by Gertrud U. Rey
Type 1 diabetes is an organ-specific autoimmune disease that is characterized by the loss of insulin-producing beta cells in the pancreas. The loss of these cells leads to decreased insulin production (hypoinsulinemia) and increased levels of glucose in the blood (hyperglycemia). While it is still unclear what exactly causes the loss of beta cells, experts agree that it is likely a combination of genetic and environmental factors. An increasing body of evidence suggests that Coxsackievirus strain B4 is an environmental trigger, because it specifically targets beta cells, causing them to die.
As with most animal disease models, methods for studying diabetes traditionally involve inbred mice to eliminate genetic variability as a complicating factor and improve the chances for reproducibility of results. However, the inbred mouse model does not accurately represent human populations, which are genetically diverse. In an effort to mimic the effects of viral infection in humans, the authors of a new study used outbred mice to analyze the impact of the Coxsackievirus B4E2 strain (CV-B4E2) in combination with a single sub-diabetogenic dose of streptozotocin (STZ) on the pancreas and pancreatic beta cells. STZ is a compound that specifically targets pancreatic beta cells and is commonly used to produce animal models for studying diabetes. The administration of multiple low (sub-diabetogenic) doses of STZ typically induces type 1 or type 2 diabetes in mice.
The authors pre-treated mice with one sub-diabetogenic dose of STZ, infected them with CV-B4E2 twelve days later, and determined whether the virus induced hyperglycemia and hypoinsulinemia five days post-infection. Control mice that had received only STZ or CV-B4E2 had blood glucose levels lower than 300 mg/dl, the threshold for hyperglycemia. However, mice that had received both STZ and CV-B4E2 had blood glucose levels that were significantly higher than this threshold and insulin levels that were significantly lower than those found in control animals. In contrast, there was no increase in blood glucose levels in STZ-treated mice that were inoculated with UV-inactivated CV-B4E2 relative to control mice, suggesting that the development of diabetogenic effects was dependent on viral infection.
Analysis of pancreatic tissues revealed that viral particles were only present through day 5 post-infection, while viral RNA was detectable through day 15 post-infection, regardless of whether the mice had received only STZ, only CV-B4E2, or both. Further analysis of pancreatic tissue also revealed inflammatory infiltrations and abnormal morphologies characteristic of diabetic lesions in hypoinsulinemic mice compared to mice with normal insulin levels.
Type 1 diabetes is considered a T-helper 1 cell-mediated disease, characterized by production of interferon γ (IFNγ), which induces secretion of interferon-inducible protein-10 (IP-10), a chemokine that promotes the migration of activated T-helper 1 cells. Both IFNγ and tumor necrosis factor α (TNFα) are implicated in inducing apoptosis of pancreatic beta cells. In parallel, infection with CV-B4E2 is detected by toll-like receptor 3, which also induces expression of IFNγ, IP-10, and TNFα. Based on this knowledge, the authors analyzed the effect of infection with CV-B4E2 on expression of these inflammatory markers on day 5 post-infection. Even though the levels of TNFα and IFNγ in recipients of both STZ and CV-B4E2 were comparable to those found in control animals, the levels of IP-10 were significantly higher. This observation is interesting considering that IP-10 is usually secreted in response to IFNγ, and suggests that the IP-10 was produced by pancreatic cells rather than as a result of an immune signaling cascade. However, because the hypoinsulinemia and hyperglycemia observed in recipients of both STZ and CV-B4E2 were likely a result of viral infection, and because this diabetogenic effect was associated with the presence of pancreatic lesions, the inflammation in the tissue was also likely due to either direct or indirect effects of the virus.
Diabetes is of high public health significance because of its potential to result in a number of secondary diseases in many different organs, including the eyes, kidneys, heart, and brain. Besides Coxsackievirus B4, several other viruses have also been associated with type 1 diabetes, including rotavirus, mumps virus, cytomegalovirus, and rubella virus. The premise that viral infection could act as a trigger in a cascade leading to insulin deficiency is intriguing. However, more in vivo studies in outbred mice are needed to clearly define possible causative mechanisms of these viral infections in the context of diabetes and host immunity.
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