Review

Air pollution exposure and cardiometabolic risk

Sanjay Rajagopalan, Robert D Brook, Pedro R V O Salerno, Brendan Bourges-Sevenier, Philip Landrigan, Mark J Nieuwenhuijsen, Thomas Munzel,
Salil V Deo, Sadeer Al-Kindi

The Global Burden of Disease assessment estimates that 20% of global type 2 diabetes cases are related to chronic Lancet Diabetes Endocrinol 2024
exposure to particulate matter (PM) with a diameter of 2·5 μm or less (PM2·5). With 99% of the global population Published Online
residing in areas where air pollution levels are above current WHO air quality guidelines, and increasing concern in February 1, 2024
https://doi.org/10.1016/
regard to the common drivers of air pollution and climate change, there is a compelling need to understand the
S2213-8587(23)00361-3
connection between air pollution and cardiometabolic disease, and pathways to address this preventable risk factor.
University Hospitals, Case
This Review provides an up to date summary of the epidemiological evidence and mechanistic underpinnings linking Western Reserve University
air pollution with cardiometabolic risk. We also outline approaches to improve awareness, and discuss personal-level, School of Medicine, Cleveland,
community, governmental, and policy interventions to help mitigate the growing global public health risk of air OH, USA
(Prof S Rajagopalan MD,
pollution exposure.
P R V O Salerno MD,
B Bourges-Sevenier BS); Division
Introduction that are phenotypically and genetically distinct have of Cardiovascular Diseases,
A changing environment and factors such as sedentary been noted, with differential susceptibility to target Department of Internal
Medicine, Wayne State
habits, seismic shifts in agrarian practices, and widespread organ complications such as cardiovascular disease,
University, Detroit, MI, USA
availability of nutrient-dense foods have irrevocably altered nephropathy, neuropathy, and retinopathy.9 Phenotypic (Prof R D Brook MD); Program
the balance between energy intake and expenditure.1 The manifestations of type 2 diabetes can include individuals for Global Public Health and
International Diabetes Federation reports that 10·5% of with excess visceral adiposity, lean individuals, and the Common Good, Boston
College, Boston, MA, USA
adults worldwide, or 537 million individuals, have type 2 individuals with predominant liver and skeletal muscle
(Prof P Landrigan MD); Centre
diabetes, with almost half of these individuals unaware deposition of fat. This phenotypic diversity complicates Scientifique de Monaco,
that they have the condition.2 By 2045, projections show genetic attribution of type 2 diabetes, as each feature Monaco (Prof P Landrigan);
that 783 million individuals will be living with type 2 might have differential genetic susceptibility, and also ISGlobal, Centre for Research in
Environmental Epidemiology,
diabetes, with 75% of these cases occurring in low-income complicates the interpretation of environmental studies,
Barcelona, Spain
and middle-income countries.2 There is strong accruing including those on air pollution. The preponderance of (Prof M J Nieuwenhuijsen PhD);
evidence linking chronic exposure to pollutants in air, soil, studies nevertheless suggests a major contribution of the Department of Cardiology,
and water with cardiometabolic health.3,4 Air pollution is by environment in shaping susceptibility to type 2 diabetes, University Medical Center of
the Johannes Gutenberg
far the most dominant environmental risk factor for health defined by glycaemic criteria, and its complications.10 University, Mainz, Germany
in general, and is responsible for over 9 million annual External factors in the built and natural environment, (Prof T Munzel MD); German
deaths globally, most of which are due to cardiovascular lifestyle and behaviours, social environment, chemical Center of Cardiovascular
causes.3,5,6 A recent Global Burden of Disease study exposures, and internal factors (such as the microbiome, Research, Partner-Site Rhine-
Main, Germany (Prof T Munzel);
estimated that a fifth of worldwide type 2 diabetes is stress, and sleep duration), which collectively constitute Louis Stokes Cleveland VA
attributable to chronic fine particulate matter (PM2·5) the exposome, have also been shown to affect Medical Center, Case Western
exposure.7 People with type 2 diabetes are likely to be more susceptibility to type 2 diabetes.11–15 Reserve School of Medicine,
susceptible to adverse health effects from PM2·5, which Cleveland, OH, USA
(S V Deo MD); DeBakey Heart
further amplifies pollution-related cardiovascular risk.3,7 Air pollution source components and and Vascular Center, Houston
This Review aims to provide an up to date summary of the relationship to metabolic disease Methodist, Houston, TX, USA
epidemiological and mechanistic evidence link­ Air pollution continues to be the world’s most pronounced (S Al-Kindi MD)
ing air pollution with diabetes, outline approaches to environmental health threat. Worldwide, poor air quality Correspondence to:
improve awareness, and review much-needed personal- accounts for 93 billion days lived with illness and more Prof Sanjay Rajagopalan,
University Hospitals, Case
level and policy interventions to help mitigate this than 6 million deaths each year, although some estimates Western Reserve University
enormous and growing global public health risk. Unless put the number of deaths well above 9 million.3 The School of Medicine, Cleveland,
otherwise stated in this Review, PM2·5 exposure in animals highest burdens of air pollution mortality are often in OH 44106, USA
almost always means inhalational exposure to concentrated large, urban cities.16 The total economic cost of air sanjay.rajagopalan@
uhhospitals.org
ambient PM2·5. Recently, preliminary evidence linking air pollution exceeds US$8 trillion, or roughly 6·1% of global
pollution and type 1 diabetes has also emerged.8 However, annual gross domestic product.17 The major sources of
given the strength of evidence for the association between modern-day air pollution in high-income countries
type 2 diabetes and air pollution, as well as its dominant include fossil fuel combustion. However, globally, other
global prevalence and relevance to cardiovascular disease, sources (eg, desert dust and volcanic ash) play a major
the focus in this Review is type 2 diabetes. role in air pollution, with growing concern related to
wildfire-associated air pollution, which is markedly
Environmental underpinnings of type 2 diabetes increasing in the USA and globally due to the effects of
Type 2 diabetes is not a single disease, but rather a group climate change.5 Air pollution chemistry and sources
of conditions broadly categorised by a single diagnostic have been reviewed extensively in previous reports, but
criterion—hyperglycaemia. Subtypes of type 2 diabetes most health effects are associated with particulate matter

www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3 1

 Review

A B

2·5 Household air pollution

Outdoor air pollution
+ Second-hand smoke
2·0 + +

Relative risk
+ +

PM2·5 concentration
in μg/m³ 1·5 + + + +
+ +
5 to 10
10 to 20
20 to 50 1·0 + +
Over 50
0 25 50 75 100 0 25 50 75 100
PM2·5 (μg/m³) PM2·5 (μg/m³)

C D

Rate per 100 000 Rate per 100000

2000 7000 12000 17000 22000 100 500 900 12000

Figure 1: Global PM2·5 and diabetes data for 2019

From Global Burden of Disease data.7 (A) Ambient PM2·5 concentrations. (B) Exposure–response curve of PM2.5 and diabetes, shown across PM2·5 0–100 μg/m³ and 0–500 μg/m³. (C) Age-standardised
prevalence of type 2 diabetes. (D) Type 2 diabetes age-standardised disability-adjusted life years associated with particulate matter pollution. PM2·5=particulate matter smaller than 2·5 μm.

fraction, with the particles being categorised by size acids and volatile organic compounds. However, the
fraction into ultrafine particles (<0·1 μm [PM0·1]), fine current understanding of each individual component’s
particles (diameter ≥0·1 μm to 2·5 μm [PM2·5]), and effect on human health is insufficient. Fresh combustion
coarse particles (diameter >2·5 μm to 10 μm [PM10]).18 PM, such as from traffic-related pollutants, is largely
Coarse particles originate from crustal materials and composed of ultrafine particles. Although there is some
agricultural and industrial practices, and can dominate evidence linking ultrafine particles with cardiometabolic
air particulate composition in certain environments. diseases, definitive data are difficult to acquire due to
PM2·5 exposure occurs primarily from fossil fuel the short-lived nature of ultrafine particles, their high
combustion from power generation and transportation, spatial variability, the focal loca­tions of exposures (such
although exposures from wildfire smoke and other as near roadways), and their high correlation to other
climate events are increasingly common and can environ­mental exposures (eg, noise).
dominate many environments for months.19–21
Air pollution is a complex mixture of gasses, particles, Global PM2.5 concentrations and burden of disease
and liquids that are continually changing and interacting Over 99% of the global population live in areas with PM2·5
with each other and natural atmospheric gasses. exposure exceeding WHO air quality guidelines (<5 µg/m³
Although PM2·5 mass has rightfully attracted attention annually) (figure 1A).23 Pollution-attributed health effects
as a target for regulation and study, more than 98% of disproportionately affect heavily popu­ lated countries,
the mass of air pollution is from gases or vapour-phase especially China and India.3,4 In 2019, only 0·18% of the
compounds, such as CO, non-methane hydrocarbons or global land area and 0·001% of the global population had
volatile organic carbons, NO2, NO, O3, and SO2.3,5,22 In an annual exposure to PM2·5 that was lower than the WHO
addition to primary pollutants formed directly by limit of 5 μg/m³.23 The mean global annual population-
combustion, many other pollutants are produced weighted PM2·5 con­centra­tion for 2000–19 was estimated at
primarily through chemical reactions in the atmosphere 32·8 μg/m³.23 Areas with higher than average Black,
and are known as secondary pollutants. Examples Asian, and Hispanic or Latino populations are routinely
include PM-associated sulphate, nitrate, and exposed to higher than average PM2·5 concentrations, with
ammonium, and many of the organic compounds evidence of significant health effects even at lower PM2·5
within PM2·5, including various inorganic and organic concentrations.24,25

