**1. Introduction: Epidemiology of sum of environmental and metabolic risk**

In the last century, many epidemiological data demonstrated that the urbanization phenomenon corroborates to increasing prevalence of metabolic diseases and cardiorespiratory diseases. It is well known that high energy food offer and sedentarism are risk factors for metabolic

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© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

diseases such as diabetes, while high levels of air pollutant emission represent a risk for cardiorespiratory diseases. Thus, almost all people living in great cities are exposed simultaneously to these two risk factors: food consumption in quantities above the necessary for health maintenance and exposure to environmental air pollution above the limits proposed by WHO.

Some numbers from WHO are really impressive. Data from Global report on diabetes (2016) show that at least 422 million people are diabetic in worldwide and that diabetes prevalence has been rising more rapidly in middle- and low-income countries [1]. In the same risk direction, Global Urban Ambient Air Pollution Database update 2016 [2] showed that 98% of these cities, with more than 100,000 inhabitants, do not meet WHO air quality guidelines. This data represents that 92% of the world population lives in places where air quality levels exceed WHO limits. Thus, we can hypothesize that probably a great amount of people are simultaneously exposed to urbanization risk factors to health.

Based on a biologically plausible hypothesis from 2004 [3], Brook et al. published data from respiratory clinics (*n* = 5228 patients) and conclude that traffic-related air pollutants were associated with type 2 diabetes mellitus (T2DM) prevalence among women [4]. Thus, in few years, at least eight studies corroborate with the first study and provide data from association between exposure to fine particulate matter (<2.5 μm, PM2.5) and T2DM prevalence (for review, please see Rajagolapan and Brook, 2012).

Actually, the WHO air quality guidelines (WHO-AQG) [6] recommend that PM2.5 levels not exceed annual mean concentration of 10 μg/m<sup>3</sup> and confirm that 92% of the world's population lives in places where air-quality levels exceed WHO limits. Interestingly, the information is presented via interactive maps, highlighting areas within countries that exceed WHO limits. Data obtained from "Most searched cities" and others in http://breathelife2030.org/ [7] and WHO ambient (outdoor) air pollution database 2016 are shown in **Figure 1**.

**Figure 1.** Fine particulate matter annual mean concentration in cities worldwide. Data obtained from WHO 2016 database [2] and published by breathlife2030.Org [7]. Data presented in terms of concentration of particles per air

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**City, Country Population City, Country Population** Zurich, Switzerland 401,144 Shanghai, China 24,152,700 London, UK 8,787,892 Mumbai, India 12,442,373 Paris, France 2,229,621 Cairo, Egypt 9,500,000 Visalia, US 131,074 Beijing, China 21,700,000 São Paulo, Brazil 12,038,175 Kampala, Uganda 1,507,080 Santiago, Chile 7,314,176 Delhi, India 16,349,832 Milan, Italy 1,368,590 Bamenda, Cameroon 2,000,000 Cubatão, Brazil 127,006 Riyadh, Saudi Arabia 6,506,700 Monterrey, Mexico 1,130,960 Gwalior, India 1,953,505 Yasuj, Iran 108,505 Zabol, Iran 130,642 Lima, Peru 10,852,210 **Total 140,732,185**

volume in μg/m<sup>3</sup>

.

Data extracted from wikipedia.com

**Table 1.** Estimate of population of cities listed in **Figure 1**.

Just for hypothesize the population under PM2.5 pollution risk, we listed in **Table 1** an estimate of habitants in each city listed in **Figure 1**. We may conclude that at least 140 millions of people are breathing an inadequate level of PM2.5. Additionally, according to WHO diabetes database, 1 person in each 11 is diabetic; thus, we can hypnotize that, only in these cities, more than 12 million of people are simultaneously under exposure of these 2 risk factors to health: diabetes and PM2.5.

As can be observed in the data listed above, air pollution in middle- and low-income countries, in majority in Asia, Latin America, and Africa, is a significant public health burden. Here, we highlighted places that often present high concentrations of PM2.5 and simultaneously a high population density suggesting an industrialized and modernized life style that corroborates to T2DM development. Accordingly, as was demonstrated more than 10 years ago, the sum of these conditions is critical for health. Diabetic patients are more susceptible to air pollution-induced cardiovascular morbidity and mortality [8, 9], and this susceptibility to PM2.5 cardiovascular effects was associated with vasoconstrictive effects observed in episodes of high levels of pollution in T2DM [10].

