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Epidemilogical Trends Strongly Suggest Exposures as Etiologic Agents in the Pathogenesis of Sporadic Alzheimer's Disease, Diabetes Mellitus, and Non-Alcoholic Steatohepatitis
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Journal of Alzheimer's Disease 17 (2009) 519-529
DOI 10.3233/JAD-2009-1070
Suzanne M. de la Monte, Alexander Neusner, Jennifer Chu and Margot Lawton
Departments of Pathology, Clinical Neuroscience, and Medicine, Rhode Island Hospital and the Warren Alpert
Medical School of Brown University, Providence, RI, USA
Supported by AA-02666, AA-02169, AA-11431, AA-12908, and K24-AA-16126 from the National Institutes of Health.
Abstract.
Nitrosamines mediate their mutagenic effects by causing DNA damage, oxidative stress, lipid peroxidation, and pro-inflammatory cytokine activation, which lead to increased cellular degeneration and death. However, the very same patho-
physiological processes comprise the "unbuilding" blocks of aging and insulin-resistance diseases including, neurodegeneration, diabetes mellitus (DM), and non-alcoholic steatohepatitis (NASH). Previous studies demonstrated that experimental exposure to streptozotocin, a nitrosamine-related compound, causes NASH, and diabetes mellitus Types 1, 2 and 3 (Alzheimer (AD)-type
neurodegeneration). Herein, we review evidence that the upwardly spiraling trends in mortality rates due to DM, AD, and Parkinson's disease typify exposure rather than genetic-based disease models, and parallel the progressive increases in human exposure to nitrates, nitrites, and nitrosamines via processed/preserved foods. We propose that such chronic exposures have
critical roles in the pathogenesis of our insulin resistance disease pandemic. Potential solutions include: 1) eliminating the use of nitrites in food; 2) reducing nitrate levels in fertilizer and water used to irrigate crops; and 3) employing safe and effective measures to detoxify food and water prior to human consumption. Future research efforts should focus on refining our ability to detect and monitor human exposures to nitrosamines and assess early evidence of nitrosamine-mediated tissue injury and insulin resistance.
INTRODUCTION
Nitrosamines and N-nitroso compounds are among
the most potent and broad acting carcinogens that can
also function as transplacental mutagens. Nitrosamine-
mediated target organ damage and mutagenesis are
heavily influenced by route of administration, dose,
chemical nature of the compound, and frequency of
exposure. Among the more than 300 N-nitroso or
nitrosamine compounds tested, over 90% have been
found to be carcinogenic in various organs including
liver, gastrointestinal tract (from esophagus to rectum),
lung, kidney, bladder, pancreas, prostate, and uterus.
All mammals are susceptible. Fried bacon, cured
meats, beer, cheese products, fish byproducts, nonfat
dry milk, tobacco, gastric juices (dietary), and water
are major regular sources of consumer exposure to ni-
trosamines. However, nitrosamine exposures also oc-
cur through manufacturing, processing, and utilization
of rubber and latex products, fertilizers, pesticides, and
cosmetics (for review, see [1]).
Nitrosamines (R1N(-R2)-N=O) are formed by a
chemical reaction between nitrites and secondary
amines or proteins. How does this occur, and what
factors contribute to human dietary exposures? First,
as a public health measure, sodium nitrite is deliber-
ately added to meat and fish to prevent toxin produc-
tion by Clostridium botulinum.
Second, sodium nitrite
is used to preserve, color, and flavor meats. Heating,
acidification, or oxidation of nitrite leads to nitrous acid
formation. The resulting nitrosonium cation (N=O+)
is a nitrosating agent that reacts with dimethylamine
to generate nitrosamines. Dimethylamine is common-
ly present in fish meal. Moreover, since ground beef,
cured meats, and bacon in particular, contain abundant
amines due to their high protein content, and they have
significant levels of added nitrates and nitrites [2], ni-
trosamines are nearly always detectable in these food
products. Finally, nitrosamines are easily generated
under strong acid conditions, such as in the stomach,
or at high temperatures associated with frying or flame
broiling. Reducing sodium nitrite content definitely
lowers nitrosamine formation in foods.