2 www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3

 Review

Dose response of air pollution and incident type 2 (type 2 diabetes) that generally ranged between 10–25%.
diabetes The association between air pollution and diabetes is
A study evaluating PM2·5 exposure and the development higher in men, groups with low socioeconomic status,
of diabetes in a group of 1 729 108 US veterans with no and individuals with other comorbidities.29 A meta-
history of diabetes was one of the first to use an integrated analysis of 31 eligible cohort studies demonstrated an
exposure–response function to estimate risk.26 An increased risk for gestational diabetes associated with
increase of 10 μg/m³ in long-term PM2·5 exposure was increased PM2·5, PM10, SO2, and NO2 concentrations.30
associated with an increased risk of diabetes (hazard The presence of obesity might also modify the risk for
ratio [HR] 1·15, 95% CI 1·08–1·22) after adjusting type 2 diabetes.31 Diabetes is a complex disease that takes
for 57 variables comprising individual-level health, years to develop, with an additional period of delayed
sociodemographic factors, physical environment, and diagnosis. Given these facts, epidemiological findings
health behaviours. At levels of exposure typical for the that have categorised type 2 diabetes at the time of clinical
USA, ambient PM2·5 was calculated to contribute to about recognition are underestimates, with the real burden of
3·2 million incident cases of diabetes and 206 105 deaths.26 disease probably substantially higher.
In an updated analysis, using data from ambient air
pollution, house­ hold air pollution, and second-hand Air pollution and obesity
smoking, the Global Burden of Disease investigators In a meta-analysis to estimate the effects of childhood
extended the range of their analysis to all known global exposure to air pollutants on weight, 15 studies were
concentrations of PM2·5 (figure 1B).7 The shape of the included.32 Both obesity and BMI were significantly
exposure–response curve was curvilinear, with a more associated with annual PM10, PM2·5, and PM0·1 exposure.
robust association at lower PM2·5 levels and an attenuation The estimate was strongest for PM2·5, with an odds ratio
of the relationship above 50 μg/m³ (HR approximately (OR) of 1·28 for weight (95% CI 1·13–1·45) and 0·11 for
1·5–1·7). Applying the exposure–response curve to the BMI (0·05–0·17) per 10 μg/m³ increment in exposure.32
global population in 2019, the study estimated that 20% In a cohort consisting of male US veterans, correlations
of all diabetes-related deaths and disability-adjusted life were significant between PM2·5 exposure and obesity
years (DALYs) globally were attributable to PM2·5 (13·5% (HR 1·08, 95% CI 1·06–1·11) and weight (1·07,
to ambient air pollution and 6·5% to household air 1·06–1·08).33 Several nationwide cohort studies in adults
pollution).27 The shape of the exposure–response curve demonstrated a link between air pollution exposure and
has helped provide a credible explanation for why even obesity and other metabolic syndrome components at
low doses of second-hand smoke or air pollution are higher levels of air pollutants.34,35 Longitudinal studies
deleterious from a car­ diometabolic perspective. The have been largely negative at lower annual PM2·5
global type 2 diabetes age-standardised prevalence is concentrations (median ≤20 μg/m³).36–38 Given that air
illustrated in figure 1C, and figure 1D depicts the PM2·5- pollution concentrations have been decreas­ing over time
associated type 2 diabetes DALY rates in 2019, obtained owing to regulation, even when PM2·5 exposure was used
from the Global Burden of Disease study.28 as a time-dependent variable to adjust for decreasing
PM2·5 concentrations, levels higher than 25 μg/m³ were
Epidemiological evidence linking PM2·5 and associated with higher risks of obesity and components of
cardiometabolic disease metabolic syndrome in at least two large national
Insulin resistance cohorts.38,39
Several studies (appendix p 2–4) have shown that short- See Online for appendix
term exposure (days) to air pollution is associated with Air pollution and diabetes-related mortality
insulin resistance, a primary predisposing condition to Several studies have explored the association between
type 2 diabetes across various concentrations and age PM2·5 and diabetes-related mortality at high and low air
groups. The development timeline in humans is rapid, pollution levels. In a study of 2·1 million adults living in
occurring within hours to days. This association has Canada, at low PM2·5 exposure levels (8·7 μg/m³; SD 3·9),
been noted in children and adults across a broad range of there was an increase in the risk of diabetes-related
ages for PM2·5 and traffic-related pollutants (such as NO2). mortality per 10 μg/m³ of PM2·5 (HR 1·49, 95% CI
However, it is important to note that air pollutants often 1·37–1·62), which persisted well below levels of 5 μg/m³.40
correlate spatiotemporally; thus, it might be challenging A study of 52 061 participants in the Danish Diet, Cancer
to isolate the effects of one pollutant in epidemiological and Health cohort found an association between increased
studies. risk for diabetes-related mortality and long-term exposure
to NO2 (mortality rate ratio 1·31, 95% CI 0·98–1·76 for
Air pollution and diabetes 10 µg/m³ increase after adjustment for confounders).41
Several meta-analyses (appendix p 5–9) have reviewed Positive associations between diabetes-related mortality
the effect of air pollution exposure on diabetes incidence and exposure to short-term NO2, CO, and SO2
and prevalence; in general, air pollution exposure was concentrations have been reported in a time series study
associated with an average increase in incident diabetes conducted in Montreal.42 In the American Cancer Society,

