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In April 2025, JAMA Network Open published the results of a unique long-term cohort study (Meta-Air2) designed to unravel the connections between air pollution, insulin resistance, and body mass index (BMI). Traffic-related air pollutants (TRAP) have previously been associated with an increase in risk for type 2 diabetes, but the mechanism has not been entirely clear, thought to be influenced at least by BMI and/or insulin resistance. However, in short-term studies, the effect of TRAP on insulin sensitivity may not be readily observed, and the order of events may be unclear, i.e., does insulin resistance precede an increase in BMI, or does the opposite occur, etc. This study set out to monitor a population of children longitudinally to observe the effects of TRAP during childhood on insulin resistance among adults, and to examine any role that BMI has on this relationship.
Participants for this 2025 study included 282 children enrolled while in kindergarten or first grade, followed to age 24, as a subset of the larger Southern California’s Children’s Health Study (CHS). BMIs were measured at ages 13, 15, and 24, with insulin sensitivity (assessed by the homeostatic model assessment of insulin resistance (HOMA-IR)) and average glucose (HbA1c) both evaluated at age 24. Exposure to nitrogen oxides (NOx), one type of particulate matter found in TRAP, was estimated from residential history, geocoded by month, and weighted during times of multiple residences, beginning during pregnancy to age 13.
This study had several conclusions; first, the NOx exposure from traffic during childhood was associated both with a greater degree of insulin resistance and a higher HbA1c by age 24. Specifically, for each standard deviation (SD) increase (18.7 parts per billion (ppb)) above mean NOx exposure, there was an associated 0.55 increase in HOMA-IR, a magnitude the authors described as “not subtle.” For context, the mean HOMA-IR in this study was 1.3, thus a 0.55 increase indicates a 42% increase (decreased sensitivity). Similarly, each SD increase in NOx levels during childhood was associated with a 0.08 increase in HbA1c levels by 24 years of age.
The second conclusion of the study was that NOx exposure during childhood was also associated with an increase in BMI by age 13. Each SD increase in exposure was associated with a BMI increase of 0.71 by age 13. From another perspective, those children with the highest quartile of exposure during childhood had a mean BMI of 21.9 at age 13, compared to a BMI of 20.0 among those with the lowest exposure. By age 24, this influence on BMI trajectory had continued, with a mean BMI of 28.4 vs. 25.1 in the highest vs. lowest exposure. It’s important to note that this exposure was during pregnancy to age 13.
But this study tried to quantify the direct effects of TRAP on insulin sensitivity, as well as the “indirect” effects that appeared to be mediated by BMI. They estimated that 58% of the drop in insulin sensitivity was directly due to NOx exposure, while the remaining 42% was mediated by BMI at age 13 and the accelerated BMI growth that resulted from exposure. Thus, it is plausible that TRAP exposure not only directly impairs insulin sensitivity over time, but also accelerates an increase in BMI that has an additional negative effect on insulin sensitivity.
The authors are careful to avoid terms like “causal,” but instead describe “direct” and “indirect” associations, as is warranted by this type of study. Yet, it seems unlikely that we would ever have a randomized and controlled trial to demonstrate clear causality, and this type of long-term longitudinal study may be the best that we will ever have. This study was also not one that reveals mechanisms of action, but the authors also describe highly plausible pathways. For example, air pollution may initiate the production of inflammatory compounds that impair adipose tissue function, leading to lipid accumulation and weight gain. Excess lipid accumulation, particularly in hepatic cells, can lead to the secretion of adipokines and cytokines, which in turn impair insulin sensitivity. This type of pathway has been outlined previously, with many likely contributors, such as direct oxidative stress of alveolar macrophages, activation of Toll-like receptors on immune cells, vascular inflammation, etc., contributing to dysfunction in adipose cells, fatty liver, insulin resistance, etc., all of which drive cardiometabolic disease.
The role of adipose tissue and BMI as mediators of toxin-induced damage is quite a complex one, with substantial implications. For instance, in a study published in 2006 in Diabetes Care, 6 persistent organic pollutants (chosen because they were common, not because they were particularly toxic) were found to strongly associate with diabetes incidence in the NHANES cohort. Indeed, among people with the greatest exposure, the risk was approximately a striking 38-fold higher. However, among people with low toxin levels, the normally robust relationship between diabetes and BMI was not present. In other words, toxins seem to be critical drivers of the development of obesity and insulin resistance, and may mediate many of the metabolic consequences, either directly or indirectly. This latest study in JAMA Network Open provides strong evidence for this dynamic.
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