Of Mice, Dogs, and Men
Animals and Diabetes/Obesity
Animals with diabetes may provide important information that relates to diabetes in humans. Animal research is often able to identify situations where the timing of exposures is important for disease development (e.g., in early life), or to identify the mechanisms involved in disease development.
Interestingly, animals are developing diabetes and obesity at increasing rates, just like humans.
Do Animals Get Diabetes?
Yes. Some animals do get diabetes naturally or in the wild, including apes, pigs, sheep, horses, cats, and dogs. All mammals produce insulin, and will develop diabetes (defined as high blood glucose levels) if their pancreatic beta cells are removed. Vets classify canine diabetes into "insulin deficiency diabetes" and "insulin resistance" diabetes (somewhat analogous to type 1 and type 2 in humans). Female dogs may also develop a canine form of gestational diabetes. There is some evidence that dogs do actually develop a form of autoimmune diabetes, that is more similar to Latent Autoimmune Diabetes in Adults (LADA) than to childhood type 1 diabetes. (Gale 2005; Nelson and Reusch, 2014), although overall, canine diabetes is very similar to type 1 (O'Kell et al. 2017a, O'Kell et al. 2017b). Interestingly, some of the same autoantibodies found in humans with type 1 diabetes have also been found in some dogs with diabetes (Davison et al. 2008), although not all studies have found these antibodies in dogs with diabetes (Ahlgren et al. 2014). Technically, only humans get type 1 diabetes (Gale 2008), although some authors do use the term type 1 to describe autoimmune diabetes in animals. Cats, meanwhile, develop a diabetes that is more similar to type 2 (Nelson and Reusch, 2014). There is debate as to how exactly classify diabetes in dogs and cats (Gilor et al. 2016).
Type 1 Diabetes in Animals: Non-Obese Diabetic Mice
Scientists generally use rodents as animal models of type 1 diabetes in the laboratory. The two main rodent strains used are non-obese diabetic (NOD) mice and Biobreeding (BB) rats. These rodents have been bred to spontaneously develop diabetes. Both animals develop a form of autoimmune diabetes that includes the presence of some autoantibodies, although there are also differences between the autoimmune diabetes in these animals and type 1 diabetes in humans. While these animals may be useful for some purposes (such as developing a cure for type 1 diabetes once it develops, or identifying biological mechanisms), their usefulness is also in question.
How useful are NOD mice for predicting the effects of various environmental factors to either cause or prevent type 1 diabetes in humans? Perhaps not very. Most interventions-- at last count, 195 of them-- delay or prevent diabetes in NOD mice (Roep and Atkinson 2004). Some of these interventions have been tried in people and have not successfully prevented or delayed type 1 diabetes. For example:
Insulin can prevent diabetes in NOD mice, but was ineffective in humans (Näntö-Salonen et al. 2008).
Oral insulin in particular prevents diabetes in NOD mice, but was ineffective in humans (Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study Group et al. 2017).
Some researchers have used NOD mice to investigate the potential role of environmental chemicals in the development of autoimmune diabetes. Some studies on chemicals and NOD mice found that some chemicals do not accelerate or can even delay diabetes in NOD mice: mercury (Brenden et al. 2001), trichloroethylene (Ravel et al. 2005), arsenic (Lee et al. 2015), dioxin (Kerkvliet et al. 2009), PCBs (Kuiper et al. 2016), fluoride (Malvezzi et al. 2018), particulate matter (air pollution) (Morita et al. 2019), and even nicotine (Mabley et al. 2002). Yet most of these chemicals have been found to accelerate autoimmunity in other strains of mice, and sometimes in humans as well. It is also notable that all of these studies were conducted with mice that were adults or nearly adults, and it may be that exposure early in life would make a difference in the findings. What these findings mean for humans is not clear.
Two studies have found that BPA exposure accelerates insulitis and diabetes development in NOD mice (Bodin et al. 2013 and Bodin et al. 2014). The first study found that long-term exposure to BPA at relatively high levels accelerated insulitis in NOD mice. The second found that exposing mothers to BPA caused their female offspring to have more severe and higher incidence of insulitis. The authors write, "In conclusion, transmaternal BPA exposure, in utero and through lactation, accelerated the spontaneous diabetes development in NOD mice. This acceleration appeared to be related to early life modulatory effects on the immune system, resulting in adverse effects later in life." (Bodin et al. 2014). Another study by these authors, on another chemical, a perfluoroalkyl substance, found that it accelerated insulitis but not diabetes in NOD mice (Bodin et al. 2016). An additional study found that while exposure from conception throughout life to BPA accelerated diabetes in NOD mice, phthalates did not, nor did a mixture of the two chemicals (Bodin et al. 2015). Using the findings of all these studies, the authors are trying to develop a screening method for potentially immunotoxic chemicals that could promote autoimmunity, especially type 1 diabetes. Different chemicals have different effects, depending on the rodent strain used, but overall there is a possibility that this might work. The authors also highlight the need to screen for multiple endpoints when examining the effect of chemicals on the immune system, not just whether or not they increase or decrease diabetes development (Berntsen et al. 2018).
A study found that chronic, high-dose exposure to DDE increased the incidence and severity of diabetes in NOD mice, and that DDE acted via the immune system and affected T-cell function (Cetkovic-Cvrlje et al. 2016). Arsenic also causes beta cell dysfunction in the pancreatic tissue of NOD mice (Ramdas et al. 2018).