www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3 3

 Review

Cancer Prevention Study II cohort, a 10-μg/m³ increase Taiwan associated urinary albumin-to-creatinine ratio
in PM2·5 was associated with an 18% increase in diabetes- measurements with PM2·5 and CO exposure.50 In an
related mortality.43 analysis of 469 933 deaths due to chronic kidney disease
across 2304 counties in the USA, the association between
Susceptibility and vulnerability PM2·5 and chronic kidney disease mortality was strongest
The health effects of air pollution from a cardiometabolic among counties with the highest social deprivation index
perspective are pronounced among low-income and (β0·70, 95% CI 0·49–0·92I), versus counties with the
minoritised racial and ethnic groups populations, partly lowest social deprivation index (β0·49, 0·41–0·56).51
due to increased exposures.24,25 Evidence also shows that Few studies have examined the association between
the benefit of lowering PM2·5 levels, even to well below the PM2·5 and diabetic retinopathy risk. In a study of newly
current US National Ambient Air Quality Standards diagnosed diabetes in Taiwan (2003–12), which included
standard of 12 mg/m³, might also be larger in these 579 patients, every 10 μg/m³ increase in PM2·5 was
populations.44,45 Although some studies have shown that associated with a 29% increase in the odds of retinopathy
people with diabetes might have greater adverse health (OR 1·29, 95% CI 1·11–1·50), whereas every 10 μg/m³
effects compared with those without diabetes at similar increase in PM10 was associated with a 37% increased risk
PM2·5 exposure levels, this is not a consistent finding in developing retinopathy (1·37, 1·17–1·61).52
because people with diabetes show substantial variation
in health (eg, duration of disease and risk factor profile) Non-alcoholic fatty liver disease
and medication treatment.45 In a nationwide cross-sectional analysis in the USA in
patients with non-alcoholic fatty liver disease (n=269 705)
Cardiovascular risk there was a positive association between ambient PM2·5
The evidence that links acute and chronic PM2·5 exposure and the odds of non-alcoholic fatty liver disease
exposure with fatal and non-fatal cardiovascular events, (adjusted OR 1·24 per 10 μg/m³ increase, 95% CI
including stroke and heart failure, has been reviewed 1·15–1·33) among hospitalised patients.53 Despite the
extensively.3,5 A small number of studies have PM2·5 exposure levels being much higher than those in
investigated PM2·5 and cardiovascular risk in type 2 the USA and Europe, similar results were also
diabetes. In a subset of the 2001 Canadian Census demonstrated using nationwide data from China.54
Health and Environment Cohort, association between
PM2·5 and cardiovascular mortality was stronger in Air pollution exposure during pregnancy and diabetes
people with diabetes (HR 1·51, 95% CI 1·39–1·65, per A recent meta-analysis investigated the association
10 μg/m³) compared with those without (1·20, between exposure to PM2·5 and gestational diabetes at
1·16–1·25), suggesting increased PM2·5 susceptibility in various stages of pregnancy.55 For the full pregnancy, the
patients with diabetes.46 In a study from China including pooled relative risk (RR) was 1·074 (95% CI 1·001–1·152).
15 477 individuals with multipollutant ascertainment Moreover, during the first and second trimesters,
(eg, PM1·0, PM2·5, PM10, SO2, NO2, and O3), diabetes status RRs of 1·015 (1·000–1·031) and 1∙021 (1·006–1·035),
potentiated the relationship between pollutants and respectively, were observed. However, no significant
cardiovascular disease in all exposures.47 association was found between preconception exposure
to PM2·5 and gestational diabetes (1·013, 0·990–1·038).
Renal and ophthalmic risk In another study from Taiwan that explored the poten­
Emerging evidence suggests that PM2·5 is associated with tial effect-modifying capacity of PM2·5 exposure on
chronic kidney disease in populations both with and development of type 2 diabetes in women with and
without diabetes. Bowe and colleagues described a linear without gestational diabetes, the odds ratio of diabetes
relationship between long-term PM2·5 exposure, incident per interquartile range increase in PM2·5 was 1·31
chronic kidney disease, and progression to end-stage (1·22–1·41), with the risks of developing type 2 diabetes
renal disease that was independent of the presence with exposure to increased PM2·5 levels being significantly
of diabetes.48 In another cohort study of more than higher in the gestational diabetes group than the non-
2·4 million US veterans with median 8·5 years of follow- gestational diabetes group.56 Despite this evidence, there
up, Bowe and colleagues found that a 10 µg/m³ increase are still substantial knowledge gaps that require further
in PM2·5 was associated with increased odds of diabetes investigations to explore the ramifications of PM2·5
and chronic kidney disease.49 Diabetes mediated 4·7% exposure during different gestational periods and the
(4·3–5·7) of the association of PM2·5 with incident esti­ potential long-term cardiometabolic effects.
mated glomerular filtration rate (eGFR) less than
60 mL/min per 1·73 m², 4·8% (95% CI 4·2–5·8) with Towards mechanistic understanding of air
incident chronic kidney disease, 5·8% (5·0–7·0) with 30% pollution-mediated metabolic risk
or greater decline in eGFR, and 17·0% (13·1–20·4) with Understanding of the pathways by which air pollution
end-stage renal disease or 50% or greater decline might contribute to the risk of heart and metabolic
in eGFR.49 A longitudinal study of people with diabetes in problems, while still evolving, have been refined over the

4 www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3

 Review

Biological intermediates
oxPAPC, unsaturated FA
STRESS
HETES or HODES NF-κB
Acyl carnitines
Oxidised lipids CRH
Particles and soluble metals Pituitary Ove
rn Air pollution
ACTH (particulates and gaseous

utr
ition
components, eg, ozone)
Endocrine response

Adrenal gland

INFLAMMATORY
Hypothalamic–pituitary–adrenal SIGNALS
activation
Autonomic
Alveoli
Alve
Alv
veoli nervous
Afferent
imbalance
Cortisol fibres

Microbiome STRESS
HYPERGLYCAEMIA SIGNALS
PAMPs Immune response
O2– DAMPs
Endothelial disruption
NADPH oxidase
TLR

Sympathetic

–
nerve +

ve
Activation of PRRs
MyD88

Macrophage (eg, TfRs) Monocyte ner

us
P
Vag

NF-κB IκB
OXIDATIVE STRESS ROS and RNS Macrophage
NF-κB NF-κB
PP
P Fas
INFLAMMATION P P50 P65 JUN
Mitochondriaa
Inflammatory Type-1 IFN genes INFLAMMATION
cytokine genes ↑Proinflammatory cytokines
↑Chemokimes
↑Adhesion molecules
Epigenetic changes ↑Acute phase reactants
Chronic inflammation
Low-grade oxidative stress

Cardiometabolic disease

Figure 2: Mechanisms of PM2·5-mediated metabolic and cardiovascular effects

ACTH=adrenocorticotropic hormone. AMP=activated molecular patterns. CRH=corticotropin releasing hormone. DAMPs=disease-activated molecular patterns.
FA=fatty acids. HETES=hydroxyeicosatetraenoic acids. HODES=hydroxyoctadecadienoates. IFN=interferon. IκB=IκB kinase. MyD88=myeloid differentiation primary
response protein 88. NADPH=nicotinamide adenine dinucleotide phosphate. NF-κB=nuclear factor κB. oxPAPC=oxidised phospholipid 1-palmitoyl-2-arachidonoyl-
sn-glycero-3-phosphorylcholine. PAMPs=pathogen. PRRs=pattern recognition receptors. RNS=reactive nitrogen species. ROS=reactive oxygen species.
TfR=transferrin receptor. TLR=toll-like receptors.

past decade.5 The generally understood pathways by autonomic imbalance; hypothalamic–pituitary–axis

which air pollution might potentiate cardiometabolic activation; nanoparticles or pollutants reaching the
disease are depicted in figure 2. Conceptually, these circulation or transmitted via neurological pathways; and
pathways could be viewed as follows: primary initiating effector mechanisms in insulin responsive organs. These
pathways that are localised in the airways and lungs, and pathways could include one or multiple mechanisms,
might comprise oxidative stress, ion channel or receptor such as endothelial barrier disruption; adipose and
activation, and inflammation; systemic transduction of hepatic inflammation; endoplasmic reticulum stress;
metabolic effects through release of biological brown adipose tissue and mitochondrial dysfunction;
intermediates (eg, oxidised lipids, cytokines, activated end-organ responses to autonomic imbalance and CNS
immune cells, microparti­cles, microRNA, endothelins); activation, includ­ing hypothalamic inflammation or

www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3 5

 Review

products—can occur, and has been implicated in

↑Bone marrow translating systemic responses.58 This transformation is
Immune system
Mobilisation
evidenced by markers and mediators such as 8-iso-
M prostaglandin2α, malondialdehyde, oxidised-LDL,
oxidised HDL species, and lipid peroxidation biomarkers,
T ↑Th1 ↓Th2 ↓Treg which have all been noted to be associated with higher
levels of PM2·5 and other air pollutant exposure in
humans.58–60 Conversely, in reducing air pollution levels
Adipose tissue
with filtration and treatment with antioxidants, fish oils
T ↑M1 ↓M2 have been shown to mitigate markers of oxidant stress in
↑Th1 ↓Th2 ↓Treg
T
M ↑Lipogenesis response to PM exposure.61
T
Air pollution ↓Lipolysis
M
Systemic transduction of air pollution effects
The direct translocation of pollutant particles and
Liver
other leachable components is now well established in

Insulin Resistance
↑Inflammation
↑Lipogenesis humans.3,5,10 The formation and transmission of reactive
↓Lipolysis bio­logical intermediates, including oxidant stress-
↑Gluconeogenesis
↓Glycolysis
generated signal transduction molecules, might mediate
Muscle systemic metabolic effects.10 Oxidative stress produced in
the lung is important in transducing systemic insulin
↓Glucose uptake resistance and inflammation. Inhalational exposure to
↓GLUT4
concentrated PM2·5 for 10 days in mice has been shown to
Brain increase circulating saturated fatty acids (eg, palmitate),
Blood–brain barrier dysfunction unsaturated fatty acids (eg, palmitoleate and myristoleate),
↑Neural inflammation acyl carnitines, and bile acid metabolites. Overexpression
Circadian disruption
of extracellular superoxide dismutase in the lung
prevented not only the increase in circulating biomarkers,
but vascular inflammation in response to concentrated
Brown adipose tissue PM2·5 exposure.62 A 2-week exposure to ultrafine particles
(diesel exhaust) led to increased lipid peroxidation and
Altered batokines
Transcriptional reprogramming
reduced plasma HDL protective capacities. Malondi­
↓Thermogenesis aldehyde and products of arachidonate metabolism, such
as hydroxyeicosate­traenoic acids and hydroxyoctadecad­
ienoates, occurred preferentially in the plasma and liver,
and less so in the lung.63 In a double-blind, randomised
Figure 3: Organ-specific mechanisms of air pollution-related insulin resistance trial in China, air filtration lowered participants’ blood
GLUT4=glucose transporter type 4. M=macrophages. T=T cells. Th1=type 1 helper T cell. Th2=type 2 helper T cell. pressure and various metabolic mediators, including
Treg=regulatory T cell.
inflammatory and oxidant stress measures.64 The effect
dysfunction, and hypothalamic–pituitary–axis activation of inflammation resolution measures in mitigating
(eg, vasoconstric­
tion, increased blood pressure, and responses to PM exposure needs to be better understood.
hypercortisolaemia); and organ responses to circadian Air pollution components or biological intermediates
disruption. can be sensed by multiple families of sensing receptors,
Specific pathways relevant to insulin resistance are including toll-like receptors (TLR2 and TLR4), nucleotide-
depicted in figure 3. In reality, the pathways can be binding domain leucine-rich repeats of nucleotide
much more complex and mutually dependent than what oligomerisation domain-like receptors, and transient
is conceptualised in figure 2 and figure 3, with receptor potential (TRPA1 and TRPV1) channels.10,57 A few
temporally overlapping timescales. Also, biological human panel studies and double-blind interventional
effects might vary based on individual predilection and trials of air-purifiers have shown an association between
the composition of air pollution. PM2·5 exposure and several plasma inflammatory markers
(eg, C-reactive protein, IL-6, and tumour necrosis
Primary initiating pathways factor-α). Reduc­tion in some of these markers with air
Oxidative stress is the first hierarchical response in filtration that suggests a cause and effect relationship, but
reaction to air pollution exposure, occurring initially the results of these studies have not always been
in the respiratory tract and lungs, and playing a key consistent.61,64–66
role in many of the subsequent pathways.57 Chemical Experimental studies with chronic inhalation exposure
transformation of endogenous thiols, fatty acids, and to concentrated ambient PM2·5 have implicated infiltration
lipids—resulting in the additional generation of reactive of monocytes as a cause of inflammation and an M1–M2

