Once upon a time, around 1980, researchers did a survey of all the people with type 1 diabetes in Iceland (it's a small country, after all; only two towns had more than 10,000 residents at that time). They made a graph of what month people with type 1 diabetes were born in, and found a surprising thing: that there were a whole lot of boys who had type 1 diabetes who were born in October. Why would that be?
They suspected viruses, but that could hardly explain a spike for only one month, over multiple years. They became suspicious of the smoked mutton that Icelanders eat during the Christmas-New Year holidays. This meat is traditionally smoked over an open fire, but since 1940 (about when the incidence of type 1 diabetes began to rise in Iceland), that method had gradually been replaced by curing the meat chemically, adding nitrate or nitrite to the salt or brine, followed by smoking. Nitrate and nitrite can react to form N-nitroso compounds. They found that the meat did in fact have high levels of N-nitroso compounds. (Streptozotocin, one of the drugs used to induce diabetes in lab animals, interestingly, is an N-nitroso compound).
The researchers determined that the parents’ consumption of the meat around the time of conception may have led to type 1 diabetes in their offspring. The boys were born in early October, and the average date of fertilization would have been 11 days after the end of the holiday season. Either it was the leftovers they ate after the holidays, or the toxic effect of the N-nitroso compounds occurred just before fertilization (Helgason and Jonasson 1981).
Just think, if the parents had only eaten this meat year round, and skipped the holiday parties, no one might have figured it out.
To confirm their findings, the researchers fed Icelandic smoked and chemically cured mutton to mice that were not prone to develop diabetes. When they fed mutton to parent mice only up to the time of fertilization, there was a change in the glucose levels in the offspring that varied depending on gender. When they fed the mutton to the parents before mating and through gestation, and to the offspring for a few weeks, about 16% of the male offspring developed diabetes, and 4% of the females. In neither case did the parents show any signs of diabetes (nor did the control mice or their offspring, who did not eat mutton). They also found that the mechanism seemed to involve the germ cells of fathers as well as mothers.
In experiments where both parents and offspring mice ate the meat, the researchers varied the levels of nitrite in the meat. They found that more male offspring developed diabetes in the group that was fed lower nitrite meat as compared to higher nitrite meat, but the opposite in females. However, the levels of nitrite added to the meat did not necessarily correlate with the resulting levels of N-nitroso compounds in the meat. Note that most of the meat used in this study fell below the allowable limits of nitrite and nitrate in meat in most countries, including the U.S. and U.K. The authors suggest that researchers look for diabetes causation in areas where foods containing N-nitroso compounds are eaten throughout the year (Helgason et al. 1982).
Nitrate, nitrite, nitrosamines, and N-nitroso compounds all contain nitrogen, are related to one another, and are not limited to Icelandic smoked mutton. Nitrosamines are a type of N-nitroso compound. In the stomach, nitrate can be converted to nitrite, and nitrite can react with amino acids to form N-nitroso compounds (Longnecker and Daniels 2001).
The main source of human exposure to N-nitroso compounds is via food. But there are other sources, such as cigarettes, car interiors, and cosmetics, to name a few. In food, the main sources are beer and processed meat and fish. Nitrate and nitrite are used as food additives, but also are found naturally in some foods. In Finnish children, the main sources of dietary nitrate are potatoes, cabbages, carrots, and beets. Sausage is the main source of nitrite (Virtanen and Knip 2003).
Nitrate is also found in water. Nitrate can leach into water from nitrogen fertilizer use, manure, or sewage (e.g., from septic tanks) (Howarth et al. 2002). The U.S. Geologic Survey reports that in the U.S., 1% of public water supplies contain excess nitrate, 9% of private wells, and 21% of shallow wells under farmland (Wolfe and Patz 2002).
Levels of molecules called "reactive nitrogen" doubled between 1961 and 1997 in the U.S., due to human activity. The largest increase was in the use of nitrogen fertilizer, but reactive nitrogen from air emissions from the combustion of fossil fuels also increased significantly (Howarth et al. 2002). (See the graphs on the historical trends page). Reactive nitrogen molecules can also increase air pollution (see the air pollution page for information on type 1 and these pollutants), and increase the acidity of precipitation and surface water (Galloway and Cowling 2002) (see below for information on drinking water acidity and type 1 diabetes).
Since the 1980s, there have been a number of studies looking to see if children exposed to higher nitrate or nitrite levels through food or water have a higher risk of type 1 diabetes. But few have looked at exposures to parents.
