712
Urmila P. Kodavanti
Air Pollution and Insulin
Resistance: Do All Roads Lead
to Rome?
Diabetes 2015;64:712–714 | DOI: 10.2337/db14-1682
AIR POLLUTION AND CHRONIC DISEASE
SUSCEPTIBILITY
The World Health Organization estimates that worldwide
in 2012, nearly 7 million deaths occurred prematurely
due to air pollution (1). In addition to respiratory and
cardiovascular diseases, air pollution exposure is also
linked to increased incidence of diabetes (2). Notably,
the prevalence of diabetes and dyslipidemia escalated ex-
ponentially in the latter half of the 20th century coinci-
dent with the manufacture, use, and release of massive
COMMENTARY
amounts of chemicals and pollution. The increase in the
prevalence of these chronic conditions also coincides with
an increase in sedentary lifestyles, calorie-rich diets, and
human stress. Together, these factors contribute to met-
abolic disease. This complex tapestry suggests that many
elements, including air pollution, are likely involved in an
interactive manner to increase the risk of certain health
conditions. Determining how air pollution might be
linked to diabetes is useful not only in understanding
how environmental factors contribute to the pathogene-
sis of this disease but also for identifying molecular
targets for potential therapeutic strategies. Improved un-
derstanding of this dynamic also provides further ratio-
nale for improving air quality standards and public
health.
Ozone is produced in the air by photochemical reaction
of components of anthropogenic emissions, and it con-
tributes substantially to the societal burden of respiratory
and cardiovascular disease. The pulmonary effects of ozone
have been studied for decades (3), with recent attention
turning to the metabolic and cardiovascular effects of this
exposure.
Environmental Public Health Division, National Health and Environmental Effects
Research Laboratory, Office of Research and Development, U.S. Environmental
Protection Agency, Research Triangle Park, Durham, NC
Corresponding author: Urmila P. Kodavanti, kodavanti.urmila@epa.gov.
The research described in this article has been reviewed by the National Health and
Environmental Effects Research Laboratory, U.S. Environmental Protection Agency
and approved for publication. Approval does not signify that the contents necessarily
reflect the views and the policies of the Agency nor does mention of trade names or
commercial products constitute endorsement or recommendation for use.
Diabetes Volume 64, March 2015
MANY MECHANISMS HAVE BEEN PROPOSED FOR
SYSTEMIC EFFECTS OF AIR POLLUTION
A number of mechanisms have been proposed for
extrapulmonary effects of inhaled pollutants. On the
basis of experimental studies examining the metabolic
effects of ambient particulate matter (chemically complex
mixtures consisting of many components) in mouse
models, Rajagopalan and Brook (4) proposed that systemic
inflammation, oxidative stress, and neuronal mechanisms
might be involved in adipose inflammation and tissue in-
sulin resistance. In this issue of Diabetes, Vella et al. (5)
report that although rats exposed to ozone did not show
systemic inflammation associated with acute metabolic
effects, they did exhibit insulin resistance in muscle tissue
resulting from lipid and protein oxidation by-products.
NEURONAL STRESS RESPONSE AS A POTENTIAL
CONTRIBUTOR TO INSULIN RESISTANCE
Rats have a reversible decrease in body temperature when
exposed to ozone (6,7). This is associated with impaired
glucose homeostasis (8) and mobilization of energy sources
during stress responses, an observation that might co-
incide with the adaptive insulin resistance in peripheral
tissues (9) that was observed in the new work by Vella
et al. (5). A growing body of evidence supports the hy-
pothesis that ozone exposure induces a neuronal re-
sponse that activates stress-sensitive centers in the
nucleus tractus solitarius (10,11). Activation of catechol-
aminergic neurons in the nucleus tractus solitarius—
central to systemic sympathetic stimulation—can mediate
an immediate action (fight-or-flight response), activate
a hypothalamus-pituitary-adrenal–mediated release of
© 2015 by the American Diabetes Association. Readers may use this article as
long as the work is properly cited, the use is educational and not for profit, and
the work is not altered.
See accompanying article, p. 1011.
diabetes.diabetesjournals.org Kodavanti 713

hormones from the adrenal cortex (12), and result in a re-
lease of glucose, free fatty acids, and branched-chain
amino acids into the circulation (Fig. 1) (13). All of these
responses have been implicated in insulin resistance (14).
WHAT IS CHANGED IN THE CIRCULATION IN
RESPONSE TO OZONE?
The lipid-rich alveolar lining fluid is known to react with
ozone and produce oxidation by-products. Vella et al. (5)
showed that oxidation of lipids and proteins can occur in
the lung, leading to increases in oxidation by-products not
only in the lung but also systemically and in muscle. They
confirmed this observation by demonstrating the effec-
tiveness of ingested N-acetyl cysteine (NAC) in reducing
ozone-induced oxidation of lipids and proteins. We have
recently observed that exposure to ozone is associated
with marked increases in a variety of free fatty acids,
branched-chain amino acids, glucose, cholesterols, and stress
and metabolic hormones in the circulation (13). Many of
these constituents can remain unaltered in the circulation,
be taken up by liver and other peripheral tissues, or have
the potential to be oxidized within the circulation and in
cells. Thus, in addition to local pulmonary-derived oxidation
by-products, the flux of these lipid and protein catabolism
by-products in the circulation likely plays a role in acute
peripheral insulin resistance (Fig. 1).