6 www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3

 Review

switch in adipose tissue. TLR4 appears to be crucial in the

effects of PM2·5, including haematopoietic efflux and tissue Food systems
Healthy municipal
infiltration.67 C–C chemokine receptor type 2 (CCR2) and food procurement;
chemokine (C–X–C motif) receptor 3 also appear to be reducing waste;
sustainable food
crucial in the inflammatory response to PM2·5 through Energy reform environments Lifestyle
distinct monocyte and T-cell mediated pathways.68 Shift to clean Regular exercise;
energy sources; planetary diets;
CCR2-knockout mice, fed high-fat chow, show reduced clean transportation sleep hygiene
adipose inflammation, improved whole-body insulin
resistance, and reduced hepatic lipid accumulation.69
Chemokine (C–X–C motif) receptor 3 knockout (CXCR3)
plays a role in the migration of activated T-cell populations
(CD44+, CD62L–, and CD4+) into adipose tissue and lungs.68
The overall effects of chronic exposure to concentrated
airborne particulate matter in the animal model appears to
be consistent with systemic type 1 immunity (type 1 helper
T cells [Th1]) dominant immune responses, with a skew
from M2 towards M1 and from Th2 towards Th1 in tissue Governmental Ecosystem
Policy changes; Urban redesign;
depots. incentives to reduce green infrastructure;
Dysregulation of the autonomic nervous system and emissions; walking trails;
sympathetic activation have been noted acutely in low-cost monitoring recreational areas

humans and animal models with inhalational exposure Health-care

organisation
to air pollution.58,70,71 Given the well known relationship Risk prediction;
between sympathetic activation and insulin resistance, climate education;
Health-care organisation
activation of this pathway in response to PM2·5 and : reform
energy m
ultrafine particle exposure (commonly inferred by an
acute reduction in heart rate variability or increase in
blood pressure and elevation in catecholamines) in both
panel studies and with direct inhalational exposure in
humans is supportive of the relevance of this pathway in Figure 4: Mitigation strategies to control air pollution-related cardiometabolic disease
insulin resistance with air pollution exposure.72
Randomised filtration interventions to lower air pollution function.58,70 Alterations in endothelial function might
levels also provide supportive evidence for the causal translate into muscle insulin resistance and hyper­
involvement of sympathetic nervous system and tension. Endothelial barrier dys­ function has been
hypothalamic–pituitary–adrenal axis activation.64,73 Acute noted in sites such as the blood–brain barrier in
experiments in canine models and studies in chronically response to PM2·5 and ultrafine particle exposure.
cannulated mice exposed to concentrated ambient PM2·5 Endothelial barrier dysfunction might provide a poten­
have documented increased blood pressure, with tial mechanism by which PM2·5 can predispose individ­
evidence of CNS and sympathetic nervous system uals to peripheral effects that include brown adipose
activation in response to PM2·5 exposure.74,75 Abnormalities tissue dysfunction, white adipose tissue inflammation,
in autonomic function or blood pressure responses are, and insulin resistance.79,80
however, not consistently observed, and might relate to
compositional differences of pollution exposures and Adipose and hepatic inflammation
study design.76,77 Inhalation of diesel exhaust ultrafine Inhalational exposure to PM2·5 hastens the development
particles caused a significant elevation within 30 min in of insulin resistance and abnormal glucose tolerance in
muscle sympathetic nerve activity metrics compared both diet-induced and genetic models of obesity.80
with filtered air. Heart rate significantly increased, and Genetic ablation of CCR2 and neutrophil cytosol factor 1
there were trends for systolic and diastolic blood (p47phox) improves concentrated airborne particulate-
pressure elevations, probably haemodynamic conse­ induced insulin resistance and adipose inflammation,
quences of sympathetic nervous system activation. Other and is indeed consistent with the important role of
components of air pollution, such as volatile organic CCR2 and oxidant stress pathways in inflammatory
compounds (eg, acrolein and 1,3-butadiene), might monocyte and macrophage recruitment into adipose
contribute to elevated blood pressure in participants with tissue and insulin resistance.69,81 Chronic concentrated
increased sympathetic tone.78 ambient PM2·5 exposure has been associated with a multi­
tude of abnormalities in the liver involving glucose
Effector mechanisms in insulin-responsive organs transport, metabolism, lipolysis–lipogenesis balance,
Previous reviews have extensively examined the effect altered insulin signalling, inflammation, and findings
of air pollution on conduit artery and resistance vessel consistent with steatohepatitis.69,82,83

www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3 7

 Review

Endoplasmic reticulum stress light at night exposure showed that, although PM2·5 and
Experimental studies provide substantial evidence that light at night induced an identical phenotype of insulin
supports activation of all three components of the resistance and metabolic dysfunction, the transcrip­
evolutionarily conserved unfolded protein response or tional and epigenetic pathways (including differentially
endoplasmic reticulum stress with PM2·5 exposure.84,85 expressed circadian genes) seemed to differ. In humans,
Endoplasmic reticulum stress is an essential regulator of metabolic syndrome parameters, sleep deprivation, and
adipocyte lipid metabolism and adipose tissue depression (circadian syndrome) were highly correlated
inflammation. Concentrated airborne particulate with PM2·5 exposure.71
exposure in C57BL/6J mice for 10 months resulted in
increased adipocyte size and lipid deposition in white Epigenomic changes
adipose tissue, together with increased endoplasmic Epigenetic reprogramming in response to environmental
reticulum stress genes (such as BiP/GRP78, Xbp-1, and exposures might represent a crucial buffer against an
Edem1) in white adipose tissue, along with genes involved adverse health response by regulating gene expression
in lipogenesis (Acaca), transport (CD36), triglyceride and chromosome integrity.95 Chronic PM2·5 exposure
synthesis (Dgat2), and adipocyte differentiation or lipid promoted substantial chromatin remodelling, especially
droplet formation (Smaf1, Ceacam1, Fsp27, Plin1, and at promoter and enhancer sites that were pliable, with
Fit2).86 cessation of exposure resulting in a reversal of changes in
chromatin accessibility and of expression of transcripts—
Brown adipose tissue effects notably those involved in insulin action, circadian
In experiments performed in metabolic cages in rhythm, and inflammation.71 Methylation changes and
C57BL/6J mice, concentrated airborne particulate epigenomic changes in networks enriched for pathways
exposure resulted in reduced VO2 and VCO2 levels and related to inflammation, thrombosis, insulin resistance,
decreased thermogenesis, consistent with a reduction in and lipid metabolism have all been noted.95
metabolism.71,87,88 These effects were associated with
a reduction in uncoupled protein-1 expression in brown Opportunities for mitigating air pollution
adipose tissue and dysregulation of multiple transcrip­ cardiometabolic health effects
tional regulators of brown adipose tissue metabolism One of the most important first steps in preventing air
and function.88 pollution-mediated metabolic diseases worldwide is to
acknowledge the impact of environmental factors such
CNS inflammation in key energy regulatory centres as air pollution on these conditions. Studies on pollution
A considerable amount of human data suggest that inequity or the differences between environmental
hypothalamic inflammation and dysregulation of energy health exposures have shown that disproportionally high
balance and glucose homoeostasis might be at the core of direct exposure to pollution and climate-related risk
type 2 diabetes.89 Both short-term and long-term exposure factors results in substantial life expectancy disparities,
to air pollutants have been shown to induce hypothalamic even between adjacent post-codes.44,96 There is a direct
inflammation and reduce metabolism, with reversal link between climate change and air pollution, and
noted in response to inhibition of inflammatory both can have direct and indirect effects on health.97
mediators in the brain.88,90 Energy balance is also Overall, climate change might worsen air quality by
impacted through the aforementioned brown adipose altering meteorological air pollution removal processes
tissue mechanisms and through alterations in the and intensifying responses in atmospheric chemistry
hypothalamic–pituitary–adrenal axis. Increased secretion from both man-made and natural sources.98 Although
of corticosterone and catecholamines has been demon­ strategies to reduce climate change can have co-benefits
strated in animal models and humans in response to in reducing air pollution, there might also be short-term
both PM2·5 and ozone exposure.64,71,90–92 In a post-hoc unintended responses that could affect climate. For
analysis of the MESA cohort, higher levels of annual NO2 instance, a reduction of sulphate emissions from ships
and PM2·5 were associated with higher epinephrine and has been linked to reduced cloud cover and global
dopamine levels.93 warming.99,100 There is a real need for dissemination of
the health impacts of climate, and dire need for
Circadian disruption integrating the health impact of climate in all policy
Previous experimental studies have demonstrated that decisions.
circadian genes are some of the most commonly Integrated mitigation strategies to address car­
expressed genes in response to air pollution exposure.94 diometabolic health that might help improve physical
C57BL/6 mice exposed to concentrated ambient PM2·5 activity and healthy nutrition, but also curb air pollution,
showed insulin resistance, reduced energy expenditure, ultimately advancing health, climate, and equity goals, are
decreased thermogenesis, decreased metabolism, and illustrated in figure 4. Policies that endorse clean energy
dysregulated circadian genes that reversed with cessation transition, enforcement of pollution control standards, and
of exposure.94 A study comparing exposure to PM2·5 with incentives for reducing processed foods and increasing

