A review on the molecular mechanisms involved in insulin resistance induced by organophosphorus pesticides

Toxicology 322 (2014) 1–13

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Toxicology journal homepage: www.elsevier.com/locate/toxicol

Review

A review on the molecular mechanisms involved in insulin resistance induced by organophosphorus pesticides Mohamed Montassar Lasram ∗ , Ines Bini Dhouib, Alya Annabi, Saloua El Fazaa, Najoua Gharbi Laboratory of Aggression Physiology and Endocrine Metabolic Studies, Department of Biology, Faculty of Sciences, Tunis, Tunisia

a r t i c l e

i n f o

Article history: Received 16 April 2014 Received in revised form 23 April 2014 Accepted 24 April 2014 Available online 5 May 2014 Keywords: Organophosphorus Insulin resistance Glucotoxicity Lipotoxicity Inflammation Oxidative stress

a b s t r a c t There is increasing evidence reporting that organophosphorus pesticides (OPs) impair glucose homeostasis and cause insulin resistance and type 2 diabetes. Insulin resistance is a complex metabolic disorder that defies explanation by a single etiological pathway. Formation of advanced glycation end products, accumulation of lipid metabolites, activation of inflammatory pathways and oxidative stress have all been implicated in the pathogenesis of insulin resistance. Ultimately, these molecular processes activate a series of stress pathways involving a family of serine kinases, which in turn have a negative effect on insulin signaling. Experimental and clinical data suggest an association between these molecular mechanisms and OPs compounds. It was first reported that OPs induce hyperglycemia. Then a concomitant increase of blood glucose and insulin was pointed out. For some years only, we have begun to understand that OPs promote insulin resistance and increase the risk of type 2 diabetes. Overall, this review outlines various mechanisms that lead to the development of insulin resistance by OPs exposure. © 2014 Elsevier Ireland Ltd. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular mechanisms of insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. The role of IRS in insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Alteration of insulin signaling pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Glucotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Lipotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Organophosphorus and glucose metabolism perturbations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Experimental studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Acute studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Chronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: AGEs, advanced glycosylation end products; AKT, protein kinase B; AP1, activator protein 1; aPKC, atypical protein kinase C; CAT, catalase; CRP, creactive protein; DAG, diacylglycerol; FFAs, free fatty acids; G6Pase, glucose-6-phosphatase; GP, glycogen phosphorylase; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, reduced glutathione; HK, hexokinase; HOMA-IR, homeostasis model assessment of insulin resistance; IKK␤, inhibitor kB kinase ␤; IL-1␤, interleukin-1␤; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; IR, insulin receptor; IRS-1, insulin receptor substrate-1; JNK, c-Jun N-terminal kinase; LDL, low density lipoprotein; MDA, malondialdéhyde; mTOR, mammalian Target of Rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate; NF-␬B, nucleor factor kappa B; NO, nitric oxide; OPs, organophosphorus pesticides; PDX-1, pancreatic-duodenal homeobox-1; PEPCK, phosphoenolpyruvate carboxykinase; PFK, phosphofructokinase; PI3-K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PTB, phosphotyrosine binding domain; PTP1B, tyrosine-protein phosphatase non-receptor type 1B; ROS, reactive oxygen species; SOD, superoxide dismutase; TAT, tyrosine aminotransferase; TNF-␣, tumor necrosis factor-␣; VLDL, very low density lipoprotein. ∗ Corresponding author at: Laboratory of Aggression Physiology and Endocrine Metabolic Studies, Department of Biology, Faculty of Sciences, El Manar University Tunis, Tunisia. Tel.: +216 53 63 71 38. E-mail addresses: lasram [email protected] (M.M. Lasram), [email protected] (S. El Fazaa), [email protected] (N. Gharbi). http://dx.doi.org/10.1016/j.tox.2014.04.009 0300-483X/© 2014 Elsevier Ireland Ltd. All rights reserved.

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The effect of organophosphorus on insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.1. The lipotoxic effects of organophosphorus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.2. The inflammatory stimulation by organophosphorus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.3. The oxidative stress induction by organophosphorus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Transparency document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

1. Introduction The progressive changes in lifestyle promoting pollution and including continuous exposure to xenobiotics lead to an epidemic progression of metabolic and endocrine diseases (Everett and Matheson, 2010). The uncontrolled use of pesticides against enemies (insects, pests, parasites, rodents) is considered as the essential policy for modern agriculture. Pesticides helped to improve crop yields by preventing, controlling and eradicating the spread of highly lethal parasitic diseases. Actually, the most used pesticides in the world are organophosphorus (OPs) and carbamates (Costa, 2006). The widespread use of OPs pesticides constitutes an important factor of metabolic diseases such as type 2 diabetes (Saldana et al., 2007; Montgomery et al., 2008). International epidemiological data reporting the prevalence of type 2 diabetes showed significant disparities between countries and ethnic groups. By cons, they uniformly reflect a significant increase in the prevalence of type 2 diabetes in industrialized or developing countries. Thus, the number of type 2 diabetics in the world would increase from 171 million in 2000 to 366 million in 2030 (Wild et al., 2004). Type 2 diabetes results from interactions between genetic susceptibility, environmental factors and lifestyle choices. Our understanding of diabetes has remained rudimentary, for the most part being limited to the impact of physical inactivity or unhealthy dietary choices (Bhatnagar, 2009). However, at the cellular and molecular levels, type 2 diabetes results from a disruption of the mechanisms controlling the capture, storage and use of glucose leading to hyperglycemia that announces an insulin resistance. It is now well known that insulin resistance may be induced or accelerated by environmental factors. Thus, factors related to lifestyle are now considered as a major determinant of the genesis of insulin resistance and hyperglycemia (Lee et al., 2007). Insulin resistance is defined as the inability of insulin to exert its physiological effects at a given concentration of the main targets: the skeleton muscle, liver and adipose tissue. Although, the end result of insulin resistance is a defect of glucose utilization by insulin target tissues, leading to diabetes. Insulin resistance is frequently associated with complex metabolic disorder and precedes the onset of type 2 diabetes (Tabák et al., 2009). The pathogenesis of common insulin resistance is not yet clarified, alteration in glucose metabolism or insulin signaling pathways, abnormal lipid metabolism and inflammation are considered as key mechanisms (Samuel and Shulman, 2012). Following nutrient consumption, insulin promotes carbohydrate uptake at key storage sites and prompts the conversion of carbohydrate and protein to lipids. Insulin, via the activation of protein kinase B (AKT), has two main functions. First, insulin inhibits the glucose synthesis and ␤-oxidation; secondly, it leads to the storage of glucose as glycogen and lipid via lipogenesis (Cho et al., 2001). Insulin resistance state is developed when insulin is unable to accomplish its metabolic effects. When insulin resistance begins to occur, pancreatic ␤ cells compensate by increasing basal insulin secretion. Since insulin secretion is less effective, type 2 diabetes is definitively established. Insulin resistance accelerates hepatic glucose production during postprandial phase causing hyperglycemia,