In terms of "hard cardiovascular events," the recent review of Brook, et al. resume several meta-analyses assessing the impact of short-term exposures to PM2.5. Accordingly, data extracted from 34 studies, each 10 μg/m<sup>3</sup> increase in PM2.5 concentration (during few hours to Fine Particulate Matter (PM2.5) Air Pollution and Type 2 Diabetes Mellitus (T2DM): When... http://dx.doi.org/10.5772/intechopen.70668 73

**Figure 1.** Fine particulate matter annual mean concentration in cities worldwide. Data obtained from WHO 2016 database [2] and published by breathlife2030.Org [7]. Data presented in terms of concentration of particles per air volume in μg/m<sup>3</sup> .


**Table 1.** Estimate of population of cities listed in **Figure 1**.

diseases such as diabetes, while high levels of air pollutant emission represent a risk for cardiorespiratory diseases. Thus, almost all people living in great cities are exposed simultaneously to these two risk factors: food consumption in quantities above the necessary for health maintenance and exposure to environmental air pollution above the limits proposed by WHO.

Some numbers from WHO are really impressive. Data from Global report on diabetes (2016) show that at least 422 million people are diabetic in worldwide and that diabetes prevalence has been rising more rapidly in middle- and low-income countries [1]. In the same risk direction, Global Urban Ambient Air Pollution Database update 2016 [2] showed that 98% of these cities, with more than 100,000 inhabitants, do not meet WHO air quality guidelines. This data represents that 92% of the world population lives in places where air quality levels exceed WHO limits. Thus, we can hypothesize that probably a great amount of people are simultane-

Based on a biologically plausible hypothesis from 2004 [3], Brook et al. published data from respiratory clinics (*n* = 5228 patients) and conclude that traffic-related air pollutants were associated with type 2 diabetes mellitus (T2DM) prevalence among women [4]. Thus, in few years, at least eight studies corroborate with the first study and provide data from association between exposure to fine particulate matter (<2.5 μm, PM2.5) and T2DM prevalence (for

Actually, the WHO air quality guidelines (WHO-AQG) [6] recommend that PM2.5 levels not

tion lives in places where air-quality levels exceed WHO limits. Interestingly, the information is presented via interactive maps, highlighting areas within countries that exceed WHO limits. Data obtained from "Most searched cities" and others in http://breathelife2030.org/ [7] and

Just for hypothesize the population under PM2.5 pollution risk, we listed in **Table 1** an estimate of habitants in each city listed in **Figure 1**. We may conclude that at least 140 millions of people are breathing an inadequate level of PM2.5. Additionally, according to WHO diabetes database, 1 person in each 11 is diabetic; thus, we can hypnotize that, only in these cities, more than 12 million of people are simultaneously under exposure of these 2 risk factors to health: diabetes and PM2.5. As can be observed in the data listed above, air pollution in middle- and low-income countries, in majority in Asia, Latin America, and Africa, is a significant public health burden. Here, we highlighted places that often present high concentrations of PM2.5 and simultaneously a high population density suggesting an industrialized and modernized life style that corroborates to T2DM development. Accordingly, as was demonstrated more than 10 years ago, the sum of these conditions is critical for health. Diabetic patients are more susceptible to air pollution-induced cardiovascular morbidity and mortality [8, 9], and this susceptibility to PM2.5 cardiovascular effects was associated with vasoconstrictive effects observed in episodes

In terms of "hard cardiovascular events," the recent review of Brook, et al. resume several meta-analyses assessing the impact of short-term exposures to PM2.5. Accordingly, data

WHO ambient (outdoor) air pollution database 2016 are shown in **Figure 1**.

and confirm that 92% of the world's popula-

increase in PM2.5 concentration (during few hours to

ously exposed to urbanization risk factors to health.

72 Diabetes and Its Complications

review, please see Rajagolapan and Brook, 2012).

exceed annual mean concentration of 10 μg/m<sup>3</sup>

of high levels of pollution in T2DM [10].

extracted from 34 studies, each 10 μg/m<sup>3</sup>

days), increased the risk for acute myocardial infarction (by 2.5%), hospitalization or death from heart failure (2.1%), stroke (1.1%), and arrhythmia (1.5%). The risk increases for longterm exposure when people live in unhealthy urban area that exceeds PM2.5 levels, reaching more than 10% increase in cardiovascular mortality. Also, if people live in polluted area, a peak of PM2.5 levels increases 10–50 fold the risk for cardiovascular events [11]. Furthermore, elderly people and women are high susceptible profile to PM2.5 effects and for T2DM development, mainly in menopause [11].

