract fra PubMed:
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 beta-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 beta-cells.
Oktober 2006
Skal slægtsnavnet "Clethrionomys" erstattes af "Myodes"?
Ifølge Wikipedia (det brugerredigerede online leksikon) blev der i 2003 holdt en konference i Rusland hvorunder en artikel (Carleton, M.D., Musser, G.G., Pavlinov, L.Y.a.) blev præsenteret som advokerer for at rødmusens slægtsnavn (Clethrionomys) retteligen burde være Myodes istedet for det godt indarbejdede Clethrionomys. I 2005 bidrog Musser and Carleton, efter Wikipedias oplysninger, med et kapitel om gnavere i "Mammal Species of the World" hvorunder slægtsnavnet Myodes også skulle være nævnt som det mest passende ifølge de nomenklaturiske regler og en kort Google search viser at denne tanke faktisk allerede er nævnt i bogen "Voles (Microtinae)" af I.M. Gromov fra 1992 (side 13 i forordet).
Det bliver spændende at se hvad den historie ender med og jeg kan konstatere at ved siden af Wikipedia's artikel er også andre online ressourcer begyndt at benævne gnavere af slægten Clethrionomys med Myodes (Se eksempelvis her). Det står imidlertid stadig idag (3. juni, 2007) 291 - 0 i Clethrionomys' favør hvis man søger efter artikler med ordene "Clethrionomys" og "Myodes" i titlen hos PubMed så et reelt navneskifte blandt forskere har nok lange udsigter - hvis det nogensinde kommer. Pubmed scoren er dags dato (25. Juni, 2008) 297 - 7 i "Clethrionomys"'s favør, hvilket gør det muligt at udregne videnskabens fremmarch indenfor dette nærmest mikroskopiske felt til hele 13 videnskabelige artikler årligt (nøj manner..).
Juli 2006
Kan bestandssvingningerne i nordlige populationer af rødmus og lemminger forklares med viral infektion?
Niklasson B, Nyholm E, Feinstein RE, Samsioe A, Hornfeldt B. Diabetes and myocarditis in voles and lemmings at cyclic peak densities-induced by Ljungan virus? Oecologia. 2006 Jul 26; [Epub ahead of print]
Abstract fra PubMed:
Although it is well-documented from theoretical studies that pathogens have the capacity to generate cycles, the occurrence and role of pathogens and disease have been poorly empirically studied in cyclic voles and lemmings. In screening for the occurrence of disease in cyclic vole and lemming populations, we found that a high proportion of live-trapped Clethrionomys glareolus, C. rufocanus, Microtus agrestis and Lemmus lemmus at high collective peak density, shortly before the decline, suffered from diabetes or myocarditis in northern Scandinavia. A high frequency of animals had abnormal blood glucose (BG) levels at the time of trapping (5-33%). In contrast, C. rufocanus individuals tested at a much lower overall density, and at an earlier stage relative to the decline in the following cycle, showed normal BG concentrations. However, a high proportion (43%) of a sample of these individuals kept in captivity developed clinical diabetes within five weeks, as determined by BG levels and a glucose tolerance test performed at that later time. A new picornavirus isolated from the rodents, Ljungan virus (LV), was assumed to cause the diseases, as LV-induced diabetes and myocarditis, as well as encephalitis and fetal deaths, were observed in laboratory mice. We hypothesize that LV infection significantly affects morbidity and mortality rates in the wild, either directly or indirectly, by predisposing the rodents to predation, and is at least involved in causing the regular, rapid population declines of these cyclic voles and lemmings. Increased stress at peak densities is thought to be an important trigger for the development of disease, as the occurrence of disease in laboratory mice has been found to be triggered by introducing stress to LV-infected animals.
November 2003
Svenske rødmus bliver også diabetiske efter en tid i fangenskab:
Niklasson B, Hornfeldt B, Nyholm E, Niedrig M, Donoso-Mantke O, Gelderblom HR, Lernmark A. Type 1 diabetes in Swedish bank voles (Clethrionomys glareolus): signs of disease in both colonized and wild cyclic populations at peak density. Ann N Y Acad Sci. 2003 Nov;1005:170-5.
Abstract fra PubMed:
Colonized bank voles (Clethrionomys glareolus) originating from Sweden developed type 1 diabetes. Animals became polydipsic, glucosuric, and hyperglycemic and gradually developed a lethal ketoacidosis. Pancreas in animals with end-stage disease showed total destruction of islet cells. Interestingly, also a high proportion of wild bank voles in cyclic populations that were trapped at (or close to) the cyclic population density peak frequently showed high blood glucose levels and pathological glucose tolerance test. Extensive islet destruction was not seen in wild bank voles at the time of capture, but did develop in some of the animals over a time period of two months. Diabetes in both colonized and wild bank voles was associated with Ljungan virus (LV). LV could be isolated from the pancreas of diabetic bank voles and antigen detected at the site of tissue damage by immunohistochemistry. In addition, picornavirus-like particles were visualized in the islets of diabetic voles using thin-section transmission electron microscopy.
