Nitrate and Nitrite
Links Between Nitrate/Nitrite and Diabetes/Obesity
A few dozen peer-reviewed studies published in scientific journals have examined the relationship between nitrate and/or nitrite and diabetes or obesity, beginning with a study on type 1 diabetes from Iceland in 1981. Those studies conclude that, "These findings suggest that an environmental factor in the etiology [causation] of human diabetes mellitus has been identified" (>Helgason et al. 1982). That environmental factor is Icelandic smoked mutton, which is high in nitrite. While this smoked mutton is not likely to be an important factor outside of Iceland, other sources of nitrate/nitrite 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.
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). N-nitrosamines are also a by-product of drinking water disinfection (Zhu et al. 2019).
Reviews of Nitrate/Nitrite and Diabetes/Obesity
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).
The Story of the Icelandic Smoked Mutton and Type 1 Diabetes
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).
Further Studies on 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:
Nitrate and Nitrite in Food
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 nitrate/nitrite, 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).
In a study from Finland, maternal dietary intake of nitrate or nitrite during pregnancy was not associated with the risk of islet autoimmunity or type 1 diabetes in the offspring genetically at risk for type 1 diabetes (Mattila et al. 2020).
Nitrate in Water
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).
Interestingly, one study exposed baby alligators to nitrate in their water tanks from the time they hatched until 5 months of age. The study found that the alligators developed signs consistent with type 1 diabetes as early as 5 weeks of age, and the signs increased by 5 months. These signs included higher blood glucose levels, fewer beta cells, increased immune activity in the pancreas, and more (Edwards et al. 2018).
Fish also develop health problems that are linked to type 1 diabetes when exposed to high levels of nitrate in water. These health problems include changes in the immune system and the gut microbiota and increasing gut permeability (Yu et al. 2020).
Interpreting Inconsistent Results
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. Not many have looked at exposures during early development either. 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 (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. 2015; Wirth et al. 2014), and autoimmunity in primates (Wei et al. 2011).
There is also evidence that nitrate is a potential endocrine disrupting compound (Edwards and Hamlin, 2018; Poulsen et al 2018). 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).
Type 2 Diabetes
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. 2017). In a Russian cross-sectional study, levels of nitrate and nitrite in blood were associated with type 2 diabetes (Gumanova et al. 2017). A study using cross-sectional U.S. data did not find an association between bodily nitrate levels and diabetes (Liu et al. 2017).
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. 2015).
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. 2015; Ohtake et al. 2015). 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. 2016). 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). Some point out that the beneficial effects of nitrate that show up in animals do not generally show up in people. They propose that this is because of differences in ascorbic acid (vitamin C) synthesis, and that taking this vitamin may help (Bahadoran et al. 2021).
Height, Weight, and Metabolic Syndrome
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. 2016). A cross-sectional U.S. study found that higher exposure to nitrate was associated with a lower risk of obesity, while higher levels of thiocyanate were associated with a higher risk of obesity, and that there was no association between perchlorate and obesity (Zhu et al. 2019).
In the Amish, nitrite levels were higher in obese/overweight people with metabolic syndrome, and were associated with higher levels of triglycerides, total cholesterol, and fasting glucose, and with lower levels of HDL ("good") cholesterol (Akram et al. 2018).
A laboratory study tested the effects of mixtures of N-nitrosamines at environmentally relevant levels, when each component was combined at extremely low concentrations, i.e., a million times lower than its "No Observed Effect Concentration (NOEC)." This exposure affected gut microbiota and increased body weight and triglyceride levels in rats (Zhu et al. 2019). (Changes to the gut microbiota are also linked to type 1 diabetes; see the Diet and the Gut page).