8 www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3

 Review

consumption of plant-based foods, will substantially reduce impact on emissions can be seen, together with cost
the burden of type 2 diabetes.3,101 The simultaneous savings. Including planetary diets in hospitals will allow
promotion of clean energy modes of public transportation much-needed alignment of health benefits with planetary
and active transport, such as walking and biking, can help goals.106
reduce air pollution and improve physical activity. Health
impact studies indicate that the health and economic Air pollution and exercise
benefits of increasing active transportation simultaneously Acute elevations in air pollution might discourage
with clean energy transportation vastly exceed those divined physical activity and increase sedentary behaviour in
by policies promoting electric mobility transition alone.102 adults and children. Several regulatory authorities, such
Thus, increasing active transport must be integral to clean as the UK Department of Environment and the US
energy policy, and new innovative urban design and Environmental Protection Agency, recommend that the
planning, such as the 15-minute City in Paris, superblocks general population should restrict outdoor physical
in Barcelona, and car-free neighbourhoods in Freiburg, are activity on days when PM2·5 levels exceed predefined
greatly needed.103 Similarly, a shift to locally sourced plant- thresholds. Based on health impact modelling studies,
based diets, even partly, might considerably reduce even in areas with very high PM2·5 concentrations (annual
greenhouse gas emissions and PM2·5 pollution, and average 120 µg/m³), the overall favourable effects of
improve metabolic health.104 Urban redesign with low- outdoor exercise—either in the form of cycling or
carbon sustainable construction materials, green infras­ walking—obviates the negative effects of inhaling high
tructure, and walking trails might help increase physical levels of air pollution, with a reduction in mortality risk
activity while reducing embodied carbon and air pollution with cycling of 15% in Beijing and 14% in New Delhi,
from the manufacturing, transportation, installation, and assuming annual average PM2·5 concentrations of
disposal of building materials.104 95 μg/m³ in Beijing and 120 μg/m³ in New Delhi.107 It is
The American Heart Association statement on personal important to note that these reported reductions in
protective actions against air pollution, which considers mortality risk are in healthy individuals, and whether
both exposure risks and individual susceptibility, provides these results are applicable to high-risk individuals (eg,
a useful framework for individuals at high risk for air individuals with type 2 diabetes and cardiovascular or
pollution-mediated health effects.61 Portable air cleaners renal disease) is unknown. Overall, the health benefits of
are practical and inexpensive in-home strategies suited regular exercise appear to outweigh the risks of pollution
for at-risk populations, and can help acutely reduce PM2·5 exposure in all but the most extreme settings.
exposures by as much as 60%.61 Several small, short-term, Nevertheless, it is a reasonable precautionary approach to
randomised studies in humans have provided proof of exercise indoors or outdoors away from pollution sources
concept that reductions in PM2·5 exposures with portable (eg, roadways) or postpone the timing of exercise, if
air cleaners can result in rapid, albeit small, reductions possible, to less polluted periods.
in blood pressure and other markers of adverse
cardiometabolic risk effects, including inflammation Challenges and opportunities for the future: air
(eg, lower C-reactive protein and IL-6), which are well pollution and beyond
established risk factors for type 2 diabetes.61 In areas Given the importance of air pollution as a relevant risk
facing very high levels of PM2·5, or during extreme air factor for cardiometabolic disease, progressive reduction
pollution events (such as occurs regionally for days to in fossil fuel emissions through the transition to clean
weeks from wildfires), indoor portable air cleaners with energy is expected to decrease the incidence of
high-efficiency particulate air filtration, in addition to cardiometabolic disease. Although air pollution
N95 face masks when travelling outdoors, might be emissions are decreasing, worsening trends in physical
warranted for individuals at high risk of cardiometabolic activity, diet, and exposures to chemical pollution could
effects. Some small studies have shown the potential for outweigh these improvements.
health protection from wearing face masks; however, The creation of sustainable environments with
more work is needed in this regard.21,61 attention to urban spatial design to encourage walking
Health-care organisations and non-profit organisations and active transportation, and with attention to the
are well positioned to not only urge governments to take key provisioning systems of food supply, energy,
action to prevent pollution-related cardiovascular disease transportation, buildings, sanitation, water, and green
by setting targets and timetables for pollution reduction, infrastructure, provide the greatest opportunity to reduce
but to lead the way in attaining net zero emission targets. car­
diometabolic disease while ensuring climate and
The economic impact of the pollution derived from the equity goals. Currently, inadequate and antiquated
US health-care system is comparable to the economic provisioning systems are responsible for multiple
impact attributable to medical errors.105 Importantly, the adverse health exposures, such as regional air pollution,
economic impact of pollution is primarily driven by air local soil or water pollution, adverse nutritional
pollution.105 By mandating sustainability standards in exposures, and climate risks. Policy, appropriate
hospitals and health-care organisations, an immediate governance, and legal frameworks enable execution of