NITROSAMNE GENERATION: THE BASICS
Nitrate exposures pose human health problems be-
cause about 5% of ingested nitrates get chemically re-
duced, forming harmful nitrites by bacterial enzymes
present in the oral cavity [3,4]. After entering the high-
ly acidic gastric juice environment, nitrites can be con-
verted to nitrous acid (HNO 2), and nitrosating agents
such as nitrous anhydride (N2O3) and nitric acid [5].
Nitrosating agents [6] and nitrites, either formed en-
dogenously or ingested directly with food or water [7]
react with amines to generate nitrosamines. Amine
precursors of N-nitroso compounds are generated from
dietary sources during the natural process of protein
digestion. Alternatively, they can be consumed di-
rectly when present in overcooked or processed meats
and over-ripened fruits and vegetables. High protein
content foods yield high levels of amine [8]. Besides
amines, choline, a nutrient found in most foods, includ-
ing meats, vegetables, peanuts, and eggs, is essential
for many biological functions [9], but can react with
nitrites to form dimethylamine (DMA), the precursor
to nitrosodimethylamine (NDMA) [4].
In essence, diets rich in amines, choline, and nitrates
lead to increased nitrosamine production relative to di-
ets that are low in nitrate, and include fish and seafood
as the main sources of amines [3,10]. Human expo-
sure to nitrates stems in part from the abundant use of
nitrate-containing fertilizers for agriculture, which re-
sults in relatively high levels of nitrates in many crops,
particularly root vegetables, such as potatoes and beets.
Vegetables, especially potatoes, account for nearly 85%
of our daily dietary intake of nitrates [3,6]. Nitrates can
also leech from the soil and contaminate water supplies
used for crop irrigation, food processing, and drinking.
Since amines and choline are essential nutrients, and
therefore cannot be eliminated from the diet, a more
feasible approach for reducing exposures to nitrates,
nitrites, and nitrosamines, would be to discontinue their
deliberate addition and permitted contamination of our
food and water sources.
NITROSAMINE SOURCES IN CONSUMABLES
The two main forms of nitrosamine that threat-
en human health are N-nitrosodimethylamine (DMN;
NDMA) and N-nitrosodiethylamine (DEN; NDEA).
NDMA and NDEA are highly toxic, semi-volatile,
organic chemicals that contaminate food and water
sources [11]. NDMA is a waste- or by-product of in-
dustrial processes such as organic nitrogen-containing
wastewater chloramination, water chlorination, rocket
fuel production, and anion exchange resin water treat-
ment [12,13]. NDMA can also be found at low levels
in tobacco smoke and foods such as cured meat, fish,
and beer [2]. NDMA contamination of drinking water
and food is problematic because, even at virtually unde-
tectable levels, the compound can be harmful, particu-
larly after long-term bioaccumulation. Experimentally,
short-term, high-level exposure to NDMA is hepato-
toxic and causes liver fibrosis [14-16], whereas chronic
low-level or moderate exposure to NMDA causes liver
tumors [14,17-19]. In humans, nitrosamine exposure
from preserved meats and fish has been correlated with
increased frequency of gastric cancer [20,21].
NDEA is a volatile water-soluble chemical that is
used as an additive for gasoline and lubricants, and
in the manufacturing of polymers, plastics, and pesti-
cides. Human exposures often occur through inges-
tion, inhalation, or skin contact with these substances.
Like NDMA, NDEA contaminates air, food, beverages,
drinking water, tobacco smoke, herbicides, and pesti-
cides, and is also an industrial pollutant. Appreciable
levels of NDEA can be found in inhaled and side-stream
tobacco smoke and cured meats. Although NDEA is
widespread in the environment, sunlight and UV irra-
diation cause it to decompose, thereby reducing expo-
sure from inhaled air and open bodies of water [22].
NDEA exposure causes cancer in liver, thyroid, gas-
trointestinal tract, and respiratory tract [22]. The main
specific carcinogenic nitrosamines associated with ex-
posure to tobacco products, including cigarettes, cigars,
and chewing tobacco, include N-nitrosonornicotine and
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [23],
the latter of which is produced by reaction of nitrite in
saliva with tobacco alkaloids such as nicotine. Since
nitrosonornicotine is also present in cigar and cigarette
smoke, non-smokers can be exposed via second-hand
smoke inhalation. Finally, nicotine replacement prod-
ucts can also serve as sources of nitrosamine expo-
sure [23]. In essence, discontinued use of tobacco and
tobacco-related products may be the single most im-
portant means of reducing nitrosamine exposure and
related adverse effects on health status.