while lipogenesis remain strongly activated by increasing acyl-CoA level, a natural inhibitor of ␤-oxidation. The main molecular mechanisms of insulin resistance are the alterations of insulin signaling, glucotoxicity, lipotoxicity, inflammation and oxidative stress. The aim of this review was to evaluate the molecular mechanisms of insulin resistance induced by OPs pesticides. First we aimed to explain several mechanisms proposed in the pathogenesis of insulin resistance. Further, the review discusses the OPs pesticides action on the molecular disruptions leading to insulin resistance and type 2 diabetes, based on the clinical and experimental evidences. 2. Molecular mechanisms of insulin resistance 2.1. The role of IRS in insulin resistance IRS proteins contain many sites of phosphorylation in tyrosine and serine residues (White, 2002). Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), by the insulin receptor (IR), results in intracellular transduction of the insulin signal, whereas serine phosphorylation, by serine kinases, modulates the function of tyrosine-phosphorylated IRS-1 in negative manner (Gual et al., 2005). Elevated serine phosphorylation inhibits the insulin signaling by downregulating IRS-1 protein levels (Shah et al., 2004) and inhibiting the interaction between IRS-1 and its downstream partner, the phosphatidylinositol 3-kinase (PI3-K) (Langlais et al., 2011). Under normal condition, insulin stimulates tyrosine phosphorylation of IRS-1, followed by serine phosphorylation to inhibit insulin signaling (Gual et al., 2005). This mechanism is a kind of negative feedback of insulin on its own signaling pathways, to maintain normal glucose level. Further, insulin, via IR, is able to induce the phosphorylation of several sites very orderly and controlled in time, allowing a very precise control during insulin action (Yi et al., 2007; Boura-Halfon and Zick, 2009). This mechanism of phosphorylation on serine residues in response to insulin is very complex since it can have positive or negative effects or both on insulin signaling (Gual et al., 2005). Nowadays, it is well understood that insulin initially stimulates IRS-1 phosphorylation by insulin receptor in positive sites (Paz et al., 1999; Gual et al., 2005; Boura-Halfon and Zick, 2009). Phosphorylation of positive sites could prevent the phosphorylation of inhibitor sites (Luo et al., 2007; Weigert et al., 2008) and thus allow optimum signal transmission. Serine residues having an inhibitory effect are phosphorylated later and allow to stop insulin signal (Boura-Halfon and Zick, 2009). Therefore, under physiological conditions, the overall phosphorylation of IRS-1 on serine residues induced by insulin results from a very controlled balance between phosphorylation sites having a positive effect and sites having a negative effect. Inhibitors sites are phosphorylated in response to insulin by the atypical protein kinase C (aPKC), the p70S6 kinase and mammalian Target of Rapamycin (mTOR) (Boura-Halfon and Zick, 2009). In physiopathological conditions the inhibitor sites are phosphorylated in response to several factors involved in insulin resistance such as inflammatory cytokines, fatty acids and reactive oxygen

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species (ROS) (Boura-Halfon and Zick, 2009). An increase in the phosphorylation of these sites, in particular, Ser307 /Ser612 /Ser632 residues is found in situations of insulin resistance in humans and animals (Gual et al., 2005). Recently, Ser307 knock-out mice were found to be insulin resistant (Copps et al., 2010), suggesting that Ser307 phosphorylation may be important for insulin-stimulated IRS-1 activity (Werner et al., 2004). It is now clear that Ser307 phosphorylation is abnormally activated in obesity and diabetes and participates to the development of insulin resistance (Boura-Halfon and Zick, 2009). 2.2. Alteration of insulin signaling pathways The defect in insulin signaling is manifested by a decrease of the phosphorylation of IRS-1. A reduction of the tyrosine kinase activity of insulin receptor has been demonstrated during chronic hyperglycemia, insulin resistance and type 2 diabetes. The association of the p85 subunit of PI3-K with IRS-1 protein and the activation of the PI3-K are also impaired in obese and diabetic cases (Cusi et al., 2000; Krook et al., 2000). Furthermore, a reduction by 80% of IRS-1 phosphorylation and PI3-K activity has been demonstrated in animal models of insulin resistance (Abdul-Ghani and DeFronzo, 2010). Lack of IRS-1 protein activity was explained by abnormal protein phosphorylation on serine residues instead of tyrosine residues, both in animals and in humans (Bouzakri et al., 2005; Karlsson and Zierath, 2007). Several mechanisms are involved in the phosphorylation of serine residues. The c-Jun N-terminal kinase (JNK) inhibits the interaction between the phosphotyrosine binding domain (PTB) of IRS-1/2 with the Tyr960 of insulin receptor. JNK is activated by pro-inflammatory cytokines, fatty acids and insulin itself, which in part explains the insulin resistance state during hyperinsulinemia (Lee et al., 2003). The phosphorylation of serine residues may also result from the increased activity of PKC which is a highly activated by lipid diet, acyl-CoA and diacylglycerol. Alternatively, the impairment of insulin signaling might be the result of inhibitor kB kinase (IKK␤) over-activation. The IKK␤/NF-␬B (nucleor factor kappa B) signaling pathway controls the expression of the major pro-inflammatory cytokines (Gao et al., 2004). This signaling pathway has been investigated in several studies using transgenic mice to understand the relationship between inflammation and insulin resistance. All studies suggest that an increase in IKK␤/NF-␬B activity may induce systemic or hepatic insulin resistance. It was therefore suggested that IKK␤ could be the link between inflammation and insulin resistance. To confirm this hypothesis, some studies have looked at the impact of over-expression or over-activation of IKK␤ in cell and animal models. In this way, it was found that the ability of insulin to activate its signaling pathway is reduced when the expression and activity of IKK␤ are high (Shoelson et al., 2003; Cai et al., 2005). Thus, the overactivities of PKC, JNK and IKK␤ during pathological process have a negative effect on insulin signaling. These serine kinases are abnormally stimulated by high level of glucose (glucotoxicity), increased concentration of lipids (lipotoxicity), inflammation and oxidative stress. 2.3. Glucotoxicity In the pathophysiologic process called glucotoxicity, chronic hyperglycemia contributes to the progressive impairment of insulin secretion and aggravates insulin resistance. Indeed, a high intracellular level of glucose desensitizes the ␤-cells to glucose stimulation. Glucotoxicity is also responsible for aggravating insulin resistance, in part through down-regulation of the glucose transporter system. On the other hand, glucose is converted by hexokinase to glucose-6-phosphate to join glycolysis pathway. During chronic hyperglycemia, hexokinase is saturated. Therefore, glucose