www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3 9

 Review

high-throughput genomic and epigenomic approaches,

Search strategy and selection criteria high-resolution metabolomics, and network science,
References for this Review were identified through searches have allowed us to take the first steps toward a
of PubMed for articles published from Jan 01, 2006, to comprehensive assessment of the exposome and its
June 30, 2023, using the search terms “diabetes”, “insulin effects on cardiometabolic health.109,110 Linking exposomic
resistance”, “exercise“, “obesity”, “cardiovascular disease”, signatures with biological surrogates and endpoints
“health impact”, and “cardiometabolic”, in combination with might provide new insights into the pathophysiology of
the term “air pollution”. Articles resulting from these cardiometabolic disease.111
searches, and relevant references cited in those articles, were
reviewed and included when appropriate. Articles were Research gaps
required to have a full-text English version. Both human and There are still substantial research gaps in our knowledge
animal studies were considered. No additional search of air pollution and its effect on cardiometabolic disease.
restriction or selection criteria was applied. A greater mechanistic understanding of the impact of the
specific subcomponents of PM2·5 is required. Further­
more, interventional studies evaluating the effect of PM2·5
urban planning decisions and regulation of risk mitigation approaches, such as personal air filtration
exposures. The shortage of policy levers and governance devices, and the effect of PM2·5 mitigation approaches
of urban decisions is at the core of unregulated urban on cardiometabolic outcomes, could provide valuable
proliferation and acceleration of adverse cardiometabolic evidence for development of individual-level interven­
outcomes in many urban environments worldwide. The tions. The effect of air pollution needs to be understood
economic valuation of the negative externalities of air in the context of multiple social and environmental
pollution, including its impact on health, can help justify exposures that might co-segregate with air pollution and
clean energy initiatives with rapid recoupment of initial drive risk associa­tions with cardiometabolic health. Given
investments. The Organization for Economic Co- the increased recognition of the dominant role that non-
operation and Development, using such a model, genetic factors play in type 2 diabetes, an effort to
estimated that global air pollution-related health-care characterise the exposome at a scale similar to that of the
costs will increase from US$21 billion in 2015 to human genome is warranted.
$176 billion in 2060.108 Furthermore, the market effects
of outdoor air pollution, due to impacts on labour Conclusion
productivity, health expenditure, and agricultural crop Air pollution is a major determinant of cardiometabolic
yields, might reach 1% of the global gross domestic disease globally, and a major contributor to climate change.
product by 2060. Importantly, air pollution continues to Efforts to reduce air pollution exposure and mitigate its
be a negative externality that is not paid for by either health effects involve raising individual awareness,
the consumer or the polluter. The use of financial appropriate policy levers to reduce sources of air pollution,
instruments to regulate pollution (polluter pays) could and measures to reduce personal health impact.
help catalyse a shift to cleaner solutions. Contributors
Although global PM2·5 guidelines are important for SR, PRVOS, and BB-S researched data, contributed to discussion, and
alignment between country policies, and a step in the wrote the first draft of the manuscript. RDB, PL, MJN, TM, SVD, and
SA-K reviewed and edited the manuscript.
right direction, national, state, and local strategies must
also be identified and developed to reduce PM2·5. Sector- Declaration of interests
We declare no competing interests.
specific plans might also help with optimising the cost-
effectiveness of PM2·5 interventions and improving Acknowledgments
This study was partly funded by NIH grants (R35ES031702,
industry accountability.108 R01ES019616, R01HL141846).
A revolution in personal devices that quantify human
References
health and provide exposure information to a range of 1 Tuomisto HL, Scheelbeek PFD, Chalabi Z, et al. Effects of
chemicals and entities, in addition to PM2·5, provides an environmental change on population nutrition and health:
opportunity to develop better predictors of human a comprehensive framework with a focus on fruits and vegetables.
Wellcome Open Res 2017; 2: 21.
health. Air pollution coexists with enduring elements in 2 International Diabetes Federation. IDF Diabetes Atlas 2021. 2021.
the built environment and other key provisioning https://diabetesatlas.org/atlas/tenth-edition (accessed July 21, 2023).
systems that foster sedentary habits, poor nutritional 3 Rajagopalan S, Landrigan PJ. Pollution and the heart. N Engl J Med
2021; 385: 1881–92.
choices, and exposures to chemicals implicated in type 2
4 Fuller R, Landrigan PJ, Balakrishnan K, et al. Pollution and health:
diabetes. The exposome concept strives to capture the a progress update. Lancet Planet Health 2022; 6: e535–47.
diversity and range of internal and external exposures in 5 Al-Kindi SG, Brook RD, Biswal S, Rajagopalan S. Environmental
the environment, such as pollution, synthetic chemicals, determinants of cardiovascular disease: lessons learned from air
pollution. Nat Rev Cardiol 2020; 17: 656–72.
dietary constituents, psychosocial stressors, and climate 6 Lelieveld J, Klingmüller K, Pozzer A, et al. Cardiovascular disease
related factors, and their corre­ sponding biological burden from ambient air pollution in Europe reassessed using
responses. Technological advances, such as unbiased novel hazard ratio functions. Eur Heart J 2019; 40: 1590–96.

10 www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3

 Review

7 GBD 2019 Diabetes and Air Pollution Collaborators. Estimates, 29 Sørensen M, Poulsen AH, Hvidtfeldt UA, et al. Effects of
trends, and drivers of the global burden of type 2 diabetes sociodemographic characteristics, comorbidity, and co-exposures on
attributable to PM2·5 air pollution, 1990–2019: an analysis of data the association between air pollution and type 2 diabetes:
from the Global Burden of Disease Study 2019. Lancet Planet Health a nationwide cohort study. Environ Health Perspect 2023; 131: 27008.
2022; 6: e586–600. 30 Liang W, Zhu H, Xu J, et al. Ambient air pollution and gestational
8 Mozafarian N, Hashemipour M, Yazdi M, et al. The association diabetes mellitus: an updated systematic review and meta-analysis.
between exposure to air pollution and type 1 diabetes mellitus: Ecotoxicol Environ Saf 2023; 255: 114802.
a systematic review and meta-analysis. Adv Biomed Res 2022; 11: 103. 31 Li X, Wang M, Song Y, et al. Obesity and the relation between joint
9 Nair ATN, Wesolowska-Andersen A, Brorsson C, et al. exposure to ambient air pollutants and incident type 2 diabetes:
Heterogeneity in phenotype, disease progression, and drug a cohort study in UK Biobank. PLoS Med 2021; 18: e1003767.
