**3. T2DM and PM2.5: The mechanism of enhanced risk**

Epidemiologic evidences have shown many effects of exposure to air pollution in the increase of hospital admissions in more susceptible individuals, as well as the increase of incidence of some diseases, from respiratory to cardiovascular diseases (Cote et al., 2008). In the last decade, the association between diabetes and air pollution was highlighted by some studies [10, 41–43].

Meo et al. reviewed studies that discuss insulin resistance, diabetes mellitus, and air pollution and conclude that in 10 studies, among 11 analyzed, the PM2.5 exposure to is associated with abnormalities in glucose homeostasis and this effect is related with inflammation, insulin resistance mitochondrial alteration, cardio-metabolic disorders, and thus, related to T2DM development. The same work confirms a clear and strong association between T2DM and exposure to particulate material especially, the exposure to small particulate matter of 10 microns (PM10) or less in diameter, such as PM2.5 [15, 45].

The polluted air, mainly by PM2,5, is related to inflammation, vascular dysfunction, and atherosclerosis by the toxicology mechanisms invocated by the PM2,5 invasion into the bloodstream [42]. Beyond this, PM2,5 is related to induction of insulin resistance and adiposity in high fat diet mice models [16, 43]. Chronic PM2,5 exposure can induce glucose intolerance, oxidative stress, and mitochondrial alteration in Langerhans islet and adipose tissue. Thus, PM2,5 inhalation represents a novel additional risk factor to T2DM [16, 43, 46].

Experimental studies attempt to explain the pathophysiological mechanisms that lead to metabolic outcomes described above. Xu et al. showed that PM2.5 exposure for 12 weeks promoted significant liver damage, evidenced by elevated levels of hepatic stress biomarkers, such as transaminases (ALT and AST) and reduced glycogen levels, alterations involved in impaired glucose tolerance and insulin resistance in mice. Also, this work demonstrated that PM2.5 exposure triggered Nrf2-mediated oxidative responses and activated the JNK-mediated inhibitory signaling pathway, resulting in hepatic dysfunction. Wherefore, hepatic insulin resistance can also be a potential mechanism of diabetes pathogenesis due to pollutants [45].

Oxidative stress is a common factor in both conditions, T2DM and PM2,5. Furthermore, the oxidative stress induced by PM2,5 also represents a pathogenic stimulus for pancreatic β-cell dysfunction [47], since it is responsible for debility on the antioxidant defenses [48].

bioenergetics profile. Since T2DM and T1DM patients exhibit higher eHSP70 levels, the perpetuation of this pro-inflammatory signal may induce loss of cell integrity and consequently

In obese T2DM subjects, the eHSP70 level is higher than nonobese T2DM suggesting that adiposity, mainly visceral adiposity and its complications, may contribute to increasing eHSP70 levels. Actually, iHSP70 may be considered a cytoprotective proteins by anti-inflammatory functions associated with normal insulin sensitivity. On the other hand, increased levels of eHSP70 chronically may be a result of chronic low-grade inflammatory state of visceral obesity [39]. Therefore, the unbalance between eHSP70 and iHSP70 levels (eHSP70/iHSP70 ratio), known as H-index, can reveal the full context of inflammatory process and insulin

Epidemiologic evidences have shown many effects of exposure to air pollution in the increase of hospital admissions in more susceptible individuals, as well as the increase of incidence of some diseases, from respiratory to cardiovascular diseases (Cote et al., 2008). In the last decade, the association between diabetes and air pollution was highlighted by some studies

Meo et al. reviewed studies that discuss insulin resistance, diabetes mellitus, and air pollution and conclude that in 10 studies, among 11 analyzed, the PM2.5 exposure to is associated with abnormalities in glucose homeostasis and this effect is related with inflammation, insulin resistance mitochondrial alteration, cardio-metabolic disorders, and thus, related to T2DM development. The same work confirms a clear and strong association between T2DM and exposure to particulate material especially, the exposure to small particulate matter of 10

The polluted air, mainly by PM2,5, is related to inflammation, vascular dysfunction, and atherosclerosis by the toxicology mechanisms invocated by the PM2,5 invasion into the bloodstream [42]. Beyond this, PM2,5 is related to induction of insulin resistance and adiposity in high fat diet mice models [16, 43]. Chronic PM2,5 exposure can induce glucose intolerance, oxidative stress, and mitochondrial alteration in Langerhans islet and adipose tissue. Thus,

Experimental studies attempt to explain the pathophysiological mechanisms that lead to metabolic outcomes described above. Xu et al. showed that PM2.5 exposure for 12 weeks promoted significant liver damage, evidenced by elevated levels of hepatic stress biomarkers, such as transaminases (ALT and AST) and reduced glycogen levels, alterations involved in impaired glucose tolerance and insulin resistance in mice. Also, this work demonstrated that PM2.5 exposure triggered Nrf2-mediated oxidative responses and activated the JNK-mediated inhibitory signaling pathway, resulting in hepatic dysfunction. Wherefore, hepatic insulin resistance can also be a potential mechanism of diabetes pathogenesis due to pollutants [45].

PM2,5 inhalation represents a novel additional risk factor to T2DM [16, 43, 46].

**3. T2DM and PM2.5: The mechanism of enhanced risk**

microns (PM10) or less in diameter, such as PM2.5 [15, 45].

β-cell dysfunction [38].

78 Diabetes and Its Complications

resistance state [16, 40].

[10, 41–43].