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is accumulated in peripheral tissues and in pancreatic ␤ cells. A high level of glucose in ␤ cells can activate the apoptotic signaling pathways (Burg, 1995). Indeed, ␤ cell apoptosis is associated with a massive increase of interleukin-1␤ (IL-1␤) autocrine synthesis. This results in the activation of the NF-␬B and PKC␦. They are responsible for the activation of the iNOS gene (inducible Nitric oxide synthase) which follows the formation of NO (nitric oxide), a major stimulus of pancreatic ␤ cells apoptosis (Carpenter et al., 2001). Pancreatic ␤ cells are sensitive to apoptotic effects of IL-1␤ because of their high degree of differentiation. IL-1␤ is the major cause of changes in the formation of Ca2+ micro-domains which would be involved in the development of necrosis (Petersen et al., 2006; Criddle et al., 2007). Further, chronic exposure of the beta cell to supraphysiologic concentrations of glucose causes oxidative stress and defective insulin gene expression accompanied by marked decreases in insulin content and abnormal insulin secretion (Robertson et al., 1992). The defect in insulin gene expression is due to the loss of pancreaticduodenal homeobox-1 (PDX-1) that activates the insulin promoter (Olson et al., 1995) (Fig. 1). Decreases in PDX-1 binding to the insulin promoter caused by oxidative stress were reported to be preceded by activation of JNK, since dominant negative JNK over-expression preserved insulin gene expression under hyperglycemic conditions (Kaneto et al., 2002). In insulin target cells, high concentration of glucose leads to the formation of AGEs (advanced glycosylation end products) by reacting with amino groups on intracellular and extracellular proteins (Thornalley et al., 1999) (Fig. 1). It was recently reported that AGEs may inhibit IRS activity when binding with its active domain (Cnop et al., 2005). AGEs may stimulate signal transduction via engagement of cellular receptors, RAGEs. The AGE–RAGE interaction perpetuates AGEs formation and cellular stress via induction of inflammation, oxidative stress, and reduces insulin responsiveness in target cells. 2.4. Lipotoxicity Lipotoxicity is another injurious outgrowth of the diabetic pathogenesis. It has many similarities to glucotoxicity, and serves as an especially strong link between obesity and insulin resistance. The concept of lipotoxicity grew from early work by Randle et al. (1965) who showed that increased availability of free fatty acids (FFAs) inhibited the glucose oxidation and uptake in rat muscle cells. Increased plasma concentrations of FFAs lead to dysfunctions in the cascade of insulin signaling. A recent study on rats fed a high fat diet suggests that ectopic FFAs accumulation is a better indicator of insulin resistance than the mass of adipose tissue (Lim et al., 2009). Recent experiments have shown a duality of action of fatty acids on pancreatic ␤ cells. During short-time exposure (few hours) to FFAs glucose-induced insulin secretion is increased. In the contrary, during chronic exposure to high concentrations of FFAs insulin secretion is inhibited (Kashemsant et al., 2012). Several hypotheses were made in order to explain the effect of prolonged exposure to fatty acids. Firstly, activation of ATP-dependent K+ pumps by an excess acyl-CoA, causes a failure of membrane depolarization of ␤ cells, and decreases the cell response to glucose stimulus (Girard, 2003). On the other hand, excess fatty acids in pancreatic ␤ cell would induce a change in gene expression of the GLUT2 (glucose transporter 2) and insulin by inhibiting the transcription factor PDX-1 (Yoshikawa et al., 2001). The accumulation of fatty acids would be responsible for both decreased response to elevated glucose concentrations resulting from the inhibition of GLUT2 expression, and decreased insulin synthesis by PDX-1 inhibition which is directly involved in the transcription complex of the insulin gene. Recently, some studies have better elucidated the role of FFAs in the IRS inactivation (Gao et al., 2004; Schenk et al., 2008). FFAs

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Fig. 1. The role of hyperglycemia in insulin resistance. Hyperglycemia may contribute to insulin resistance by promoting the formation of AGEs in insulin target cells. AGEs increased phosphorylation of IRS-1 at serine307 residues. The serine phosphorylation leads to the ubiquitination and degradation of IRS-1, thus blocking insulin action downstream of receptor activation. On the other hand, high levels of glucose in ␤ cells cause oxidative stress and ROS formation via mitochondrial pathway. This leads to the activation of stress-sensitive pathways such as JNK which down-regulates the PDX-1 involved in insulin gene expression. (Abbreviations: AGEs, advanced glycosylation end products; IRS-1, insulin receptor substrate 1; JNK, c-jun N-terminal kinase; PDX-1, pancreatic-duodenal homeobox-1; ROS, reactive oxygen species.)

directly or through the intermediates such as diacylglycerol (DAG) or ceramide, activate the serine-kinase PKC␪, which becomes phosphorylated at threonine 538 residue. Phosphorylated PKC␪ starts a downstream activation of other two serine-kinases, the JNK and the IKK␤. JNK and IKK␤ associate with IRS-1, promoting its serinephosphorylation on serine307 in rodents (serine312 in humans) (Greene et al., 2003; Gual et al., 2005) (Fig. 2). The serine phosphorylation is responsible for IRS-1 blocking and the occurrence of insulin

Fig. 2. The role of free fatty acids in insulin resistance. Fatty acids, in their activated form (acyl-CoA), are metabolized via oxidation or storage. When fatty acid flux exceeds the capacity of these pathways, fatty acids and their intermediates such as DAG and ceramide accumulate and activate PKC␪, which becomes phosphorylated. Phosphorylated PKC␪ starts a downstream activation of two serine-kinases, the JNK, and the IKK. JNK and IKK associate with IRS-1, promoting its serine-phosphorylation. The serine phosphorylation is responsible for IRS-1 blocking and the occurrence of insulin resistance by interrupting insulin receptor/IRS interaction and promoting IRS-1 protein degradation. (Abbreviations: DAG, diacylglycerol; FATP1, fatty acid transport protein 1; FFAs, free fatty acids; IKK, inhibitor of ␬kinase; IRS-1, insulin receptor substrate 1; JNK, c-jun N-terminal kinase; PKC, protein kinase C-theta.)