Maj 2003
Metoden med at bruge "Stress" som modulator af diabetesfrekvensen hos rødmus i fangenskab demonstreres for første gang af rent Dansk team:
Freimanis T,
Heller KE,
Schonecker B,
Bildsoe M. Effects of postnatal stress on the development of type 1 diabetes in bank voles (Clethrionomys glareolus). Int J Exp Diabesity Res. 2003 Jan-Mar;4(1):21-5.
Zoological Institute, University of Copenhagen, Copenhagen, Denmark.
Abstract fra PubMed:
Wild bank voles (Clethrionomys glareolus) kept in the laboratory under barren housing conditions develop high incidences of type 1 diabetes mellitus due to beta cell-specific lysis in association with the appearance of GAD65, IA-2, and insulin autoantibodies. Wild-caught and immediately analyzed voles show no histological signs of diabetes, and the disease may therefore be induced by circumstances related to the housing of the animals in captivity. We tested the possibility that postnatal stress by either maternal separation or water immersion at different intervals would induce diabetes in adult bank voles. We found that low-frequent stress during the first 21 days of life increases, whereas high-frequent stress markedly reduces, the incidence of type 1 diabetes in adulthood. These results differentiate the role of early-experienced stress on subsequent type 1 diabetes development and emphasize that the bank vole may serve as a useful new animal model for the disease.
Maj 2003
Diagnosen Type 1 diabetes konfirmeret hos Danske rødmus, holdt en tid i fangenskab:
Niklasson B, Heller KE, Schonecker B, Bildsoe M, Daniels T, Hampe CS, Widlund P, Simonson WT, Schaefer JB, Rutledge E, Bekris L, Lindberg AM, Johansson S, Ortqvist E, Persson B, Lernmark A. Development of type 1 diabetes in wild bank voles associated with islet autoantibodies and the novel ljungan virus. Int J Exp Diabesity Res. 2003 Jan-Mar;4(1):35-44.
Abstract fra PubMed:
Wild bank voles (Clethrionomys glareolus) may develop diabetes in laboratory captivity. The aim of this study was to test whether bank voles develop type 1 diabetes in association with Ljungan virus. Two groups of bank voles were analyzed for diabetes, pancreas histology, autoantibodies to glutamic acid decarboxylase (GAD65), IA-2, and insulin by standardized radioligand-binding assays as well as antibodies to in vitro transcribed and translated Ljungan virus antigens. Group A represented 101 trapped bank voles, which were screened for diabetes when euthanized within 24 hours of capture. Group B represented 67 bank voles, which were trapped and kept in the laboratory for 1 month before being euthanized. Group A bank voles did not have diabetes. Bank voles in group B (22/67; 33%) developed diabetes due to specific lysis of pancreatic islet beta cells. Compared to nondiabetic group B bank voles, diabetic animals had increased levels of GAD65 (P < .0001), IA-2 (P < .0001), and insulin (P = .03) autoantibodies. Affected islets stained positive for Ljungan virus, a novel picorna virus isolated from bank voles. Ljungan virus inoculation of nondiabetic wild bank voles induced beta-cell lysis. Compared to group A bank voles, Ljungan virus antibodies were increased in both nondiabetic (P < .0001) and diabetic (P = .0015) group B bank voles. Levels of Ljungan virus antibodies were also increased in young age at onset of newly diagnosed type 1 diabetes in children (P < .01). These findings support the hypothesis that the development of type 1 diabetes in captured wild bank voles is associated with Ljungan virus. It is speculated that bank voles may have a possible zoonotic role as a reservoir and vector for virus that may contribute to the incidence of type 1 diabetes in humans.
Maj 2003
Selv tidsskriftet Science synes resultaterne er værd at nævne:
Science 9 May 2003:
Vol. 300. no. 5621, p. 867
Editors' Choice: Highlights of the recent literature
Infection with specific strains of virus and autoimmunity are each implicated in the destruction of insulin-producing cells of the pancreas that leads, eventually, to the development of type 1 diabetes.
In a study of wild bank voles, Niklasson et al. found evidence for a direct association between type 1 diabetes and infection by a novel picorna virus. Although no diabetes could be detected in recently captured voles, one-third of those kept in captivity developed elevated blood glucose levels and showed destruction of cells by 1 month. Diabetic animals developed elevated antibodies to the new virus, as well as to proteins familiar as potential autoimmune targets in human diabetes. Inoculation of nondiabetic voles with the virus correlated with the onset of varying degrees of cell destruction and viral presence in the pancreatic islets, suggesting a direct role for the virus in the disease. A preliminary study of children with type 1 diabetes also revealed a modest increase in antibodies to the same picorna virus, suggesting that it might contribute to some cases of human type 1 diabetes, possibly as a result of zoonosis from this rodent reservoir. -- SJS
Exp. Diabesity Res. 4, 35 (2003).
2003
Stereotyperende rødmus udviser kønsforskel overfor Serotonin: Hunner potentielle modeldyr for depression/anxiety?