MECHANISMS OF CELLULAR INJURY
Nitrosamines exert their toxic and mutagenic effects
by functioning as alkylating agents. In brief, metabolic
processing converts nitrosamines into active methylat-
ing agents that are highly reactive with nucleic acids, al-
tering gene expression and causing DNA damage. Ac-
tivated nitrosamines, most commonly alkylate N-7 of
guanine, lead to destabilization and increased breakage
of DNA [17]. In addition, activated nitrosamines gen-
erate reactive oxygen species such as superoxide (O
2-) and hydrogen peroxide (H2O2), causing increased ox-
idative stress, DNA damage, lipid peroxidation, and
protein adduct formation [24]. Oxidative stress and
DNA damage lead to activation of pro-inflammatory
cytokines, insulin resistance, and aging, all of which
are key elements in the pathogenesis of Type 2 diabetes
mellitus (T2DM), neurodegeneration, and malignancy.
The consequences of nitrosamine-mediated tissue in-
jury may vary with the phenotypic properties of the tar-
get cells, i.e., proliferating cells may be more prone to
undergo malignant transformation, whereas terminally
differentiated cells may instead undergo senescence or
degeneration.
NITRATES, NITRITES, NITROSAMINES, AND
NITROSAMINE-RELATED COMPOUNDS IN
DISEASE
Investigations about the role of nitrosamines in the
pathogenesis of human disease have primarily focused
on carcinogenesis, yet the basic cellular and molecu-
lar alterations produced by nitrosamine exposure are
fundamentally similar to those that occur with aging,
Alzheimer's disease (AD), non-alcoholic steatohepati-
tis (NASH), and T2DM. All of these non-neoplastic dis-
eases are associated with increased insulin resistance,
DNA damage, lipid peroxidation, oxidative stress, and
pro-inflammatory cytokine activation [25-31]. The
prevalence rates of AD, NASH, obesity, and T2DM
have all increased exponentially over the past several
decades, and thus far, show no hints of plateau [32-37].
Of particular note is that the rather short time inter-
val associated with dramatic shifts in disease incidence
and prevalence rates is more consistent with exposure-
related, rather than genetic etiologies (discussed later).
An important clue regarding the probable connec-
tion between nitrosamine exposure and AD, NASH,
and diabetes mellitus was provided by experimental da-
ta demonstrating that treatment with Streptozotocin [2-
deoxy-2-(3-methyl-3-nitrosoureido-D-glucopyranose
(C8H15N3O7)] (STZ), a glucosamine-nitrosourea
compound and derivative of N-methyl-N-nitrosourea
(MNU), causes AD-type neurodegeneration with cog-
nitive impairment, T1DM, T2DM [38-44], or hepatic
steatosis with chronic inflammation and scarring, i.e.,
NASH [45]. Of further interest is the finding that sim-
ilar disease models can be produced by delivery of ei-
ther a single large dose (40-60 mg/kg) [43], or repeated
smaller doses [42] of STZ. STZ is taken up by cells
via glucose transporters [46], and once metabolized,
liberates N-nitrosoureido. STZ inhibits DNA synthesis
and kills cells by lowering ATP and nicotine adenine
dinucleotide (NAD+) content [43].
Structurally, STZ is quite similar to nitrosamines,
and like other N-nitroso compounds, including NDEA
and NDMA [47], STZ's MNU causes cellular injury
and disease by functioning as: 1) an alkylating agent
and potent mutagen resulting in cancer development in
various organs [48]; 2) an inducer of DNA adducts,
most significantly N7-methylguanine, which lead to in-
creased apoptosis [49]; 3) a mediator of unscheduled
DNA synthesis that triggers cell death [48]; 4) an in-
ducer of single-strand DNA breaks; 5) a stimulus for
nitric oxide (NO) formation following breakdown of its
nitrosamine group [43]; and 6) an enhancer of the xan-
thine oxidase system leading to increased production
of superoxide anion, H2O2, and OH - radicals [50].
In essence, STZ-induced cellular injury is mediated by
the generation of reactive oxygen species with atten-
dant increased levels of superoxide, nitric oxide, and
lipid peroxidation, all of which cause DNA damage.
Radical ion accumulation leads to inhibition of oxida-
tive metabolism, mitochondrial dysfunction [43], de-
creased ATP production [51], activation of poly-ADP
ribosylation, and finally cell death.