resistance through interruption of IR/IRS interaction (Aguirre et al., 2002). 2.5. Inflammation For many years, a number of studies have made the connection between inflammation and diabetes. It has first been shown that the administration of high doses of sodium salicylate, decreased glycosuria in diabetic patients (Shoelson et al., 2007). Other studies examining the role of inflammation in insulin resistance patients have demonstrated the hypoglycemic action of salicylates and identified the IKK␤/NF-␬B axis as a molecular target (Yuan et al., 2001; Hundal et al., 2002). Since, the insulin resistance was frequently associated with inflammation (Tilg and Moschen, 2008). Different cell types are involved in this inflammation. It is known that adipocytes secrete many pro-inflammatory mediators (Deng and Scherer, 2010) such as tumor necrosis factor-␣ (TNF-␣) and interleukin-6 (IL-6) which have an impact on the whole body including the liver, muscle and adipocyte cells. In addition, many elements have shown that chronic activation of pro-inflammatory pathways in target cells can promote the insulin resistance. High levels of pro-inflammatory cytokines such as TNF-␣, IL-6 and CRP (C-reactive protein) were found in insulinresistant and type 2 diabetes subjects (de Luca and Olefsky, 2008; Shoelson et al., 2007). Furthermore, TNF-␣ concentration is higher in the blood and adipose tissue of obese rodents, and the inhibition of TNF-␣ enhances insulin sensitivity in these animals (Hotamisligil et al., 1993). The action of pro-inflammatory cytokines is involved in the activation of JNK and IKK␤/NF-␬B signaling pathways. It was demonstrated that signaling pathways of JNK (Hirosumi et al., 2002; Bandyopadhyay et al., 2002) and IKK␤ (Yuan et al., 2001; Cai et al., 2005) are activated and up-regulated in skeletal muscle of diabetes patients and insulin-resistant rodents. These kinases phosphorylate the transcription factors AP1 (activator protein 1) and NF-␬B, which activate the transcription of a number of genes involved in the inflammatory response, leading to decreased insulin

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sensitivity. Finally, deficiency or inhibition of JNK or IKK␤ prevents insulin resistance in murine models (Arkan et al., 2005; Solinas and Karin, 2010). 2.6. Oxidative stress Under physiological conditions, there is a balance between the production of free radicals and endogenous antioxidant defense mechanisms. These mechanisms involve mostly specific enzymes and antiradical molecules that scavenge free radicals, such as vitamins. Polyunsaturated fatty acids in cell membranes are the main target of reactive oxygen species (ROS). This results in the formation of lipid peroxides which decompose into products such as 4-hydroxynonenal, ethane, pentane and malondialdehyde (MDA). Oxidative stress plays an important role in the pathogenesis of insulin resistance during the postprandial period when hyperglycemia induced a disruption of the redox status. In fact, when present in low concentrations (micromolar), ROS are involved in the activation of certain signaling pathways (Droge, 2005) and could be involved in such insulin signal transduction. Several old investigations showed on adipocytes cultures that hydrogen peroxide mimics the metabolic effects of insulin: activation of glucose transport, lipid and glycogen synthesis and inhibition of lipolysis (May and de Haen, 1979). These effects were associated with an activation of the signaling pathway of insulin (Heffetz et al., 1992), activation of PI3 kinase and AKT (Shaw et al., 1998). Another study has confirmed that the hydrogen peroxide produced early in response to insulin actives its signaling pathway (Schmid et al., 1998). The activation of insulin signaling pathway would requires preliminary steps which promote oxidative autophosphorylation of the insulin receptor and trigger the cascade of phosphorylation leading to cellular responses of insulin. Furthermore, the activation of NADPH oxidase in response to insulin quickly leads to a moderate production of hydrogen peroxide which would act as a second messenger of insulin (Hildebrandt et al., 2004; Goldstein et al., 2005). However, prolonged exposure to ROS induces disturbance of redox status and can inhibit the insulin signaling pathway leading to insulin resistance. The first mechanism of the deleterious effects of ROS is the activation of protein phosphatases involved in the insulin signaling extinction such as PTP1B (tyrosine-protein phosphatase nonreceptor type 1) (Saltiel and Pessin, 2002; Asante-Appiah and Kennedy, 2003). PTP1B proteins inhibit the insulin receptor and IRS proteins phosphorylation on tyrosine residues (Gual et al., 2005). Other keys of insulin signaling events seem to be affected by the excess of hydrogen peroxide. On 3T3L1 adipocyte cells, the addition of hydrogen peroxide alters the association between IRS-1 and PI3 kinase by changing the distribution of these two proteins in the cytosol (Nomiyama et al., 2004). Indeed, insulin resistance is a complex mechanism which seems to be initiated and promoted by glucotoxicity, lipotoxicity, inflammation and oxidative stress. The major molecular mechanisms involved in insulin resistance are presented in Fig. 3. In the next sections of the review we will discuss how OPs pesticides can induce insulin resistance, since they are known to be glucolipotoxic, to promote inflammatory process and oxidative stress. 3. Organophosphorus and glucose metabolism perturbations 3.1. Clinical studies Numerous publications have reported the impact of OPs insecticides on disturbance of glucose metabolism and risk of type 2 diabetes (Akyildiz et al., 2009; Kumar and Nayak, 2011).

Fig. 3. Molecular mechanisms of insulin resistance. Pro-inflammatory cytokines lead to the induction of inflammatory signaling pathways in metabolic cells through the activation of toll-like receptor (TLR). Three prominent kinases downstream of these receptors are JNK, IKK␤ and PKC␪, which play important roles in relaying stress signals throughout the cell and engaging metabolic responses. All three of these kinases can inhibit insulin signaling via serine phosphorylation of IRS-1. This phosphorylation leads to the ubiquitination and degradation of IRS-1, thus blocking insulin action downstream of receptor activation. In addition, FFAs directly or through the intermediates such as DAG or ceramide, activate the serine-kinase PKC␪. Further, high concentration of glucose leads to the formation of AGEs which may interact with IRS-1 through the RAGEs receptors. Finally, high levels of glucose cause oxidative stress and ROS formation. ROS may activate serine kinases and reverse gene expression leading to insulin resistance. The serine kinases JNK, IKK␤ and PKC␪ can induce an inflammatory response through activation of the transcription factors AP-1 and NF-␬B, which upregulate inflammatory mediator gene expression and exacerbate the insulin receptor inactivation. (Abbreviations: AGEs, advanced glycosylation end products; AP-1, activator protein-1; DAG, diacylglycerol; FATP1, fatty acid transport protein 1; FFAs, free fatty acids; IKK, inhibitor of ␬kinase; IRS-1, insulin receptor substrate 1; JNK, c-jun N-terminal kinase; NF-␬B, nucleor factor kappa B; PKC, protein kinase C; RAGEs, receptor for advanced glycation end products; ROS, reactive oxygen species.)