Van der Werf et al. (2007) suggests that NOD mice are probably not appropriate to use for studying the role of viruses in the development of type 1 diabetes in humans; likewise, NOD mice may not be entirely appropriate to use to examine the effects of environmental chemicals on type 1 diabetes in humans. Researchers have in fact joked, "If you look cross-eyed at NOD mice, you prevent diabetes" (Roep and Atkinson 2004), although others point out that not quite everything prevents diabetes in NOD mice, and that the effects of various interventions may depend on timing and dosage (Shoda et al. 2005). Personally, I would not suggest giving children mercury, trichloroethylene, arsenic, nicotine, or dioxin with the hope that they might prevent type 1 diabetes, despite their apparently beneficial effects on NOD mice.
While animal studies may be occasionally informative, we really need studies on humans who are exposed to these chemicals, at different levels, and at different periods of life, and in mixtures that we encounter in the real world, to really see what the effects on humans will be. NOD mice may or may not be appropriate for examining the effects of environmental chemicals or other environmental factors on the development of type 1 diabetes in humans. The ability of chemicals to influence the development of diabetes or autoimmunity in animals that are not bred to spontaneously develop these conditions might be more revealing.
Other Animals and Diabetes
Can other animals be used to study the potential effects of chemicals or other environmental factors on the development of type 1 diabetes? Perhaps. I have not found any studies on chemicals and BB rats, and I do not know if these animals could be a useful model or not. Perhaps dogs can, but I am not going to advocate for medical research on dogs.
Most convincing might be the ability of chemicals to induce diabetes in animals that are not prone to develop the disease. Helgason et al. (1982), for example, found that if mice consumed meat cured with nitrite before mating and during pregnancy, and their offspring consumed it for a time, then some of the offspring developed glucose abnormalities and diabetes. This strain of mice does not normally develop diabetes. This study supports previous findings in humans suggesting that parental consumption of this meat around the time of conception can lead to the development of type 1 diabetes in their children (see the Nitrate and Nitrite page for information).
Interestingly, zebrafish are one animal that is becoming useful in studying the effects of toxic chemicals (zebrafish studies are described on numerous pages on this website). It also turns out that the zebrafish pancreas develops similarly to the human pancreas. These fish are now being used to try to figure out a potential cure for diabetes (Prince et al. 2017).
Other Animals and Autoimmunity
A number of pages on this website discuss the ability of chemicals to induce or exacerbate autoimmunity in various strains of rodents (see, for example, the pages on bisphenol A, dioxin, heavy metals, phthalates, and trichloroethylene). What rodents were used in these studies? Many of them used rodents that are genetically susceptible to the autoimmune disease systemic lupus erythematosus (SLE, also known as lupus). Whether these findings would have any relevance for type 1 diabetes is not known. Some researchers are also beginning to investigate the effects of chemicals on animals not prone to autoimmunity or autoimmune diseases.
Phthalates have been shown to induce autoimmunity in various strains of mice, including some that are not prone to autoimmunity. Different strains show differing effects, however, in that the susceptible strains show signs of disease (in this case, SLE), while the others do not (Lim and Ghosh 2005).
When mice not genetically prone to autoimmune disease were treated prenatally with dioxin (TCDD) during immune system development, they had immune dysregulation that included autoantibody production, and suggested an increased risk for later autoimmune disease. These findings suggest that developmental exposure to TCDD may increase the risk of autoimmune disease. These mice, however, are more sensitive than other strains of mice to the effects of dioxin (Mustafa et al. 2008).
While exposure to mercury can induce or exacerbate autoimmunity in genetically susceptible rodents (Hemdan et al. 2007), mercury has also been shown to induce autoimmunity even in mice that are not genetically susceptible to autoimmunity (Abedi-Valugerdi 2009). Exposure to mercury in combination with a bacterial infection aggravated autoimmune disease in genetically susceptible mice. And, mice that were not genetically susceptible to autoimmunity were made susceptible (Abedi-Valugerdi et al. 2005).
These examples show cases where chemicals could induce or affect autoimmunity even in animals not prone to autoimmunity. The health effects of the exposures varied by strain of animal. Perhaps the potential effects of environmental chemicals on the development of type 1 diabetes would likewise vary based on the genetic background of the individual.
Does Living With Animals Affect the Risk of Diabetes?
Living with a dog (or more than one dog) during the first year of life was not associated with a higher or lower risk of developing type 1 diabetes in childhood (Wernroth et al. 2017). Living with dogs or cats during pregnancy is not associated with a higher or lower risk of the offspring developing type 1 either, although living with a hamster was associated with an increased risk of type 1 in the offspring (perhaps due to infections in the pet?) (Faresjö and Ludvigsson 2018). Children with type 1 who actively care for a pet at home do have blood sugar control than those who don't, however (Maranda and Gupta 2016). And pet ownership may help reduce children's susceptibility to air pollutants (Lawrence et al. 2018).
For type 2 diabetes, a long-term Swedish study found that owners of a dog with diabetes were more likely to develop type 2 diabetes during follow-up than owners of a dog without diabetes. The same did not apply for cats (Delicano et al. 2020). We don't know why, but it could be that dog owners are exposed to the same household chemicals as their dogs.
Diabetes/Obesity in Wildlife
I do not know of much research in the question of whether or not wild animals get diabetes. I did see two studies that are interesting though. Both documented higher glucose levels in fish exposed to polluted river water, one in the Great Lakes region (Thomas et al. 2017), and one in Brazil (Souza-Bastos et al. 2017).
Interestingly, the obesity epidemic is not limited to human beings. Other species have also gained weight over the past decades, including feral rats (both urban and rural), laboratory animals (kept in controlled conditions), and domestic dogs and cats. It would be hard to explain all of these trends if diet and exercise were the only factors influencing obesity (Klimentidis et al. 2011).