Development of hyperglycemia and diabetes in captive Polish bank voles
Highlights
► Captive Polish bank voles can develop diabetes resembling human type 1 and type 2. ► Inherited factors increase proneness to develop diabetes in this model. ► Three times maternal deprivation may decrease the risk of diabetes. ► Impaired fasting glucose is associated with hyperinsulinemia, enlarged kidneys, lungs and liver.
Introduction
Diabetes mellitus (DM) is a group of metabolic disorders characterized by elevated serum glucose level, accompanied by many non-specific symptoms, such as polyuria or polydipsia [18]. Type 1 diabetes (T1DM) results from decrease or lack of insulin production due to autoimmune destruction of β-cells [1]. Type 2 diabetes (T2DM), the most frequent type of diabetes, is preceded by a progressive insensitivity to insulin [61]. Insulin resistance is usually followed by insufficient insulin secretion due to exhaustion and death of β-cells, which later results in complete lack of endogenous hormone [11].
The autoimmune response leading to T1DM can be influenced by genetic susceptibility and environmental factors like stress, diet, or viral infections [43]. Possible contribution of enteroviruses, retroviruses, coxsackie viruses, rubella viruses, cytomegaloviruses, or Epstein–Barr viruses in induction of diabetes in animal models and human populations has been repeatedly suggested [26], [45], [60]. Viruses can trigger destruction of insulin-producing cells in animals, acting via different mechanisms, including a direct β-cell lysis, bystander activation of autoreactive T cells, loss of regulatory T cells, and molecular mimicry [57]. On the other hand, stress is supposed to precipitate diabetes, increase the insulin resistance and trigger or promote the progress of diabetes-related autoimmunity [51]. Accordingly, it was demonstrated that psychological stress in human infants is associated with significantly increased frequencies of T1DM [27]. Also in the BB rats, the model of T1DM, psychological stress such as restraint, rotation, and crowding, independent of weight gain or food intake, significantly reduced the average age of onset and increased the prevalence of diabetes [16].
The most commonly used models of diabetes are mice or rats injected with streptozotocin (STZ) or alloxan. Depending on the dose and time-course of treatment the generated pathology resembles T1DM or T2DM [46]. The genetic models include NOD (Non-obese Diabetic), db/db, ob/ob, and NZO (New Zealand Obese) mice or BB, ZDF (Zucker Diabetic Fatty), and Goto-Kakizaki rats. These strains demonstrate various degrees of hyperglycemia and insulinemia, accompanied or not by obesity [30], [44]. Some models of diabetes have been developed after observation that animals taken from their natural environment develop diabetes mellitus in laboratory. Among these are the sand rat (Psammomys obesus), the spiny mouse (Acomys cahirinus), the tuco-tuco (Ctenomys talaru), the Chinese hamster (Cricetulus griseus), the Djungarian hamster (Phodopus sungorus), and the South African hamster (Mystromys albicaudatus) [34], [53].
Studies performed in Danish populations of bank voles (Myodes glareolus) showed that approximately 20% of captive individuals displayed polydipsia, accompanied by glucosuria [18], [48]. Moreover, the development of polydipsia was associated with progression of typical symptoms of T1DM, such as hyperglycemia, glucosuria, ketonuria, ketonemia, and destroyed β-cells [36]. Individuals showing high blood glucose levels and impaired glucose tolerance were also found among the bank voles originating from Sweden, trapped at a local population peak of medium density [37]. Although autoantibodies and the β-cell destruction were not seen in wild animals, the diabetic symptoms did develop in some of them over a time period of two months in captivity [37]. Interestingly, two reports indicated a role of Ljungan virus (LV) in destruction of β-cells, the picornavirus detected in the bank voles from Denmark and Sweden [36], [37], and from northern Italy [24]. LV has also been found in montane voles (Microtus montanus), and red-backed voles (Myodes gapperi) from the USA [55]. It has been even hypothesized that the bank vole might be a vector for this pathogen, increasing the risk of T1DM in humans [40]. However, RNA from LV has not been found in human T1D [35], and all independent studies have failed to establish a connection between LV and human T1D [54].
Captive Danish bank voles have been suggested as a lean model of diabetes, specifically T1DM [49]. On the other hand, captive individuals originating from Swedish population had elevated serum glucose and insulin levels, and the development of glucose intolerance led to diabetes with features of both T1DM and T2DM [6], [8]. There are no data, however, concerning the prevalence and characterization of diabetes in the bank voles from other geographic regions. Therefore, the aim of our study was to investigate the frequency and physiological effects of glucose metabolism disorders in captive bank voles from Poland.
Analyses done in diabetes-prone Danish voles demonstrated that probability of T1DM development in adulthood can depend on postnatal stress [18]. Two types of stressors were tested: low- and high-frequent maternal deprivation, which turned-out to be ineffective, and immersions in luke-warm water, which influenced the later proneness to develop T1DM, but in both directions – either increasing the prevalence of diabetes when applied as a low-frequent stress or decreasing it, when applied as a high-frequent stress [18]. In our study we investigated whether postnatal low-frequent stress (maternal deprivation) may influence development of diabetes in Polish captive bank voles. We compared the reaction of animals from subgroups with or without family history of diabetes.
Section snippets
Animals
All experiments were performed in animal facility of the Faculty of Biochemistry, Biophysics and Biotechnology of the Jagiellonian University. Breeding pairs were received from animal facility of the Institute of Environmental Sciences of the Jagiellonian University [28], [47]. This colony was reared from about 320 animals originally captured in the field in Niepołomice Forest (southern Poland) in Summer/Autumn 2000 and 2001. Approximately two generations per year were produced, with more than
Characterization of healthy population of the bank voles
Measurements carried out in individuals at the age of 3–4 months, without any visible symptoms of diabetes (N = 284 individuals), demonstrated a distribution of blood glucose concentrations with the mean ± SD value of 71.1 ± 19.14 mg/dL (Fig. 1). Values for 25th, 50th, 75th, 90th, and 95th percentiles were respectively 57.75 mg/dL, 69.0 mg/dL, 80.25 mg/dL, 95.7 mg/dL, and 106.85 mg/dL. Mean glucose level was similar in females and males (p = 0.5, t = 0.675, df = 282, Student t-test). Thus, in the studied colony
Discussion
We report here for the first time the discovery of diabetes in a captive population of Polish bank voles, providing also its biochemical characterization. Using the animals with known pedigrees we demonstrated that hyperglycemia in the voles without family history of diabetes is relatively rare: 26% of such individuals displayed an impaired fasting glucose incidences during the first 6 months of life but none of them became diabetic. However, in animals with FHD, namely with ancestors showing
Acknowledgments
This work was supported by grants N N301 005239 from Ministry of Science and Higher Education and PhD grant from Adamed Ltd. The Faculty of Biochemistry, Biophysics and Biotechnology of the Jagiellonian University is a beneficiary of the structural funds from the European Union Structural Funds (grant Nos.: POIG02.01.00-12-064/08 and 02.02.00-00-014/08, POIG 01 01.02.00-109/09 and 01 01.02.00-069/09). The source colony of voles was maintained from Ministry of Science and Higher Education grant
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These authors contributed equally to this work.