Hyperglycemia was reported in humans accidentally exposed to malathion (Ramu et al., 1973; Sungur and Güven, 2001). Other clinical observations reported a concomitant increase of blood glucose and insulin in many families exposed to OPs (Meller et al., 1981). The same observations were described by other studies reported in Table 1. Moreover, in a large prospective agricultural health study of incident diabetes in licensed pesticide applicators in the USA, the prevalence of diabetes increased with OPs pesticides (Montgomery et al., 2008). It was reported by the Agricultural Health Study, increased gestational diabetes incidences during the first trimester of pregnancy among women during residential OPs exposure (Saldana et al., 2007). Another study conducted by Raafat et al. (2012) among farmers without diabetes, signaled that there was a significant increase in mean values of malathion blood concentration when they compared with a non-farming control population. There was a positive correlation between malathion levels and insulin resistance, assessed by homeostasis model of insulin resistance (HOMA-IR). The authors concluded that chronic exposure to OPs pesticides in farmers without diabetes tends to induce insulin resistance. 3.2. Experimental studies 3.2.1. Acute studies The majority of experimental studies designed to evaluate the effects of OPs on glucose homeostasis have reported a pronounced hyperglycemia, as an immediate consequence of OPs administration. There have been several case reports of transient

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Table 1 Summary of epidemiological and clinical studies on the effects of OPs on the risk of diabetes. Study

Exposure

Cases

Results

Meller et al. (1981)

OP poisoning

Case report

Moore and James (1981)

OP poisoning

Case report

Martín et al. (1996)

OP compounds

506

Shobha and Prakash (2000) Wu et al. (2001) Yanagisawa et al. (2006) Saldana et al. (2007) Montgomery et al. (2008) Akyildiz et al. (2009) Kumar and Nayak (2011) Raafat et al. (2012)

OP poisoning Methamidophos Sarin OP compounds OP compounds OP poisoning OP poisoning Malathion

51 Case report Case report 506 1176 Case report Case report 218

Hyperglycemia Risk of diabetes mellitus Hyperglycemia Glycosuria Pancreatitis Diabetes insipedus Transient glycosuria Hyperglycemia Hyperglycemia Gestational diabetes mellitus Risk of diabetes Risk of diabetes Risk of diabetes Hyperglycemia Insulin resistance Risk of diabetes

hyperglycemia in rats treated with a single dose of malathion (Ramu and Drexler, 1973; Rodrigues et al., 1986; Matin and Husain, 1987), diazinon (Husain and Ansari, 1988; Matin et al., 1990; Seifert, 2001), acephate or monocrotophos. Similarly, Seifert (2001) described a reversible hyperglycemia in mice exposed to a single intraperitoneal injection of diazinon. According to the same author, hyperglycemia reaches a peak after about 2 h of injection, and seems to persist for 6 days. Furthermore, it was reported that OPs stimulate glycogenolysis and gluconeogenesis to enhance hyperglycemia. Thus, the activities of glycogen phosphorylase (GP) and phosphoenolpyruvate carboxykinase (PEPCK) are stimulated after acute OPs exposure (Matin et al., 1990; Teimouri et al., 2006). The results of the main studies published in this framework are summarized in Table 2. 3.2.2. Chronic studies Chronic administration of lower doses of malathion (Abdollahi et al., 2004; Pournourmohammadi et al., 2005; Panahi et al.,

2006; Basiri et al., 2007; Ruckmani et al., 2011; Mostafalou et al., 2012), fenitrothion (Afshar et al., 2008), or acephate (Deotare and Chakrabarti, 1981) shows the same increase in blood glucose in adult rats. Several studies signaled the same disturbances after OPs chronic exposure (Hagar and Fahmy, 2002; Alahyary et al., 2008; Lassiter et al., 2008; Elsharkawy et al., 2013; Hamza et al., 2014). Furthermore, Pournourmohammadi et al. (2005) reported hyperglycemia and hyperinsulinemia in rats fed a diet containing increasing concentrations of malathion (5, 10 and 20 mg/kg) for 28 days. Similar results were found by Panahi et al. (2006) after a daily intraperitoneal injection of malathion on rats for 4 weeks. By cons, normoglycemia was observed after chronic malathion exposure in mice (Sadeghi-Hashjin et al., 2008). Similarly, Gowda et al. (1983) and Rezg et al. (2007) reported the same normoglycemia associated with an increase of liver glycogen storage in rats exposed to malathion during 15 and 32 days respectively. The authors have explain the divergent results by the difference of the experimental protocols, likewise, the dose, the duration of treatment and the

Table 2 Summary of acute and subacute studies on the effects of OPs on glucose metabolism in rats. Study

Pesticide

Dose

Results

Rodrigues et al. (1986) Matin and Husain (1987)

Malathion Malathion

650 mg/kg 500 mg/kg

Husain and Ansari (1988)

Diazinon

40 mg/kg

Matin et al. (1990)

Diazinon

40 mg/kg

Romero-Navarro et al. (2006) Panahi et al. (2006)

Dichlorvos Malathion

20 mg/kg 3, 15, 75 mg/kg

Teimouri et al. (2006)

Diazinon

Ghafour-Rashidi et al. (2007)

Diazinon

Lasram et al. (2008)

Malathion

15, 30, 60 mg/kg 15, 30, 60 mg/kg 200 mg/kg

Joshi and Rajini (2009)

Acephate

140 mg/kg

Acker and Nogueira (2012)

Chlorphyrifos

50 mg/kg

Joshi and Rajini (2012)

Monocrotophos

1.8 mg/kg

↑ Glycemia ↑ Glycemia ↓ Brain glycogen ↑ GP ↑ PGM ↑ HK ↑ Glycemia ↓ Brain glycogen ↑ GP ↑ PGM ↓ HK ↓ PFK ↑ Glycemia ↓ Brain and liver glycogen ↑ GP ↑ PGM ↑ HK ↓ Hepatic glucokinase ↑ Glycemia ↑ Insulinemia ↑ Glycemia ↓ GP, ↑ PEPCK ↑ Glycemia ↑ Insulinemia ↑ Glycemia ↓ Hepatic glycogen ↑ Glycemia ↓ Hepatic glycogen ↑ G6Pase ↑ TAT ↑ Glycemia ↑ Hepatic glycogen ↑ G6Pase ↑ TAT ↑ Glycemia ↑ Hepatic glycogen ↑ TAT

G6Pase, glucose-6-phosphatase; GP, glycogen phosphorylase; HK, hexokinase; PEPCK, phosphoenolpyruvate carboxykinase; PFK, phosphofructokinase; TAT, tyrosine aminotransferase. HK and PFK are involved in glycolysis; GP and PGM, are involved in glycogenolysis, PEPCK, G6Pase, and TAT are involved in gluconeogenesis.