NITROSAMINE COMPOUNDS AND INSULIN
RESISTANCE-MEDIATED DISEASES
STZ treatment causes T1DM [44,52], T2DM [53-
55], steatohepatitis [45], and neurodegeneration [38-
41]. The spectrum of disease produced is dictated
by the dose and route of administration of STZ. In-
traperitoneal delivery of STZ causes T1DM, T2DM,
or NASH, with high doses usually resulting in T1DM,
and lower repeated doses causing T2DM or steato-
hepatitis. Intracerebral (ic) STZ administration causes
neurodegeneration in the absence of T1DM, T2DM,
or NASH, indicating that the brain can be a selective
target of MNU/nitrosamine-mediated injury or neu-
rotoxicity. Importantly, these disease entities share
a common theme, but vary with respect to nature
and degree of target-organ injury, insulin deficiency
and/or insulin resistance, increased oxidative stress
and DNA damage, increased levels of nitric oxide
and free radicals, pro-inflammatory cytokine activation,
and mitochondrial dysfunction with deficiencies in ATP
production. Specific effects of ic-STZ-induced neu-
rodegeneration include: increased amyloid-ß protein
precursor-amyloid-ß (AßPP-Aß) deposition, AßPP
gene expression, and tau phosphorylation, accompa-
nied by cognitive impairment [38,41,56], deficits in
acetylcholine homeostasis [38,41] and neurotrophin
gene expression [57], as typically occur in AD [58].
Since the cognitive deficits and neurodegeneration
caused by ic-STZ can be abrogated by concurrent
delivery of insulin [59], or early intervention with
peroxisome-proliferator activated receptor (PPAR) ag-
onists, which function as both insulin-sensitizer and
anti-inflammatory/antioxidant agents [38], this AD
model mechanistically overlaps with both T1DM and
T2DM, prompting us to coin the term, "Type 3 Dia-
betes" [38,41]
In essence, at the core of AD pathology, DM, and
NASH is insulin resistance with associated deficits
in glucose utilization and energy metabolism, and in-
creased levels of chronic inflammation and oxidative
stress [60-65]. Although for years, disturbances in
metabolic function have been recognized features of
both DM and AD [60], the mediators of these abnor-
malities were not understood. However, the more re-
cent and growing interest in the roles of insulin resis-
tance and insulin deficiency syndromes, including AD,
has opened doors to more diversified investigational
approaches. Correspondingly, epidemiological trend
analysis demonstrated significant associations between
AD and T2DM, revealing the nearly two-fold increased
risk of developing AD in subjects with T2DM [25,65-
71]. In addition, other studies showed associations be-
tween obesity or peripheral insulin resistance and cog-
nitive impairment [72,73]. Since NASH and AD are
associated with T2DM, T2DM and NASH are associat-
ed with obesity and metabolic syndrome, while AD and
T1DM are associated with insulin deficiency, there ap-
pears to be a 3-way Venn-diagram type overlap among
AD, T2DM, and NASH. But, is there a common cause?
EVIDENCE THAT DIABETES MELLITUS AND
ALZHEIMER'S ARE EXPOSURE-RELATED
DISEASES
We were prompted to consider the potential role
of nitrosamines as environmental toxins mediating
insulin-resistance diseases, including NASH, T2DM,
and AD because STZ has a methylnitrosourea group
and its effects on DNA and cellular functions are similar
to those of nitrosamine compounds, including NDEA
and NDMA (Fig. 1). However, since in low, sub-
mutagenic doses, STZ causes insulin resistance, we
considered the concept that low-dose chronic expo-
sure to NDEA, NDMA, and other nitrosamines may
cause insulin-resistance mediated diseases rather than
malignancy. To assess the validity of an exposure hy-
pothesis in relation to the pathogenesis of T2DM and
AD, it was first necessary to demonstrate epidemio-
logical trends that mirrored effects of exposure-related
diseases such as infectious diseases, rather than genet-
ic diseases which remain relatively stable over a peri-
od of decades. Therefore, we graphed and analyzed
time-dependent, age-stratified mortality rates from all
causes, AD, Parkinson's disease (PD), diabetes melli-
tus, cerebrovascular disease, chronic liver disease, lym-
phomas, leukemias, and HIV-AIDS from 1968 to 2005.