response in type 2 diabetes. Nat Med 2022; 28: 982–88. 32 Huang C, Li C, Zhao F, Zhu J, Wang S, Sun G. The association
10 Rajagopalan S, Al-Kindi SG, Brook RD. Air pollution and between childhood exposure to ambient air pollution and obesity:
cardiovascular disease: JACC state-of-the-art review. a systematic review and meta-analysis.
J Am Coll Cardiol 2018; 72: 2054–70. Int J Environ Res Public Health 2022; 19: 4491.
11 Bunker A, Wildenhain J, Vandenbergh A, et al. Effects of air 33 Bowe B, Gibson AK, Xie Y, et al. Ambient fine particulate matter
temperature on climate-sensitive mortality and morbidity outcomes air pollution and risk of weight gain and obesity in US veterans:
in the elderly; a systematic review and meta-analysis of an observational cohort study. Environ Health Perspect 2021;
epidemiological evidence. EBioMedicine 2016; 6: 258–68. 129: 47003.
12 De la Fuente F, Saldías MA, Cubillos C, et al. Green space exposure 34 Han W, Xu Z, Hu X, et al. Air pollution, greenness, and risk of
association with type 2 diabetes mellitus, physical activity, and overweight among middle-aged and older adults: a cohort study in
obesity: a systematic review. Int J Environ Res Public Health 2020; China. Environ Res 2023; 216: 114372.
18: 97. 35 Zheng X, Tang S, Liu T, et al. Effects of long-term PM2·5 exposure on
13 Dzhambov AM. Long-term noise exposure and the risk for type 2 metabolic syndrome among adults and elderly in Guangdong,
diabetes: a meta-analysis. Noise Health 2015; 17: 23–33. China. Environ Health 2022; 21: 84.
14 Motairek I, Lee EK, Janus S, et al. Historical neighbourhood 36 Matthiessen C, Lucht S, Hennig F, et al. Long-term exposure to
redlining and contemporary cardiometabolic risk. J Am Coll Cardiol airborne particulate matter and NO2 and prevalent and incident
2022; 80: 171–75. metabolic syndrome—results from the Heinz Nixdorf Recall Study.
15 Münzel T, Sørensen M, Hahad O, Nieuwenhuijsen M, Daiber A. Environ Int 2018; 116: 74–82.
The contribution of the exposome to the burden of cardiovascular 37 Kim JS, Chen Z, Alderete TL, et al. Associations of air pollution,
disease. Nat Rev Cardiol 2023; 20: 651–69. obesity and cardiometabolic health in young adults: the Meta-AIR
16 Khomenko S, Cirach M, Pereira-Barboza E, et al. Premature study. Environ Int 2019; 133(Pt A): 105180.
mortality due to air pollution in European cities: a health impact 38 Voss S, Schneider A, Huth C, et al. ENVINT-D-20-01309: long-term
assessment. Lancet Planet Health 2021; 5: e121–34. exposure to air pollution, road traffic noise, residential greenness,
17 Awe YA, Larsen BK, Sanchez-Triana E. The global health cost of PM2·5 and prevalent and incident metabolic syndrome: results from the
air pollution: a case for action beyond 2021. International population-based KORA F4/FF4 cohort in Augsburg, Germany.
development in focus. 2022. https://documents.worldbank.org/en/ Environ Int 2021; 147: 106364.
publication/documents-reports/documentdetail/455211643691938459/ 39 Chen YC, Chin WS, Pan SC, Wu CD, Guo YL. Long-term exposure
the-global-health-cost-of-pm2-5-air-pollution-a-case-for-action- to air pollution and the occurrence of metabolic syndrome and its
beyond-2021 (accessed July 23, 2023). components in Taiwan. Environ Health Perspect 2023; 131: 17001.
18 Al-Kindi SG, Brook RD, Biswal S, Rajagopalan S. Environmental 40 Brook RD, Cakmak S, Turner MC, et al. Long-term fine particulate
determinants of cardiovascular disease: lessons learned from air matter exposure and mortality from diabetes in Canada. Diabetes Care
pollution. Nat Rev Cardiol 2020; 17: 656–72. 2013; 36: 3313–20.
19 DeFlorio-Barker S, Crooks J, Reyes J, Rappold AG. 41 Raaschou-Nielsen O, Sørensen M, Ketzel M, et al. Long-term
Cardiopulmonary effects of fine particulate matter exposure among exposure to traffic-related air pollution and diabetes-associated
older adults, during wildfire and non-wildfire periods, in the USA mortality: a cohort study. Diabetologia 2013; 56: 36–46.
2008–10. Environ Health Perspect 2019; 127: 37006. 42 Goldberg MS, Burnett RT, Yale JF, Valois MF, Brook JR.
20 Wettstein ZS, Hoshiko S, Fahimi J, Harrison RJ, Cascio WE, Associations between ambient air pollution and daily mortality
Rappold AG. Cardiovascular and cerebrovascular emergency among persons with diabetes and cardiovascular disease.
department visits associated with wildfire smoke exposure in Environ Res 2006; 100: 255–67.
California in 2015. J Am Heart Assoc 2018; 7: e007492. 43 Pope CA 3rd, Turner MC, Burnett RT, et al. Relationships between
21 Hadley MB, Henderson SB, Brauer M, Vedanthan R. Protecting fine particulate air pollution, cardiometabolic disorders, and
cardiovascular health from wildfire smoke. Circulation 2022; cardiovascular mortality. Circ Res 2015; 116: 108–15.
146: 788–801. 44 Josey KP, Delaney SW, Wu X, et al. Air pollution and mortality at
22 Brook RD, Rajagopalan S, Pope CA 3rd, et al. Particulate matter air the intersection of race and social class. N Engl J Med 2023;
pollution and cardiovascular disease: an update to the scientific 388: 1396–404.
statement from the American Heart Association. Circulation 2010; 45 Kan H, Jia J, Chen B. The association of daily diabetes mortality and
121: 2331–78. outdoor air pollution in Shanghai, China. J Environ Health 2004;
23 Yu W, Ye T, Zhang Y, et al. Global estimates of daily ambient fine 67: 21–26.
particulate matter concentrations and unequal spatiotemporal 46 Pinault L, Brauer M, Crouse DL, et al. Diabetes status and
distribution of population exposure: a machine learning modelling susceptibility to the effects of PM2·5 exposure on cardiovascular
study. Lancet Planet Health 2023; 7: e209–18. mortality in a national Canadian cohort. Epidemiology 2018;
24 Jbaily A, Zhou X, Liu J, et al. Air pollution exposure disparities across 29: 784–94.
USA population and income groups. Nature 2022; 601: 228–33. 47 Yang B-Y, Guo Y, Markevych I, et al. Association of long-term
25 Yazdi MD, Wang Y, Di Q, et al. Long-term effect of exposure to exposure to ambient air pollutants with risk factors for
lower concentrations of air pollution on mortality among US cardiovascular disease in China. JAMA Netw Open 2019; 2: e190318.
Medicare participants and vulnerable subgroups: a doubly-robust 48 Bowe B, Xie Y, Li T, Yan Y, Xian H, Al-Aly Z. Particulate matter air
approach. Lancet Planet Health 2021; 5: e689–97. pollution and the risk of incident CKD and progression to ESRD.
26 Bowe B, Xie Y, Li T, Yan Y, Xian H, Al-Aly Z. The 2016 global and J Am Soc Nephrol 2018; 29: 218–30.
national burden of diabetes mellitus attributable to PM2·5 air 49 Bowe B, Xie Y, Yan Y, Xian H, Al-Aly Z. Diabetes minimally
pollution. Lancet Planet Health 2018; 2: e301–12. mediated the association between PM2·5 air pollution and kidney
27 Landrigan PJ, Fuller R, Acosta NJR, et al. The Lancet Commission outcomes. Sci Rep 2020; 10: 4586.
on pollution and health. Lancet 2018; 391: 462–512. 50 Chin W-S, Chang Y-K, Huang L-F, Tsui H-C, Hsu C-C, Guo Y-LL.
28 Institute for Health Metrics and Evaluation. GBD results. 2020. Effects of long-term exposure to CO and PM2.5 on microalbuminuria
https://vizhub.healthdata.org/gbd-results/ (accessed Jan 13, 2024). in type 2 diabetes. Int J Hyg Environ Health 2018; 221: 602–08.