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time between the last administration and blood sampling. Despite these differences, it is well recognized that OPs exposure seems to induce a disruption of glucose homeostasis. Actually, the impact of OPs on insulin resistance and type 2 diabetes is currently under debate in the context of the exponential increase of the OPs use and their effects on human health. If several studies suggest that hyperglycemia is an unavoidable consequence of pesticides, the mechanisms involved are poorly understood and, in particular, the concomitant increase in blood sugar and insulin is not yet well established. Some authors have attributed the alterations of glucose metabolism, to an excessive release of adrenaline after cholinergic stimulation of the adrenal medulla. Increased and prolonged release of adrenaline could lead to intense adrenergic syndrome characterized by hyperglycemia and hypertension (Rahimi and Abdollahi, 2007). Likewise, it has been shown that OPs alter the metabolic pathways of gluconeogenesis and glycogenolysis in the liver, skeletal muscle, adipose tissue and brain to increase glucose production (Rahimi and Abdollahi, 2007). Indeed, the activities of enzymes involved in gluconeogenesis, tyrosine aminotransferase (TAT) and glucose-6-phosphatase (G6Pase), are increased after the administration of acephate (Joshi and Rajini, 2009), chlorphyrifos (Acker and Nogueira, 2012) or monocrotophos (Joshi and Rajini, 2012). Further, Abdollahi et al. (2004) and Mostafalou et al. (2012) showed that chronic administration of malathion in rats induced a significant increase in the activity of PEPCK (Table 3). Similarly, high activities of GP and phosphoglucomutase (PGM), have been reported in rats treated with malathion or diazinon (Matin and Husain, 1987; Husain and Ansari, 1988). 4. The effect of organophosphorus on insulin resistance Several experimental studies have shown that OPs can induce insulin resistance in animal models (Pournourmohammadi et al., 2005; Panahi et al., 2006; Rahimi and Abdollahi, 2007; Mostafalou et al., 2012). The authors suggested that insulin resistance induced by OPs pesticides is prompted by different molecular and cellular mechanisms. Thus, the progressive installation of insulin resistance has been explained by the dysfunction of pancreatic ␤ cells, or the decrease of insulin action in target tissues. Indeed, dysfunction of insulin-secreting cells plays an important role in the induction of insulin resistance. Pournourmohammadi et al. (2005) studied the effects of malathion on insulin secretion and demonstrated an alteration of glucokinase activity in pancreatic ␤-cells. This enzyme plays a crucial role in the regulation of insulin secretion in response to glucose. Panahi et al. (2006) showed that the activities of glucokinase and glutamate dehydrogenase in insulin-secreting cells are stimulated after acute or chronic exposure to malathion, nevertheless, these high activities were insufficient to overcome hyperglycemia. Moreover, the secretion of insulin in response to glucose is controlled by the system via the cholinergic muscarinic receptors located on the surface of pancreatic ␤-cells (Duttaroy et al., 2004). It is well known that OPs acts by inhibition of acetylcholinesterase leading to an accumulation of acetylcholine and to over-stimulation of its receptors. Prolonged acetylcholine stimulation can reduce the sensitivity of the ␤ cells to glucose (van Koppen and Kaiser, 2003). Nevertheless, insulin resistance induce by OPs may be the results of accumulation of FFAs, cytokines and ROS. 4.1. The lipotoxic effects of organophosphorus Numerous studies have reported a disruption of lipids metabolism in experimental animals exposed to OPs. It was showed that acute administration of malathion increases plasma levels of triglycerides, total cholesterol and LDL (low density lipoprotein).

7

Similarly, acute administration of chlorphyrifos increased plasma LDL, VLDL (very low density lipoprotein) and triglycerides rates (Acker and Nogueira, 2012). Similar results were reported in rats exposed daily to malathion during 28 days (Kalender et al., 2010) and 32 days (Rezg et al., 2010). The administration of dichlorvos during 4 and 7 weeks increased the rate of total plasma cholesterol (Ogutcu et al., 2008). Other authors have cited the same results (Ibrahim and El-Gamal, 2003; Kalender et al., 2005; Youssef et al., 2006). One of the mechanisms likely involved in OPs-induced dyslipidemia is increased hepatic production of VLDL and LDL offset (Kissebah et al., 1982). This appears to be related to several factors such as an increase of the substrates required to the biosynthesis of triglyceride (free fatty acid), a resistance to the inhibitory effect of insulin against the production of VLDL and an increase of lipogenesis de novo in hepatocytes (Taskinen, 1992). Dyslipidemia may contribute to insulin resistance by altering the insulin signaling pathways. At the molecular level, a significant accumulation of intramuscular metabolites of FFAs such as acyl-CoA, ceramide, diacylglycerol (DAG) may over-activate the PKC, IKK␤ and JNK (Krebs and Roden, 2005; Schinner et al., 2005). Among the many substrates of these kinases, there are the insulin receptor and the IRS-1 which are inactivated when phosphorylated on serine residues as mentioned previously (Figs. 2 and 3). 4.2. The inflammatory stimulation by organophosphorus A number of studies related an induction of inflammatory processes in the central system nervous, cardiac and pancreatic tissues. Myocarditis, pericarditis, interstitial inflammation, edema, and other histopathological findings were reported among 13 patients who died as a result of OPs poisoning (Anand et al., 2009). Further, fenthion was found to induce inflammation, edema, vacuolization, and necrosis in myocardial tissue, and these features are alleviated by the administration of diphenhydramine (Yavuz et al., 2008). Pancreatitis has also been reported in acute OPs poisoning case studies (Harputluoglu et al., 2003; Hamaguchi et al., 2006; Roeyen et al., 2008). Other works proved that OP compounds can directly increase the secretion of pro-inflammatory cytokines. The increase in proinflammatory cytokines such as TNF-␣ and IL-6 was observed in rats treated with diazinon (Hariri et al., 2010), fenthion (Yurumez et al., 2007) and malathion (Ayub et al., 2003). Similarly, primary cultures of human fetal astrocytes treated with chlorphyrifos showed an increased mRNA synthesis of IFN-␥ (interferon-gamma) and IL-6 (Duramad et al., 2006; Mense et al., 2006). Consistent with these observations, dermal exposure to chlorpyrifos during 7 days increases cytokines expression in astrocyte cells in mouse brains (Lim et al., 2011). In addition, transcript and protein levels of the pro-inflammatory cytokines TNF-␣, IL-1␤, and IL-6 are elevated in the hippocampus, piriform cortex and thalamus of rats and mice following acute soman exposure (Dhote et al., 2007; Dillman et al., 2009; Johnson and Kan, 2010). Sarin acts similarly, increasing levels of TNF-␣, IL-1␤, and IL-6 in the cortex and hippocampus of rats (Chapman et al., 2006). In the last study, it was reported that cytokine levels return to control values after 1–2 days of exposure, but a second increase in cytokine levels is observed in a subset of rats after 30 days of exposure, indicating that inflammation can persist long after the initial exposure. Additionally, rats repeatedly exposed to low doses of sarin vapor exhibits high levels of IL-1␤, TNF-␣, and IL-6 in the brain (Henderson et al., 2002). Administration of low levels of malathion during 14 or 90 days increased macrophage function and mast cell degranulation in mice (Rodgers and Xiong, 1997a,b). The rise of pro-inflammatory cytokines contributes to the activation of some redox-sensitive transcription factors such as NF-␬B