Schoenecker B, Heller K.E. (2003). Stimulation of serotonin (5-HT) activity reduces spontaneous? stereotypies in female but not in male bank voles (Clethrionomys glareolus). Stereotyping female voles as a new animal model for human anxiety and mood disorders? Appl. Anim. Behav. Sci., vol. 80 (2); 161-170
Zoological Institute, University of Copenhagen, Tagensvej 16, DK-2200 N, Copenhagen, Denmark
Abstract:
Spontaneously stereotyping female and male bank voles were injected daily (except on days assigned for monitoring behaviour) during 3 weeks with placebo, the neurolepticum clozapine or the SSRI antidepressant citalopram. Clozapine blocks dopamine (DA) receptors and acts as a partial serotonin (5-HT) antagonist, while citalopram is a specific 5-HT agonist. Stereotypies in both sexes were left unaffected by clozapine treatment, but citalopram markedly reduced stereotypy levels in females. Animal stereotypies have been widely used in models to provide insight into the underlying pathophysiological processes in human mental disturbances. The present findings highlight the importance of examining sex as a significant variable in evaluating responses to pharmacotherapy, and the demonstrated effect of citalopram indicates that stereotyping female bank voles may be useful in new animal models for human anxiety and mood disorders.
2001
Serotonin dæmper den stereotypiske adfærd som rødmus typisk udviser under formodet stress:
Schoenecker B, Heller KE. (2001). The involvement of dopamine (DA) and serotonin (5-HT) in stress-induced stereotypies in bank voles (Clethrionomys glareolus). Appl Anim Behav Sci.;73(4):311-319.
Zoological Institute, University of Copenhagen, Tagensvej 16, DK-2200 N, Copenhagen, Denmark Abstract from PubMed:
In order to clarify the dependency of stress-induced stereotypies on dopamine (DA) and serotonin (5-HT) functioning, undisturbed and acutely stressed stereotyping bank voles were treated during 3 weeks with the commonly used human atypical neurolepticum clozapine and the SSRI antidepressant citalopram. Clozapine blocks DA receptors (D sub (4)) and acts as a partial 5-HT antagonist (5-HT sub (2) receptors), while citalopram increases 5-HT transmitter activity. Levels of stereotypies were quantified under undisturbed conditions during the treatment period and immediately after the acute stress of handling and injections. It was demonstrated that stereotypies are markedly increased after acute stress and that citalopram effectively mitigates this stress effect. Stereotypies under undisturbed conditions were left unaffected by both clozapine and citalopram treatments.It is suggested that stress-induced increases in stereotypies are more dependent on 5-HT than DA functioning.
Juli 2000
Første indikation af at rødmus i fangenskab kan udvikle diabetes mellitus:
Schoenecker B,
Heller KE,
Freimanis T. Development of stereotypies and polydipsia in wild caught bank voles (Clethrionomys glareolus) and their laboratory-bred offspring. Is polydipsia a symptom of diabetes mellitus? Appl Anim Behav Sci. 2000 Jul 1;68(4):349-357.
Zoological Institute, University of Copenhagen, Tagensvej 16, DK-2200 N, Copenhagen, Denmark Abstract fra PubMed:
The development of stereotypies and polydipsia was studied in wild caught bank voles (P: n=92) and their laboratory-bred offspring (F1: n=248). All animals were kept isolated in barren cages in the laboratory. In the P generation, no individuals developed stereotypies, but 22% developed polydipsia (>21 ml/day water intake against normally 10 ml/day). Polydipsia was more frequent among males (34%) than females (13%). In F1, 30% developed locomotor stereotypies alone, 21% showed polydipsia alone, and, additionally, 7% developed both stereotypies and polydipsia. Fewer males than females developed stereotypies (23% vs. 38%), whereas polydipsia was more frequent in males than in females (30% vs. 11%). The occurrence and distribution of polydipsia among sexes were the same in F1 and P. The distribution of different types of stereotypies in stereotyping voles were backward somersaulting (BS, 80%), high-speed jumping (JUMP, 29%), pacing following a fixed route (PF, 12%) and windscreen wiper movement (WIN, 5%). Some individuals (10%) showed two or more different types of stereotypies. The average age for developing stereotypies was 96 days while polydipsia was registered at the age of 63 days in both sexes. Voles showing both polydipsia and stereotypies developed polydipsia later (79 days) than polydipsic voles not showing stereotypies. This difference was especially pronounced in stereotyping females in which the occurrence of polydipsia was postponed to the age of 114 days. Polydipsic voles were tested positive for glucosuria indicating that polydipsia could be a symptom of diabetes mellitus. It is suggested that the development of stereotypies and polydipsia among bank voles in the laboratory are the results of frustration and prolonged stress. Stereotypies seem to depend on frustrative experiences early in life, while polydipsia may be related to diabetes mellitus caused by the experience of prolonged stress. Moreover, circumstances related to the development of stereotypies may be adaptive by reducing the risks of prolonged stress, including the development of fatal polydipsia.
Sidst opdateret den 21. august, 2011 |