www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3 11

 Review

51 Motairek I, Sharara J, Makhlouf MHE, et al. Association between 73 Faridi S, Brook RD, Yousefian F, et al. Effects of respirators to
particulate matter pollution and CKD mortality by social reduce fine particulate matter exposures on blood pressure and
deprivation. Am J Kidney Dis 2023; 81: 497–99. heart rate variability: a systematic review and meta-analysis.
52 Pan S-C, Huang C-C, Chin W-S, Chen B-Y, Chan C-C, Guo YL. Environ Pollut 2022; 303: 119109.
Association between air pollution exposure and diabetic retinopathy 74 Bartoli CR, Wellenius GA, Coull BA, et al. Concentrated ambient
among diabetics. Environ Res 2020; 181: 108960. particles alter myocardial blood flow during acute ischemia in
53 VoPham T, Kim NJ, Berry K, Mendoza JA, Kaufman JD, conscious canines. Environ Health Perspect 2009; 117: 333–37.
Ioannou GN. PM2·5 air pollution exposure and non-alcoholic fatty 75 Ying Z, Xu X, Bai Y, et al. Long-term exposure to concentrated
liver disease in the Nationwide Inpatient Sample. Environ Res 2022; ambient PM2·5 increases mouse blood pressure through abnormal
213: 113611. activation of the sympathetic nervous system: a role for hypothalamic
54 Guo B, Guo Y, Nima Q, et al. Exposure to air pollution is associated inflammation. Environ Health Perspect 2014; 122: 79–86.
with an increased risk of metabolic dysfunction-associated fatty 76 Sullivan JH, Schreuder AB, Trenga CA, et al. Association between
liver disease. J Hepatol 2022; 76: 518–25. short term exposure to fine particulate matter and heart rate
55 Zhou X, Li C, Cheng H, et al. Association between ambient air variability in older subjects with and without heart disease. Thorax
pollution exposure during pregnancy and gestational diabetes 2005; 60: 462–66.
mellitus: a meta-analysis of cohort studies. Environ Sci Pollut Res Int 77 Peretz A, Kaufman JD, Trenga CA, et al. Effects of diesel exhaust
2022; 29: 68615–35. inhalation on heart rate variability in human volunteers. Environ Res
56 Pan SC, Huang CC, Chen BY, Chin WS, Guo YL. Risk of type 2 2008; 107: 178–84.
diabetes after diagnosed gestational diabetes is enhanced by 78 McGraw KE, Riggs DW, Rai S, et al. Exposure to volatile organic
exposure to PM2·5. Int J Epidemiol 2023; 52: 1414–23. compounds—acrolein, 1,3-butadiene, and crotonaldehyde—is
57 Gangwar RS, Bevan GH, Palanivel R, Das L, Rajagopalan S. associated with vascular dysfunction. Environ Res 2021; 196: 110903.
Oxidative stress pathways of air pollution mediated toxicity: recent 79 Münzel T, Sørensen M, Gori T, et al. Environmental stressors and
insights. Redox Biol 2020; 34: 101545. cardio-metabolic disease: part II-mechanistic insights. Eur Heart J
58 Münzel T, Gori T, Al-Kindi S, et al. Effects of gaseous and solid 2017; 38: 557–64.
constituents of air pollution on endothelial function. Eur Heart J 80 Rao X, Montresor-Lopez J, Puett R, Rajagopalan S, Brook RD.
2018; 39: 3543–50. Ambient air pollution: an emerging risk factor for diabetes mellitus.
59 Lin Y, Ramanathan G, Zhu Y, et al. Pro-oxidative and Curr Diab Rep 2015; 15: 603.
proinflammatory effects after travelling from Los Angeles to 81 Weisberg SP, Hunter D, Huber R, et al. CCR2 modulates
Beijing: a biomarker-based natural experiment. Circulation 2019; inflammatory and metabolic effects of high-fat feeding. J Clin Invest
140: 1995–2004. 2006; 116: 115–24.
60 Li J, Zhou C, Xu H, et al. Ambient air pollution is associated with 82 Sun Q, Yue P, Deiuliis JA, et al. Ambient air pollution exaggerates
HDL (high-density lipoprotein) dysfunction in healthy adults. adipose inflammation and insulin resistance in a mouse model of
Arterioscler Thromb Vasc Biol 2019; 39: 513–22. diet-induced obesity. Circulation 2009; 119: 538–46.
61 Rajagopalan S, Brauer M, Bhatnagar A, et al. Personal-level 83 Zheng Z, Xu X, Zhang X, et al. Exposure to ambient particulate
protective actions against particulate matter air pollution exposure: matter induces a NASH-like phenotype and impairs hepatic
a scientific statement from the American Heart Association. glucose metabolism in an animal model. J Hepatol 2013;
Circulation 2020; 142: e411–31. 58: 148–54.
62 Hill BG, Rood B, Ribble A, Haberzettl P. Fine particulate matter 84 Liu C, Ying Z, Harkema J, Sun Q, Rajagopalan S. Epidemiological
(PM2·5) inhalation-induced alterations in the plasma lipidome as and experimental links between air pollution and type 2 diabetes.
promoters of vascular inflammation and insulin resistance. Toxicol Pathol 2013; 41: 361–73.
Am J Physiol Heart Circ Physiol 2021; 320: H1836–50. 85 Laing S, Wang G, Briazova T, et al. Airborne particulate matter
63 Yin F, Lawal A, Ricks J, et al. Diesel exhaust induces systemic lipid selectively activates endoplasmic reticulum stress response in the
peroxidation and development of dysfunctional pro-oxidant and lung and liver tissues. Am J Physiol Cell Physiol 2010; 299: C736–49.
pro-inflammatory high-density lipoprotein. 86 Mendez R, Zheng Z, Fan Z, Rajagopalan S, Sun Q, Zhang K.
Arterioscler Thromb Vasc Biol 2013; 33: 1153–61. Exposure to fine airborne particulate matter induces macrophage
64 Li H, Cai J, Chen R, et al. Particulate matter exposure and stress infiltration, unfolded protein response, and lipid deposition in
hormone levels: a randomised, double-blind, crossover trial of air white adipose tissue. Am J Transl Res 2013; 5: 224–34.
purification. Circulation 2017; 136: 618–27. 87 Liu C, Bai Y, Xu X, et al. Exaggerated effects of particulate matter air
65 Pope CA 3rd, Hansen ML, Long RW, et al. Ambient particulate air pollution in genetic type II diabetes mellitus. Part Fibre Toxicol 2014;
pollution, heart rate variability, and blood markers of inflammation 11: 27.
in a panel of elderly subjects. Environ Health Perspect 2004; 88 Liu C, Fonken LK, Wang A, et al. Central IKKβ inhibition prevents
112: 339–45. air pollution mediated peripheral inflammation and exaggeration of
66 Brook RD, Urch B, Dvonch JT, et al. Insights into the mechanisms type II diabetes. Part Fibre Toxicol 2014; 11: 53.
and mediators of the effects of air pollution exposure on blood 89 Myers MG Jr, Affinati AH, Richardson N, Schwartz MW. Central
pressure and vascular function in healthy humans. Hypertension nervous system regulation of organismal energy and glucose
2009; 54: 659–67. homeostasis. Nat Metab 2021; 3: 737–50.
67 Kampfrath T, Maiseyeu A, Ying Z, et al. Chronic fine particulate 90 Ying Z, Xu X, Bai Y, et al. Long-term exposure to concentrated
matter exposure induces systemic vascular dysfunction via NADPH ambient PM2·5 increases mouse blood pressure through abnormal
oxidase and TLR4 pathways. Circ Res 2011; 108: 716–26. activation of the sympathetic nervous system: a role for
68 Deiuliis JA, Kampfrath T, Zhong J, et al. Pulmonary T cell activation hypothalamic inflammation. Environ Health Perspect 2014;
in response to chronic particulate air pollution. 122: 79–86.
Am J Physiol Lung Cell Mol Physiol 2012; 302: L399–409. 91 Miller DB, Ghio AJ, Karoly ED, et al. Ozone exposure increases
69 Liu C, Xu X, Bai Y, et al. Air pollution-mediated susceptibility to circulating stress hormones and lipid metabolites in humans.
inflammation and insulin resistance: influence of CCR2 pathways Am J Respir Crit Care Med 2016; 193: 1382–91.
in mice. Environ Health Perspect 2014; 122: 17–26. 92 Kodavanti UP. Stretching the stress boundary: linking air pollution
70 Hahad O, Rajagopalan S, Lelieveld J, et al. Noise and air pollution health effects to a neurohormonal stress response.
as risk factors for hypertension: part II-pathophysiologic insight. Biochim Biophys Acta 2016; 1860: 2880–90.
Hypertension 2023; 80: 1384–92. 93 Hajat A, Diez Roux AV, Castro-Diehl C, et al. The association
71 Palanivel R, Vinayachandran V, Biswal S, et al. exposure to air between long-term air pollution and urinary catecholamines:
pollution disrupts circadian rhythm through alterations in evidence from the multi-ethnic study of atherosclerosis.
chromatin dynamics. iScience 2020; 23: 101728. Environ Health Perspect 2019; 127: 57007.
72 Brook RD, Xu X, Bard RL, et al. Reduced metabolic insulin sensitivity 94 Rajagopalan S, Park B, Palanivel R, et al. Metabolic effects of
following sub-acute exposures to low levels of ambient fine air pollution exposure and reversibility. J Clin Invest 2020;
particulate matter air pollution. Sci Total Environ 2013; 448: 66–71. 130: 6034–40.

12 www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3

 Review

95 Wu H, Eckhardt CM, Baccarelli AA. Molecular mechanisms of 104 Rajagopalan S, Vergara-Martel A, Zhong Z, et al. The Urban
environmental exposures and human disease. Nat Rev Genet 2023; Environment and Cardiometabolic Health. Circulation 2024 (in press).
24: 332–44. 105 Rabin AS, Pinsky EG. Reducing health care’s climate impact—
96 Clark LP, Tabory S, Tong K, et al. A data framework for assessing mission critical or extra credit? N Engl J Med 2023; 389: 583–85.
social inequality and equity in multi-sector social, ecological, 106 Willett W, Rockström J, Loken B, et al. Food in the anthropocene:
infrastructural urban systems: focus on fine-spatial scales. J Ind Ecol the EAT–Lancet Commission on healthy diets from sustainable food
2022; 26: 145–63. systems. Lancet 2019; 393: 447–92.
97 Orru H, Ebi KL, Forsberg B. The interplay of climate change and air 107 Giallouros G, Kouis P, Papatheodorou SI, Woodcock J, Tainio M.
pollution on health. Curr Environ Health Rep 2017; 4: 504–13. The long-term impact of restricting cycling and walking during
98 Fiore AM, Naik V, Leibensperger EM. Air quality and climate high air pollution days on all-cause mortality: health impact
connections. J Air Waste Manag Assoc 2015; 65: 645–85. assessment study. Environ Int 2020; 140: 105679.
99 Watson-Parris D, Christensen MW, Laurenson A, Clewley D, 108 Development Organisation for Economic Co-operation and
Gryspeerdt E, Stier P. Shipping regulations lead to large reduction Development. The economic consequences of outdoor air pollution.
in cloud perturbations. Proc Natl Acad Sci USA 2022; 2016. https://www.oecd.org/environment/indicators-modelling-
119: e2206885119. outlooks/Policy-Highlights-Economic-consequences-of-outdoor-air-
100 Scovronick N, Budolfson M, Dennig F, et al. The impact of human pollution-web.pdf (accessed Jan 13, 2024).
health co-benefits on evaluations of global climate policy. 109 Vermeulen R, Schymanski EL, Barabási AL, Miller GW. The
Nat Commun 2019; 10: 2095. exposome and health: where chemistry meets biology. Science 2020;
101 Kaufman JD, Elkind MSV, Bhatnagar A, et al. Guidance to reduce the 367: 392–96.
cardiovascular burden of ambient air pollutants: a policy statement 110 Zhang P, Carlsten C, Chaleckis R, et al. Defining the scope of
from the American Heart Association. Circulation 2020; 142: e432–47. exposome studies and research needs from a multidisciplinary
102 Maizlish N, Rudolph L, Jiang C. Health benefits of strategies for perspective. Environ Sci Technol Lett 2021; 8: 839–52.
carbon mitigation in US transportation, 2017–2050. 111 Motairek I, Makhlouf MHE, Rajagopalan S, Al-Kindi S. The
Am J Public Health 2022; 112: 426–33. exposome and cardiovascular health. Can J Cardiol 2023;
103 Nieuwenhuijsen MJ. New urban models for more sustainable, 39: 1191–203.
liveable and healthier cities post Covid 19; reducing air pollution,
noise and heat island effects and increasing green space and Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an
physical activity. Environ Int 2021; 157: 106850. Open Access article under the CC BY 4.0 license.

www.thelancet.com/diabetes-endocrinology Published online February 1, 2024 https://doi.org/10.1016/S2213-8587(23)00361-3 13