HIV-AIDS served as a positive control for disease that
is caused by exposure to an infectious agent. The da-
ta source was the US Department of Health and Hu-
man Services, Centers for Disease Control and Pre-
vention National Center for Health Statistics database
(www.cdc.gov/nchs/hus.htm). To first determine the
degree to which death rates from these diseases corre-
lated with increasing age, we computed areas under the
curves corresponding to death rates over time versus
age group, i.e., 45-54, 55-64, 65-74, 75-84, and 85+
years (Fig. 2). The graphs demonstrate that the highest
rates of death from nearly all of these disease occurred
in the older age groups, indicating that they are aging-
associated. Exceptions included chronic liver disease
and HIV-AIDS, which had higher death rates in the
earlier age groups.
To determine the degree to which the mortality rates
had shifted upward or downward over time, we graphed
age-stratified death rates for each disease. This ap-
proach enables direct comparison of death rates from
any given disease in, for example, 65-74 year olds in
1970 versus the same age group in 2005. Moreover,
by superimposing or aligning graphs for all age groups
within a disease category, it was possible to determine
the rank order of death rates with respect to age group
(Fig. 3). However, to clearly visualize specific disease
trends, the death rates corresponding to individual age
brackets were re-plotted to scale on separate graphs
(Fig. 4). Among individuals 45-54, 55-64, 65-74, 75-
84, and 85+ years old, the death rates from all causes
progressively declined over time (Fig. 3A). Similarly,
death rates from cerebrovascular disease (Figs 3E, 4A-
4E) and chronic liver disease (Fig. 3F) also declined
within each age group over time. Nonetheless, for each
of these diseases, the death rates were highest among
the 85+ group followed by the 75-84 year olds, while
the other three groups were lower but tightly clustered.
In contrast, the trends for lymphomas and leukemias
remained relatively stable (Fig. 3G, 3H), except for the
time-dependent upward drift in death rate from lym-
phoma among 85+ year olds (Fig. 3G).
Death rates from HIV-AIDS exhibited classical
exposure-associated increases from 1985 to 1995, fol-
lowed by precipitous declines due to increased avail-
ability of effective anti-retroviral drugs (Figs 3F, 4F-
4J). Trends mapping death rates from DM were U-
shaped for all age groups in that the rates sharply de-
clined after 1968, reaching a nadir in -1980,
but subsequently increased to levels that were similar to, or
higher than in 1968, with modest hints of plateau over
the last 3-4 years (Figs 3D, 4K-4O). Death rates from
AD (Figs 3B, 4P-4T) and PD (Figs 3C, 4U-4Y) exhib-
ited opposite trends relative to cerebrovascular disease
and all causes of death due to increased rather than de-
creased rates within each age group over time. Of note
is that between 1968 and 2005, the death rates from AD
increased by 4-fold in the 55-64, 20-fold in the 64-74,
150-fold in the 75-84, and 800-fold in the 85+ year old
groups. With respect to PD, the death rates increased
about 2-fold in the 65-74, 3-fold in the 75-84, and near-
ly 6-fold in the 85+ age groups from 1980-2005 (PD
death rates were not tracked prior to 1980). Therefore,
besides bucking the trends with respect to other major
aging-associated diseases, the relatively short intervals
associated with dramatic increases in death rates from
DM, AD, and PD are more consistent with exposure-
related rather than genetic etiologies. Moreover, the
strikingly higher and climbing mortality rates in older
age brackets suggest that aging and/or longer durations
of exposure have greater impacts on progression and
severity of these diseases. The U-shaped curve for DM
is particularly disconcerting because presumably the
recognition and treatments are better today than they
were in 1980, yet mortality is higher. Perhaps factors
contributing to the pathogenesis of DM prior to 1970
differ from those in modern times,which seem to render
DM a more "malignant" and uncontrollable disease.
Since human exposures to nitrates, nitrites, and ni-
trosamines are likely to occur due to fertilizer use, con-
sumption of processed and preserved foods, and agri-
cultural products that heavily rely in fertilizer use (e.g.,
grains), we examined US population growth (Fig. 5A),
annual use/consumption of nitrate-containing fertiliz-
ers (Fig. 5B), annual sales for a popular fast food fran-
chise (Fig. 5C), sales for a major meat processing com-
pany (Fig. 5D), consumption of grain (Fig. 5E), and
consumption of watermelon and cantaloupe (Fig. 5F).