Subsequent studies focusing on type 1 diabetes and dietary nitrate/nitrite/N-nitroso compounds have found some associations, but not consistently (reviewed in Virtanen and Knip 2003). For example, a Swedish study found that children with type 1 diabetes had eaten more food containing nitrosamines, nitrite, and nitrate than those without diabetes (Dahlquist et al. 1990). A large study in Finland found that children with type 1 diabetes and their mothers ate more nitrite than children (and their mothers) who did not have diabetes. There was no difference for nitrate/nitrite in drinking water (Virtanen et al. 1994). Two other studies, however, did not find associations between dietary nitrite/nitrate, although they did not control for other variables (Virtanen and Knip 2003).
De la Monte et al. (2009) propose that higher diabetes mortality rates are due to increases in human exposure to nitrate, nitrite, and nitrosamines through processed and preserved food. They propose that these compounds play critical roles in the development of diseases associated with increased insulin resistance, including type 2 diabetes. (Increased insulin resistance may also play a role in the development of type 1 diabetes). These researchers have found that nitrosamines can cause insulin resistance in animals (Tong et al. 2009), and the effect is exacerbated by a high fat diet (de la Monte 2009). A meta-analysis that combined data from 20 studies found that higher processed meat consumption is associated with higher rates of diabetes (Micha et al. 2010). And, a study that followed men over time also found that higher processed meat consumption was associated with an increased risk of type 2 diabetes (Männistö et al. 2010). In animals, nitrate exposure has been found to affect the function of the immune system of birds (Rodriguez-Estival et al. 2010), and early nitrosamine exposure exacerbate the effects of a high fat diet in rats, promoting diabetes (Tong et al. 2010). (See the types of diabetes page for information on the relationship of type 2 diabetes with type 1).
Higher nitrate levels in drinking water have sometimes been associated with an increased incidence of type 1 diabetes (e.g., Parslow et al. 1997; Kostraba et al. 1992), but not necessarily (e.g., van Maanen et al. 2000; Moltchanova et al. 2004; Muntoni et al. 2006). A recent prospective study in Germany that followed people over time did not find nitrate or nitrite levels in drinking water during the first year of life to be associated with the development of type 1-related autoimmunity (Winkler et al. 2008). Exposure levels differed in these studies, making direct comparisons difficult.
Possibly related, a study in Norway found that people whose drinking water was more acidic had four times as many cases of type 1 diabetes compared to people who drank less acidic water (Stene et al. 2002), and the prospective study from Germany mentioned above also found that autoantibody-positive children who drank more acidic water had a somewhat faster progression to type 1 diabetes (Winkler et al. 2008). Why acidic water might affect the development of type 1 diabetes is not known.
Nitrosamines have been found to cause oxidative stress, DNA damage, and inflammation (De la Monte et al. 2009). High doses of some N-nitroso compounds can cause diabetes via the generation of free radicals that damage beta cells (see the oxidative stress page) (Kostraba et al. 1992). The N-nitroso compound streptozotocin is thought to act by fragmenting DNA and destroying the beta cells (Lenzen 2008b).
Interestingly, the Icelandic studies follow a similar pattern as is seen with other environmental contaminants that can affect health (described on the autoimmunity page). That is,
There is also evidence that nitrate is a potential endocrine (hormone) disrupting compound. In addition to the many known toxic effects of nitrate and nitrite in humans and animals, nitrate has been shown to disrupt thyroid function, alter the production of hormones, and may be involved in some of the endocrine disrupting effects seen in young wildlife (Guillette 2006).
In sum, "These findings suggest that an environmental factor in the etiology [causation] of human diabetes mellitus has been identified" (Helgason et al. 1982). Well, that's one anyhow! Icelandic smoked mutton. Of course, this mutton is not likely to be a factor outside of Iceland, but other sources of nitrite/nitrate may be.
While the results of the various follow-up studies has been mixed, none of the studies included all sources of nitrate/nitrite/N-nitroso compound exposures, or focused on exposures to parents before or around the time of conception. It may be that timing is critical to the effects of nitrate/nitrite.
Men and women trying to conceive a baby should avoid eating Icelandic smoked mutton (and other foods with added nitrite). Whether nitrate or nitrite show toxic effects at other times in life is not clear, but is possible. De la Monte et al. (2009) suggest that as a society we should eliminate the use of nitrite in food, reduce nitrate levels in fertilizer, and detoxify food and water before consumption.