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fire, but since 1940 (about when the incidence of type 1 diabetes began to rise in Iceland), that method had gradually been replaced by curing the meat chemically, adding nitrate or nitrite to the salt or brine, followed by smoking.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 (STZ), 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).
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:
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). A more recent study of Canadian youth found a positive trend between nitrate intake via food during the year before diagnosis, although the trend was not statistically significant. They did not find a correlation between nitrite or nitrosamines and type 1 diabetes development (Benson et al. 2010).
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 always (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).
Due to the inconsistent results of subsequent studies, it is not entirely clear whether or not nitrate/nitrite increases the risk of type 1 diabetes. However, few follow-up studies have looked at exposures to parents, especially around the time of conception, as the Icelandic studies did. It may be that timing is critical to the effects of nitrate/nitrite. In addition, most of the follow-up studies did not include measurements of all exposures to nitrate/nitrite, but instead focused on only water or only food.
There are a few mechanisms by which nitrate/nitrite compounds may be able to affect the risk of diabetes. Nitrosamines have been found to cause oxidative stress, DNA damage, and inflammation (de la Monte et al. 2009a). High doses of some N-nitroso compounds can cause diabetes via the generation of free radicals that damage beta cells directly (see the oxidative stress page) (Kostraba et al. 1992).
The N-nitroso compound streptozotocin (STZ), used to induce type 1 diabetes in laboratory animals, is thought to cause diabetes by fragmenting DNA and directly destroying the beta cells (Lenzen 2008b). STZ also causes alterations in gut microbiota in rodents (Patterson et al. 2014; Wirth et al. 2014), and autoimmunity in primates (Wei et al. 2011).
There is also evidence that nitrate is a potential endocrine 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).
A longitudinal study from Iran found that people with a higher intake of nitrite (animal-based and total nitrite, but not plant-based) and low vitamin C intake had a higher risk of type 2 diabetes. There was no association between nitrate intake and type 2 diabetes (Bahadoran et al. 2016). In a Russian cross-sectional study, levels of nitrate and nitrite in blood were associated with type 2 diabetes (Gumanova et al. 2016).
De la Monte et al. (2009a) 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. 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 et al. 2009b). Early-life nitrosamine exposure exacerbates the effects of a high fat diet in rats, promoting diabetes (Tong et al. 2010). Nitrosamine exposure also increases "bad" LDL cholesterol levels and decreases "good" HDL cholesterol levels in rats (Sheweita et al. 2014). Meanwhile, cod liver oil ameliorates nitrite-induced insulin resistance in rats (Al-Gayyar et al. 2014).
In humans, 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). Processed meat tends to be high in nitrite.
On the other hand, other authors have found that dietary nitrite improves insulin resistance and glucose tolerance in rodents with diabetes, because dietary nitrite can be a source of nitrogen oxide (NO), which is essential for insulin signalling (Gheibi et al. 2017; Khilifi et al. 2014; Ohtake et al. 2014). Animals fed a low-nitrate/nitrite diet developed metabolic syndrome, glucose intolerance, and gained weight (Kina-Tanada et al. 2017). I am not sure how to interpret these conflicting studies; maybe a certain amount of nitrate/nitrite is necessary, but too much can be harmful-- but that is a guess. The source may also be important, e.g., if it is from plant or animal sources. Perhaps, as Gheibi et al. (2017) found, since nitrite increases insulin secretion and insulin content in beta cells, in the shorter term that could improve glucose levels, but over time that could lead to insulin resistance and beta cell stress. Some authors in fact argue that nitrate has turned "from villain to hero" in metabolic disease, and that nitrate can have anti-diabetes and anti-obesity effects. Dose may be involved here; many of the toxic effects were found at very high dose levels. Whereas things like green leafy vegetables, clearly healthy, are a major source of dietary nitrate (McNally et al. 2015). A two-part review of the history of the debate on dietary nitrate argues that vegetables containing nitrate are a component of a healthy diet (Khatri et al. 2017; Mills et al. 2017).
Interestingly, a trial gave obese people a glucose drink followed by nitrate or a placebo to see if it would help them deal with high blood sugar. The nitrate did not affect glucose or insulin levels. It did, however, reduce oxidative stress (Ashor et al. 2016).
One thing that nitrate does is to block iodide uptake into the thyroid gland, thus affecting growth and development. Other chemicals can also do this, including perchlorate and thiocynate. A longitudinal U.S. study looked at growth in girls to see if it was related to combined levels (during childhood) of nitrate, perchlorate, and thiocynate. They found that higher levels of these chemicals were associated with lower waist circumference and body mass index (BMI), and not related to height (Mervish et al. 2015).
A review finds that at low exposure levels, nitrate in drinking water is not associated with type 1 diabetes, but at higher exposure levels it is. Similarly, dietary nitrite may be a risk factor for type 1 diabetes, but generally at higher exposure levels (Bahadoran et al. 2016).
In sum, "These findings suggest that an environmental factor in the etiology [causation] of human diabetes mellitus has been identified" (Helgason et al. 1982). That is, Icelandic smoked mutton. While this mutton is not likely to be a factor outside of Iceland, other sources of nitrite/nitrate may be.
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.
To download or see a list of all the references cited on this page, see the collection Nitrate/nitrite and diabetes/obesity in PubMed.