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Table 3 Summary of chronic and subchronic studies on the effects of OPs on glucose metabolism in rats. Study

Pesticide

Dose

Results

Deotare and Chakrabarti (1981)

Acephate

250 mg/kg

Reena et al. (1989) Sarin and Gill (1999)

Dimethoate Dichlorvos

150 mg/kg 6 mg/kg

Hagar and Fahmy (2002)

Dimethoate

21 mg/kg

Abdollahi et al. (2004)

Malathion

100, 200, 400 ppm

Pournourmohammadi et al. (2005)

Malathion

100, 200, 400 ppm

Rezg et al. (2006)

Malathion

100 mg/kg

Panahi et al. (2006)

Malathion

100, 200, 400 ppm

Basiri et al. (2007)

Malathion

20 mg/kg

Alahyary et al. (2008) Lassiter et al. (2008) Ruckmani et al. (2011) Mostafalou et al. (2012)

Diazinon Parathion Malathion Malathion

75 mg/kg 0.1 or 0.2 mg/kg 50% 25, 50, 100 mg/kg

Elsharkawy et al. (2013)

Chlorpyrifos

30 mg/kg

Pakzad et al. (2013)

Diazinon

70 mg/kg

Hamza et al. (2014)

Chlorpyrifos

6.75 mg/kg

↑ Glycemia ↓ Hepatic glycogen ↑ Glycemia ↑ Glycemia ↓ Brain glycogen ↑ GP ↓ PFK ↓HK ↑ Glycemia ↓ Insulinemia ↑ Glycemia ↑ GP ↑ PEPCK ↑ Glycemia ↑ Insulinemia ↑ GP ↑ PFK Normoglycemia ↑ Hepatic glycogen ↓ GP ↑ HK ↑ Glycemia ↑ Insulinemia ↑ Glycemia ↑ GP ↑ PEPCK ↑ Glycemia ↑ Glycemia ↑ Glycemia ↑ Glycemia ↑ PEPCK ↑ G6Pase ↑ Glycemia ↓ Hepatic glycogen ↑ Glycemia ↓ Insulinemia ↑ Glycemia ↑ Insulinemia

G6Pase, glucose-6-phosphatase; GP, glycogen phosphorylase; HK, hexokinase; PEPCK, phosphoenolpyruvate carboxykinase; PFK, phosphofructokinase. HK and PFK are involved in glycolysis; GP is involved glycogenolysis, PEPCK and G6Pase are involved in gluconeogenesis.

(Karami-Mohajeri and Abdollahi, 2011). Interestingly, it has been proved that NF-␬B activation in hepatocytes has a causative role in developing hepatic insulin resistance (Arkan et al., 2005; Cai et al., 2005). In fact, NF-␬B is activated by pro-inflammatory cytokines and also induces their transcription in the state of insulin resistance (Mohseni Salehi Monfared et al., 2009). Thus, pro-inflammatory cytokines are involved in impaired glucose homeostasis through its interaction with different points of insulin-signaling pathway (Kajbaf et al., 2007; Ansari et al., 2008; Amini-Shirazi et al., 2009). Alternatively, the impairment of insulin signaling might be the result of JNK and/or IKK␤ over-activation by pro-inflammatory cytokines. It was supported an increase in IKK␤/NF-␬B activity may induce insulin resistance in insulin-target cells. Furthermore, the serine kinase JNK activated by endoplasmic reticulum stress, inflammation, and lipotoxicity is believed to contribute to insulin resistance. In this way, JNK KO mice are more sensitive to insulin (Aguirre et al., 2000). However, recent studies of the JNK KO mice demonstrate that loss of JNK impairs hepatic insulin sensitivity and predisposes the liver to steatosis when mice are placed on a highfat diet (Sabio et al., 2008, 2009). In addition, JNK activation in other tissues (adipose tissue, skeletal muscle, and brain) impairs insulin action (Sabio et al., 2010). These results suggest that JNK-dependent inflammation may regulate insulin sensitivity in a tissue-specific manner. 4.3. The oxidative stress induction by organophosphorus Currently, oxidative stress is the second aspect of OPs toxicity after cholinesterase inhibition, and remains today under investigation. Induction of free radicals, lipid peroxidation and impaired antioxidant status by OPs has been widely studied in humans and animals (Gupta et al., 2001; Akhgari et al., 2003). The observations reported in manufacturing workers accidentally exposed to OPs pesticides are also similar. Vidyasagar et al. (2004) reported

an increase of MDA level and superoxide dismutase (SOD) activity in human cases accidentally poisoned by various OPs. Ranjbar et al. (2002) also reported an increase in MDA levels and reduced thiols and total antioxidant capacity among manufacturing workers exposed to different doses of OPs pesticides. Similar findings were reported by Shadnia et al. (2005), Soltaninejad et al. (2007) and Tope and Panemangalore (2007). Experimental studies have reported similar changes in rats. Thus, acute and chronic exposure of male rats to different doses of malathion, causes the same changes in the redox status in the liver, muscle and kidney (Possamai et al., 2007). Akhgari et al. (2003) also reported an increase in oxidative stress parameters in the liver and erythrocytes of rats exposed to malathion for 4 weeks. Oral administration of malathion in rats during 45 days, increases the levels of MDA and decreases the activity of all antioxidant enzymes and reduced glutathione (GSH) levels in the liver and kidney (Al-Othman et al., 2011). Additionally, an imbalance between oxidative/antioxidant status has been reported in the liver of mice exposed to dimethoate (Sivapriya and Jayanthisakthisekeran Venkatraman, 2006) and chlorphyrifos (Aly et al., 2010). Similar results were observed by in vitro studies. Indeed, it was reported that the incubation of rat erythrocytes with different doses of phosphomidon increases the activity of SOD and catalase (CAT) and reduces the activity of glutathione reductase (GR) (Datta et al., 1992). The same authors noted an increase in MDA levels and CAT with a reduced GSH level and glutathione peroxidase (GPx) activity in serum. Similar results have been reported by Yamano and Morita (1992) in the hepatocyte cultures isolated and incubated with high doses of dichlorvos (Cicchetti and Argentin, 2003). Reactive oxygen species are mainly produced as a result of biotransformation reactions of OPs compounds by cytochrome P450 which catalyze the oxidation reactions of OPs (Buratti et al., 2005). During these reactions, an excess of free radicals is generated. Rahimi and Abdollahi (2007) attributed the increase of ROS