The redox unbalance promoted by exposure to air pollution can stimulates an inflammatory processes, contributing to installation of a metabolic disorder. The role of inflammation in the toxicity mediated by PM2,5 is associated to the increase in alveolar immunological response (increased phagocytic cell count) and to pro-inflammatory cytokines production by these cells in the alveolar surface [49], accompanied by increased lung oxidative damage [50–52], which generally evolute to systemic oxidative stress, a risk for diabetes complications.

Postulated mechanisms of action include oxidative stress and low-grade inflammation, endothelial dysfunction, visceral adipose tissue inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction [5, 53]. Thus, both acute and chronic PM2,5 exposures are associated to inflammatory and oxidative markers, as well as in T1DM and T2DM, but it is not clear the real effects of diabetes plus air pollution combination. However, the pathophysiology involved in this case increases the global risk of death by increasing the susceptibility to air pollution damage [10].

Cell stress response, observed by alteration in HSPs levels in different organs, is a defensive and cytoprotective response in both conditions, exposure to pollutants and metabolic diseases. However, there are few pieces of evidence about PM2,5 exposure concomitant to T2DM development that explores heat shock response [16].

The HSPs naturally are very sensitive elements to any chemical attack to the cells and are extensive used as biomarker of environmental exposures. In this sense, the iHSP70 expression during cellular challenges indicates that these proteins can be candidate to monitoring air pollution aggression to the health organism [54]. One study showed increase in the iHSP70 in the lung and heart one day after course particle exposure [55], and the authors discussed the plausibility of oxidative stress and/or cytokines in HSPs-induced expression as cellular defense at molecular levels, inhibiting pro-inflammatory pathways. In this way, low doses (12.5 μg/ml) of PM2,5 can increase eHSP70 in human bronquial epithelial culture [56]. Thus, the strong correlation among oxidative stress and inflammation induced by PM2,5 inhalation promotes both increase in the iHSP70 and eHSP70 content, reinforcing the purpose of use these proteins as an important biomarker of homeostatic equilibrium in environmental challenges [16, 57, 58].

Simulating urbanized conditions (consumption of high fat diet and exposure to PM2.5) [16] showed that subchronic exposure to PM2.5, even at low doses (5 μg-day, intranasal administration), potentiates metabolic dysfunction in HFD-fed mice, which are T2DM-susceptible. The effects of PM2.5 in T2DM mice presented a positive correlation between adiposity, increased body weight and glucose intolerance, and increased glucose and triacylglycerol plasma levels. Also, in this study, pancreas exhibited lower iHSP70 expression, accompanied by 3.7-fold increase in the plasma to pancreas [eHSP72]/[iHSP70] ratio (H-index). This study represents an experimental evidence that the combination of two relevant challenges to the organism, from different origins (environmental and dietary factors), promotes alterations in cell stress response (measurable by plasma/tissue H-index), reinforcing the chaperone balance [([eHSP72]/[iHSP70]) status] as a biomarker of T2DM risk.

**Appendices and nomenclatures (Optional)**

Fine Particulate Matter (PM2.5) Air Pollution and Type 2 Diabetes Mellitus (T2DM): When...

http://dx.doi.org/10.5772/intechopen.70668

81

eHSP70: 70 kDa extracellular heat shock proteins.

HSP70-KO: 70 kDa heat shock proteins knockout mice. iHSP70: 70 kDa intracellular heat shock proteins.

NADPH: dihydronicotinamide adenine dinucleotide phosphate;

RAGES: advanced glycation products binding to specific receptors.

AGEs: advanced glycation products. ALT: alanine aminotransferase. AST: aspartate aminotransferase. ATMs: Adipose tissue macrophages.

FOXO1: forkhead box protein O1. GLUT4: glucose-transporter type 4.

HSP70: 70 kDa heat shock proteins.

iNOS: inducible nitric oxide synthase.

FFA: free fat acid.

HFD: high fat diet.

HSF-1: heat shock factor. HSP: heat shock proteins.

IL-1β: interleukin-1beta. IL-6: interleukin-6. IL-8: interleukin-8.

kDa: kilodalton.

NO: nitric oxide.

mRNA: messenger RNA.

NF-kB: factor nuclear kappa B.

NOS-2: nitric oxide synthase-2. PM2,5: Fine Particulate Matter.

RNS: nitrosative species.

ROS: reactive oxygen species. T2DM: type 2 diabetes mellitus.

TNF-α: tumor necrosis factor alpha. WHO: world health organization.

If a short-term PM2.5 exposure promotes innumerous damages, long-term exposure may evidence chronic effects on human health. Xu et al. showed in experimental mice model that long-term PM2.5 exposure induces alterations on adipose tissue and leads to mitochondrial dysfunction. If PM2.5 exposure is associated with other risk factors for T2DM, such as inadequate eating behavior, it observed an increase in adiposity, body weight, and glucose intolerance [16], as well as increase in glucose and triacylglycerol plasma levels. Exposure to PM2.5 can markedly potentiate metabolic dysfunction in an already compromised organism, promoting relevant alteration in cell stress response.

The implications to health of a link between PM2.5 pollutants exposure and T2DM are critical problems to public health since air pollution is a pervasive risk factor that affects many people worldwide. In this way, it is important to highlight that modest reduction of pollution exposure may provide substantial public health benefits [45]. The underlying mechanisms responsible for this adverse effect in response to ambient PM2.5 air pollution need to be further investigated [43]. Both experimental and epidemiologic studies suggest that environmental exposures to air pollutants can increase the risk of insulin resistance, which lead to a link between air pollution and T2DM.