In animals, hyperglycemia state can be produced by pancreatectomy, by toxins administration that in appropriate doses cause selective destruction of the β cells of the pancreatic islets (as streptozocin or alloxan), by administration of drugs that inhibit insulin secretion, or by administration of anti-insulin antibodies. Also, strains of mice, rats, hamsters, guinea pigs, miniature swine, and monkeys that have a high incidence of spontaneous diabetes mellitus have also been described. However, due to high prevalence of T2DM related to lifestyle, several experimental data obtained from high fat diet (HFD) animal models have been used with success to induce the disruption of insulin signaling in liver, skeletal muscle, or adipose tissue

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The HFD models help us to comprehension of the mechanisms described up to now for T2DM. As reviewed recently, it was proposed that the activation of transcription factor forkhead box protein O1 (FOXO1) in the liver and disruption of glucose-transporter translocation (GLUT4) to the surface membrane in skeletal muscle as the first steps of insulin resistance [17]. The resultant hyperglycemia and chronic hyperinsulinemia are hypothesized to disrupt insulin suppression of adipocyte lipolysis [17]. Additionaly, the active metabolism of adipose tissue may contribute to hyperinsulinemia since in HFD feeding, it occurs in the deregulation of hepatocyte gluconeogenesis (such as FOXO1), which causes increased hepatic glucose output, and deregulate the glucose transporter GLUT4 response to insulin in muscle, which results in decreased glucose uptake by muscle. In this case, the hypertrophy of adipose tissue can be interpreted as the first step of insulin resistance development that results in hypergly-

Persistent hyperglycemia causes tissue damage by different mechanism that involves oxidative stress. Increased uptake of glucose results in increased intracellular glucose concentration, that in turns, increased polyol pathway flux. This metabolic pathway uses dihydronicotinamide adenine dinucleotide phosphate (NADPH) that is required for maintaining the levels of the major intracellular nonenzymatic antioxidant defense, the glutathione. Nonenzymatic reaction of glucose and other glycation compounds formed advanced glycation products (AGEs) that modify intracellular proteins functions. Also, AGEs binding to specific receptors (RAGES) can induces reactive oxygen species (ROS) production. Finally, increased levels of AGEs and glucose (intracellularly and extracellularly) increased protein kinase C activation and hexosamine pathway flux. All these mechanisms listed above are involved in decrease nitric oxide (NO) production (vascular impaired function) and activation of factor nuclear kappa B (NF-kB), major pro-inflammatory transcript factor (for details,

Chronic hyperglycemia is strongly associated with enhanced oxidative stress with overproduction of ROS and nitrosative species (RNS), a reduction of the activity of antioxidant enzymes is known to cause endothelial dysfunction and insulin resistance [19]. Thus, oxidative stress constitutes as an important factor implicated not only in the T2DM development itself but also in the development of diabetic complications [18, 20]. T2DM is well known a cause of microangiopathies, observed at least by the three major diabetic complications, namely, diabetic retinopathy, nephropathy, and neuropathy. Also, T2DM constitutes a major risk factor for macroangiopathy, such as coronary artery disease and cerebrovascular disease.

causing hyperinsulinemia and thus, the development of T2DM [15, 16].

cemia and T2DM.

please see Giacco and Borwnlee, 2010).

The pathophysiologic mechanisms evolved in susceptibility to cardiorespiratory PM2.5 effects in T2DM subjects, as well as the enhancing effect of PM2.5 exposure on development of T2DM, are discussed below. The number and the complexity of these mechanisms are positive correlated to the importance for life maintenance. In this chapter, we presented pathophysiologic mechanisms based on oxidative stress, inflammation, and heat shock response, with major contribution from experimental studies. These issues were selected considering as representative of the ability of an organism to respond physiologically (by adequate and quick ways) to the environmental challenges or internal changes in the metabolism as an essential characteristic that permits the life. As background of this discussion, there is the comprehension of the concept that homeostasis regulation of one variable is dependent on many cooperative or synergic mechanisms, that may be activated simultaneity or by steps, in terms of redox response, cell by cell signaling, and/or by molecular stress response. Since T2DM and PM2.5 may be considered as stress situations that can promote damage to organism, and also are conditions that require adaptation/protection responses in the stressed cells, the comprehension of multi-integrative physiologic response can provide mechanistic explanation of epidemiological data listed above. Whereas high-intensity challenges to organism can overload the defensive response mechanisms, chronic and moderate intensity challenges can induce internal "recalibration" of many systems to survive [12]. Then, in the light of this "integrative" and "evolutionary" perspective is important to consider the expressive and complex effects of PM2.5 exposure and T2DM on these variables discussed below: (a) the pro/anti-inflammatory balance; (b) the metabolic regulation (flux and consumption of energy sources); (c) the redox status (pro/antioxidant balance); and (d) heat shock response.
