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Association of Dietary Exposure to Nitrites and Nitrates With Type 2 Diabetes Risk
Nitrites and nitrates occur naturally in water and soil and are commonly ingested from drinking water and dietary sources. They are also used as food additives, mainly in processed meats, to increase shelf life and to avoid bacterial growth. Experimental studies suggested both benefits and harmful effects of nitrites and nitrates exposure on type 2 diabetes (T2D) onset, but epidemiological and clinical data are lacking. We aimed to study these associations in a large population-based prospective cohort study, distinguishing foods and water-originated nitrites/nitrates from those from food additives.
METHODS AND FINDINGS
Overall, 104,168 adults from the French NutriNet-Santé cohort study (2009 to 2021, 79.1% female, mean age [SD] = 42.7 [14.5]) were included. Associations between self-reported exposure to nitrites and nitrates (evaluated using repeated 24-h dietary records, linked to a comprehensive food composition database and accounting for commercial names/brands details of industrial products) and risk of T2D were assessed using cause-specific multivariable Cox proportional hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). During a median follow-up duration of 7.3 years (interquartile range: [3.2; 10.1] years), 969 incident T2D cases were ascertained. Total nitrites and foods and water-originated nitrites were both positively associated with a higher T2D risk (HRtertile 3 vs.1 = 1.27 (95% CI 1.04 to 1.54), Ptrend = 0.009 and 1.26 (95% CI 1.03 to 1.54), Ptrend = 0.02, respectively). Participants with higher exposure to additives-originated nitrites (i.e., above the sex-specific median) and specifically those having higher exposure to sodium nitrite (e250) had a higher T2D risk compared with those who were not exposed to additives-originated nitrites (HR higher consumers vs. non-consumers = 1.53 (95% CI 1.24 to 1.88), Ptrend < 0.001 and 1.54 (95% CI 1.26 to 1.90), Ptrend < 0.001, respectively). There was no evidence for an association between total, foods and water-originated, or additives-originated nitrates and T2D risk (all Ptrend = 0.7). No causal link can be established from this observational study. Main limitations include possible exposure measurement errors and the lack of validation versus specific nitrites/nitrates biomarkers; potential selection bias linked to the healthier behaviors of the cohort's participants compared to the general population; potential residual confounding linked to the observational design, as well as a self-reported, yet cross-checked, case ascertainment.
The findings of this large prospective cohort did not support any potential benefits for dietary nitrites and nitrates. They suggested that a higher exposure to both foods and water-originated and additives-originated nitrites was associated with higher T2D risk in the NutriNet-Santé cohort. This study provides a new piece of evidence in the context of current debates about updating regulations to limit the use of nitrites as food additives. The results need to be replicated in other populations.
ClinicalTrials.gov NCT03335644 (https://clinicaltrials.gov/ct2/show/NCT03335644).
Dietary exposure to nitrites and nitrates in association with type 2 diabetes risk: Results from the NutriNet-Santé population-based cohort studyPLoS Med 2023 Jan 01;[EPub Ahead of Print], B Srour, E Chazelas, N Druesne-Pecollo, Y Esseddik, FS de Edelenyi, C Agaësse, A De Sa, R Lutchia, C Debras, L Sellem, I Huybrechts, C Julia, E Kesse-Guyot, B Allès, P Galan, S Hercberg, F Pierre, M Deschasaux-Tanguy, M Touvier
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The relationship between dietary nitrate and nitrite exposure and human disease has been extensively studied and heavily debated ever since the 1970s, when the formation of potentially carcinogenic N-nitrosamines from these anions was shown to occur in the gastrointestinal tract.1 Srour and colleagues now focus on nitrate and nitrite in relation with type 2 diabetes in their study and find an increased risk of diabetes with higher intake of nitrite from food and additives, while nitrate as so many times before comes out as not harmful. There is reason to doubt the direct relationship between nitrate and nitrite intake and disease in humans in general, which has been made clear by some simple observations and calculations. The two dominant sources of nitrate and nitrite in our bodies are represented by food and endogenous formation, the latter being derived from the nitric oxide (NO) pathway.2 Even for nitrite, the major dietary exposure in most cases is not from processed food or meat but, in fact, from vegetables. This is because some vegetables contain very high amounts of nitrate, which is partly converted to nitrite in our bodies by bacteria in the oral cavity and in saliva, where nitrate is usually accumulated.2 In addition, endogenous NO is a major contributor, as nitrate and nitrite are the major oxidation products of this vital signalling molecule.3 It is important to note that the concentration of nitrite in saliva in absence of any nitrate or nitrite intake is still around 100 to 200 μM, with >1 L saliva produced every day, giving a baseline nitrite exposure of around 5 to 10 mg. The contribution from food additives is 0.3 mg/day, according to Srour and colleagues. Thus, exposure to endogenous nitrite is already 15 to 30 times greater than that to nitrite from additives, raising serious questions about the causal link between direct nitrite exposure and type 2 diabetes. Any role of N-nitrosamines preformed in food products is more difficult to exclude. We should also remember that there is a reason for adding nitrate and nitrite to processed food and meat besides enhancing appearance and color, which is to stop the growth of serious pathogens, most notably Clostridium botulinum.
While a high consumption of processed food containing additives is associated with increased risk for certain diseases, a causal link between nitrate and nitrite content in these products and the disease pathology is by no means clear.