Watermelon and cantaloupe served as controls since
they are not typically associated with nitrate or ni-
trite exposure, DM, or AD. Business sales data were
obtained from the companies' websites or stock ex-
change databases, and agricultural sales/consumption
data were obtained from USDA websites. The results
demonstrated that the US population nearly doubled
between 1955 and 2005. Although nitrogen-
containing fertilizer consumption increased by 230% over the
same interval, its usage doubled between 1960 and
1980, just preceding the insulin-resistance epidemics.
Sales from a popular fast food franchise and a major
meat processing company increased more than 8-fold
from 1970 to 2005, and grain consumption increased
5-fold. In contrast, watermelon consumption remained
relatively flat, while cantaloupe consumption nearly
doubled, paralleling population growth, although over-
all per capita consumption remains relatively low com-
pared with processed foods.
HYPOTHESIS
Epidemiological data revealed staggering growths in
prevalence and/or mortality rates for T2DM, obesity,
NASH, and AD, and significant overlap between AD
or NASH and T2DM. Basic, translational, and clinical
research studies have demonstrated that AD neurode-
generation, like T2DM and NASH, is associated with
insulin resistance as well as increased oxidative stress,
DNA damage, NO-mediated injury, and ATP deficits
caused by mitochondrial dysfunction and impaired in-
sulin signaling, but with prominent or selective
involvement of the brain. Experimental animal models pro-
vided evidence that STZ administration causes Type
1, Type 2, or Type 3 diabetes, depending on dose and
route of administration. In addition, STZ treatment
causes hepatic steatosis associated with insulin resis-
tance, pro-inflammatory cytokine activation, increased
oxidative stress, DNA damage, lipid peroxidation, and
cell death culminating in fibrogenesis, i.e., a model of
NASH [48,74].
Returning to the epidemiological data, the time
course of increasing prevalence rates of T2DM, NASH,
and AD cannot be explained on the basis of gene
mutations, and instead, mirror the classical trends of
exposure-related diseases. Since STZ is structurally re-
lated to nitrosamines and produces similar biochemical
and molecular lesions in cells and tissues, it is conceiv-
able that chronic exposure to relatively low levels of ni-
trites and nitrosamines through processed foods, water,
and fertilizers, is responsible for our current epidemics
and probably also the pandemics of T2DM, NASH, and
AD. The link to obesity is through excessive consump-
tion of nutritionally irresponsible processed foods. If
this hypothesis is correct, potential solutions would in-
clude: 1) eliminating the use of nitrites and nitrates in
food processing, food preservation, and agriculture; 2)
taking steps to prevent formation of nitrosamines; and
3) employing safe and effective measures to detoxify
food and water prior to human consumption. In addi-
tion, further development of highly sensitive measures
to detect the footprints, e.g., measures of amine nitrosa-
tion, and assess levels of nitrosamine exposure in body
fluids such as urine or cerebrospinal fluid, and in tissues
such as liver, brain, adipose tissue, and muscle, could
help identify individuals at risk for developing T2DM,
NASH, and/or AD.
CONCLUSIONS
Nitrosamines are potent mutagens that cause DNA
damage, oxidative stress, cell death, and cancer. How-
ever, the structural relatedness of nitrosamines to STZ
demands attention because STZ is a proven mutagen,
but in low doses causes Types 1 and 2 diabetes mel-
litus, hepatic steatohepatitis, or AD-type neurodegen-
eration. We hypothesize that widespread exposures to
nitrites and nitrosamines in our environment have criti-
cal roles in the pathogenesis of these insulin-resistance
and insulin-deficiency related diseases. Epidemiolog-
ical trends support exposure rather than genetic caus-
es of these diseases, and exposures to nitrites and
nitrosamines through food, water, agriculture have in-
creased just prior to and within the same interval due
to proliferation of food processing, increased require-
ment for food preservation to enable "safe" storage
and long distance shipping, and the use of fertilizers
to enhance crop growth and meet growing demand for
produce. Tobacco use contributes to the problem, but
public health measures have already been taken to re-
duce public exposure. Sincere efforts should be made
to significantly curtail or eliminate human exposure to
nitrates and nitrites, and re fine extant biotechnology
to monitor exposure, metabolite formation, and asso-
ciated cellular and tissue injury linked to nitrosamine-
mediated insulin resistance-related diseases, including
T2DM, NASH, and AD.
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