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generation to the intense glucose release from hepatic glycogenolysis and therefore the concomitant release of ATP. Another mechanism of ROS generation described by Milatovic et al. (2006), suggests that the increased energy is associated with the inhibition of oxidative phosphorylation induced by ROS consumption. High energy consumption lowers the ability of cells to maintain the energy level. This may results in disturbances in the cellular redox system and an excess of ROS can be generated (Milatovic et al., 2006). Increasingly experimental and clinical data suggest that oxidative stress through free radicals plays a role in the pathophysiology of insulin resistance (Ceriello, 2003). Several epidemiological studies have observed in cohorts of diabetic subjects a significant correlation between fasting glucose and various markers of oxidative stress. Fasting blood glucose was positively correlated with plasma MDA and ROS concentrations (Gopaul et al., 2001; Trevisan et al., 2001; Menon et al., 2004). The importance of oxidative stress in the etiology of insulin resistance is also suggested by studies demonstrating the beneficial effect of an antioxidant supplementation on insulin sensitivity. On obese Zucker rats, a model of insulin resistance, the addition of vitamin E for 4 weeks reduces the oxidative stress markers (Laight et al., 1999). The improvement in the redox status is accompanied by a decrease in blood glucose and fasting insulin. Similar results were obtained in humans (Paolisso et al., 1993). Free radicals affect the signaling cascade of insulin, in a dosedependent manner. It has been shown that low concentrations of ROS play an important role in the insulin signaling by inhibiting the activity of tyrosine phosphatase. This improves the basal tyrosine phosphorylation of insulin receptor and its substrates (Mahadev et al., 2004). Other studies have shown that in conditions of intense oxidative stress, the insulin signaling is diminished (Frank et al., 2006). These findings are based on the studies related to the glucose uptake, glycogen metabolism and protein synthesis in cells exposed to hydrogen peroxide. The exact link between oxidative stress and insulin signaling is not fully understood. However, it was confirmed that high concentrations of ROS cause the phosphorylation of IRS-1 on serine residues, which reduces the transcription of GLUT4 gene (Morino et al., 2006). Furthermore, high concentrations of ROS activate some stress-sensitive signaling pathways, such as NF-␬B and JNK pathways (Ogihara et al., 2004).

5. Conclusion There are a lot of evidences on the effect of OPs pesticides on glucose metabolism disruption and insulin resistance. OPs activate the metabolic pathways in brain, skeletal muscles and liver in favor of increased glucose production (Rahimi and Abdollahi, 2007). Hyperglycemia may occur due to OPs intoxication as a result of glycogenolysis and gluconeogenesis stimulation. In the initial stages of poisoning, glucose is used to supply energy to meet the stress situation and serve as the major source of energy (Mostafalou et al., 2012). Prolonged hyperglycemia is responsible for insulin resistance and insulin deficiency. In insulin target cells, high level of glucose stimulates the AGEs formation. There is a growing body of evidence that AGEs accumulation is involved in the pathogenesis of insulin resistance and type 2 diabetes. AGEs may contribute to insulin resistance by a variety of mechanisms, including generation of oxidative stress, inflammation and their direct interaction with IRS-1 (Henriksen et al., 2011). Further, OPs induced lipid disorders and increased triglycerides and FFAs synthesis. It is well known that dyslipidemia plays an important role during the early stages of insulin resistance, in particular by activating serine kinases as PKC␪ and JNK leading to the inhibition of IRS-1 activity (Krebs and Roden, 2005). Thus, high concentrations of FFAs may contribute to

9

Fig. 4. Possible mechanisms of insulin resistance induced by organophosphorus pesticides. OPs and their toxic metabolites may cause damage at the cellular level due to their lipophilic nature and their interaction with biomolecules. Cell damage may induce inflammatory and oxidative stress conditions. Pro-inflammatory cytokines and ROS would therefore over-activate the serine kinase leading to inactivation of the IRS-1 and promoting insulin resistance.

the installation of insulin resistance by reducing insulin-stimulated glucose uptake in liver and skeletal muscle. On the other hand, OPs promote pro-inflammatory cytokines which are responsible for JNK and IKK␤ pathways activation. Cytokines-induced IKK␤ activation leads to NF-␬B translocation and the increased expression of proinflammatory mediators that can negatively regulate the insulin receptor/IRS-1 signaling (de Luca and Olefsky, 2008; Samuel and Shulman, 2012). In addition to pro-inflammatory cytokines, OPs cause oxidative stress leading to impairments in metabolism of carbohydrates. Furthermore, mitochondrial impairment disrupts activity of respiratory chain, due to biotransformation reactions of OPs, promotes anaerobic metabolism and enhance ROS formation. An increased concentration of reactive molecules triggers the activation of serine kinase cascades such as JNK and IKK␤, and others that in turn phosphorylate multiple targets, including the insulin receptor and the IRS proteins (Henriksen et al., 2011). In explanation, we therefore hypothesize that OPs and their toxic metabolites may cause damage at the cellular level due to their lipophilic nature and their interaction with biomolecules. Cell damage stimulates pro-inflammatory and ROS formations which promote insulin resistance by the inhibition of insulin signaling pathways (Fig. 4). Regarding the relationships between OPs exposure and insulin resistance, more molecular studies are needed to clarify the issue. At this stage, we believe this review useful for development more studies in order to better understand the mechanism of OPs compounds toxicity on human being. Future strategies have to explore the effect of antioxidant drugs as protectors against OPs toxicity. Indeed, it was reported that N-acetylcysteine protects against oxidative stress and experimental diabetes in rats (Kamboj et al., 2009). Further, N-acetylcysteine preserves insulin content, insulin gene expression and PDX-1 binding to the insulin promoter (Kamboj and Sandhir, 2011). Vitamin E has beneficial effects on glucose metabolism in rats (Ihara et al., 2000). Glicazide, a commonly sulfonylurea used in the treatment of type 2 diabetes, has been reported to protect pancreatic beta cells against hydrogen peroxide (Kimoto et al., 2003). These findings suggest that antioxidants therapy may represent a helpful pharmacologic approach to the effect of OPs on insulin resistance.

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