MECHANISMS OF PERIPHERAL INSULIN
RESISTANCE
Most research on insulin resistance has shown a role
for circulating factors and mediators in impairing in-
sulin signaling in different tissues. Many published studies
focus on mediators that induce activation of stress kinases.
These include c-Jun N-terminal kinases and tissue-specific
isoforms of protein kinase C, which affect tyrosine versus
serine phosphorylation of insulin receptor substrate-1. Ac-
tivation of these stress kinases leads to impaired Akt-
mediated glucose transporter-4 translocation to the
cell membrane and glucose intracellular transport (15).
A variety of extracellular and intracellular biological
components has been implicated in impairment of in-
sulin signaling. These include free fatty acids (15),
branched-chain amino acids (16), steroid and stress hor-
mones (17), cytokines (18), diacylglycerol, ceramides
(15), and intracellular free radicals derived from mito-
chondria (19). Although many studies have supported
the contribution of oxidatively modified biological
molecules, nonoxidized metabolites have also been im-
plicated in insulin resistance (15,20). The intracellu-
larly generated ceramides from fatty acyl-CoA and
sphingosine have contributed to insulin resistance in
muscle and liver cells (15). With regard to impairment
of insulin signaling by air pollution, a key goal is to

Figure 1—Many potential mechanisms might be involved in air pollution–induced insulin resistance and diabetes. While exposure to ozone
or other gas and particulate matter components of air pollution upon inhalation can oxidatively modify surfactant lining and cellular
components, it can also activate a classic stress response to injury through direct sympathetic stimulation and activation of hypothala-
mus-pituitary-adrenal axis. A variety of systemic homeostatic metabolic and inflammatory mechanisms might be involved through neuro-
hormone regulation, which rapidly changes the metabolic processes in multiple tissues and the circulating factors. Many of these factors
are involved in tissue-selective insulin resistance, dyslipidemia, and the neuronal modulation of homeostatic mechanisms. The question
that remains is how these acute changes in processes might upon chronic air pollution exposure contribute to sustained peripheral insulin
resistance, dyslipidemia, diabetes, and cardiovascular disease. PM, ambient particulate matter; O3, ozone.
714 Commentary
identify systemically released metabolic by-products/
biological components and to determine their oxida-
tion status.
The most intriguing finding of Vella et al. (5) is that
ozone increases lipid and protein oxidation by-products
in the bronchoalveolar lavage fluid (BALF) and serum in
parallel with increased muscle insulin resistance. The
authors show that although the ozone-induced lung in-
jury (protein leak) and inflammatory cell influx were
not reduced in rats pretreated with NAC, the levels of
thiobarbituric acid–reactive substances and protein car-
bonyls were decreased in BALF and in the circulation.
This suggests that although NAC pretreatment was in-
effective in protecting the lung from vascular leakage
and inflammation, it reduced oxidation systemically
and improved insulin signaling in muscle. Because incuba-
tion of myoblast cultures with BALF from ozone-exposed
rats stimulated c-Jun N-terminal kinase–mediated signal-
ing and replicated in vivo ozone effect on insulin signal-
ing, Vella et al. (5) believe that these oxidants are involved
in muscle insulin resistance. This observation is sup-
ported by detection of labeled oxygen in the blood after
inhalation of labeled ozone in rats (21). However, more
studies are warranted to precisely identify individual lipid
oxidation by-products and their sites of generation and
clearance and to determine the contribution (and possible
chemical modifications) of systemically released fatty
acids, amino acids, and hormones in peripheral insulin
resistance.
FACTORS TO CONSIDER IN FUTURE STUDIES
The outcome of NAC intervention in the study by Vella
et al. (5) is interesting and it raises questions about
the role of oxidation by-products and where they may
be generated after ozone inhalation. However, high-
concentration ozone exposure, especially during the night
and in experiments of exceedingly long duration (16 h),
which has been shown to cause remarkable lung injury
in rats, is not likely to occur in a real-world scenario for
humans. Moreover, we are still far from understanding
if transient insulin resistance can be exacerbated or if
adaptation is likely over extended periods, as noted
with other biological end points on repeated chronic
episodic ozone exposure (7,8). Considering the magni-
tude of the health burden of air pollution on chronic
neurological and cardiovascular disease, lipidemia, ec-
topic lipid accumulation, nonalcoholic steatohepatitis,
and diabetes in healthy and genetically compromised
individuals, more studies like that by Vella et al. (5)
are needed to fully understand the impact of this ex-
posure on chronic disease. However, based on observed
changes in a myriad of circulating factors (hormones, fatty
acids, cholesterol, amino acids, and oxidation by-products
of lipids and proteins) and alterations of peripheral meta-
bolic homeostasis, it is quite possible that multiple mech-
anisms are involved in in vivo ozone-induced insulin
resistance.
Diabetes Volume 64, March 2015
Acknowledgments. The author thanks Drs. Gary Hatch, Stephen Gavett,
Wayne Cascio, and Ian Gilmour (U.S. Environmental Protection Agency) for their
critical review of the manuscript.
Duality of Interest. No potential conflicts of interest relevant to this article
were reported.
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