Organophosphate pesticides and new-onset diabetes mellitus:From molecular mechanisms to a possible therapeutic perspective

Ya-Ling Chung,Yi-Chou Hou,I-Kuan Wang,Kuo-Cheng Lu,Tzung-Hai Yen

Ya-Ling Chung,Department of Medical Laboratory,Cardinal-Tien Hospital,New Taipei City 231,Taiwan

Yi-Chou Hou,Department of Internal Medicine,Cardinal Tien Hospital,New Taipei City 231,Taiwan

Yi-Chou Hou,Graduate Institute of Clinical Medicine,College of Medicine,Taipei Medical University,Taipei 110,Taiwan

Yi-Chou Hou,Kuo-Cheng Lu,School of Medicine,Fu Jen Catholic University,New Taipei City 24205,Taiwan

I-Kuan Wang,Department of Nephrology,China Medical University Hospital,Taichung 404,Taiwan

I-Kuan Wang,College of Medicine,China Medical University,Taichung 404,Taiwan

Kuo-Cheng Lu,Division of Nephrology,Department of Medicine,Fu Jen Catholic University Hospital,New Taipei City 242,Taiwan

Kuo-Cheng Lu,Division of Nephrology,Department of Medicine,Taipei Tzu Chi Hospital,Buddhist Tzu Chi Medical Foundation,New Taipei City 231,Taiwan

Tzung-Hai Yen,Department of Nephrology,Chang Gung Memorial Hospital,Linkou 333,Taiwan

Tzung-Hai Yen,School of Traditional Chinese Medicine,College of Medicine,Chang Gung University,Taoyuan 333,Taiwan

Abstract Organophosphate is a commonly used pesticide in the agricultural sector.The main action of organophosphate focuses on acetylcholinesterase inhibition,and it therefore contributes to acute cholinergic crisis,intermediate syndrome and delayed neurotoxicity.From sporadic case series to epidemiologic studies,organophosphate has been linked to hyperglycemia and the occurrence of newonset diabetes mellitus.Organophosphate-mediated direct damage to pancreatic beta cells,insulin resistance related to systemic inflammation and excessive hepatic gluconeogenesis and polymorphisms of the enzyme governing organophosphate elimination are all possible contributors to the development of newonset diabetes mellitus.To date,a preventive strategy for organophosphatemediated new-onset diabetes mellitus is still lacking.However,lowering reactive oxygen species levels may be a practical method to reduce the risk of developing hyperglycemia.

Key Words:Organophosphate;Pesticide;New-onset diabetes mellitus;Mechanism;Reactive oxygen species

INTRODUCTION

Organophosphate is a commonly used pesticide in the agricultural sector because of its bioavailability.The main action of the organophosphate focuses on acetylcholinesterase inhibition.Because of its wide use,intoxication of organophosphate has been commonly encountered by physicians.Intoxication can be divided into acute cholinergic crisis,intermediate syndrome and delayed neuropathy[1].Among the complications induced by organophosphates,diabetes mellitus is a common yet often overlooked metabolic complication.The aim of this review is to analyze the molecular pathogenesis mechanisms of new-onset diabetes mellitus after organophosphate exposure.

ORGANOPHOSPHATE TOXICITY:ACUTE CHOLINERGIC CRISIS AND CHRONIC OXIDATIVE STRESS GENERATION

The main action of organophosphate is to inhibit acetylcholinesterase within the nervous system,and therefore,acetylcholine overactivity exists within the synapse and neuromuscular junction[2].Neurological manifestations are the cardinal symptoms of organophosphate intoxication through the activation of muscarinic receptors and include myosis,excessive secretions,seizures,severe muscle paralysis,cardiorespiratory depression and even death in organophosphate overdose patients[3].The hydrophobic character of organophosphate leads to its accumulation in adipose tissue,and therefore,intermediate syndrome with delayed neurologic injury might occur through the generation of oxidative stress.Gultekinet al[4]demonstrated that organophosphate treatment could activate lipid peroxidase and therefore generate reactive oxygen species(ROS)by exhausting glutathione and superoxide dismutase in a dose-dependent manner.Similar oxidative stress with excessive acetylcholinesterase activity has been reported in workers with chronic exposure to organophosphate[5].Apart from neurotoxicity,accumulation within different tissues could cause different end-organ damage in the chronic phase.The mitogen-activated protein kinase (MAPK)signaling pathway could activate associated kinases,such as extracellular responsive kinases,c-Jun N-terminal kinase(JNK)and p38 MAPK,which could worsen downstream apoptosis[6].The main contributor to MAPK signaling from organophosphates is mediated by oxidative stress.Fromin vitrostudies,the administration of organophosphate could activate the expression of quinone oxidoreductase-1,heme oxygenase 1,paraoxonase-1,catalase or superoxide dismutase in blood mesenchymal stem cells[7]or human umbilical vein endothelial cells[8].Therefore,distant organ damage should arouse concern in chronic organophosphate-intoxicated subjects.

CLINICAL STUDIES OF NEW-ONSET DIABETES MELLITUS AFTER ORGANOPHOSPHATE EXPOSURE

Previous studies revealed that organophosphate exposure could increase the risk of new-onset diabetes mellitus(Tables 1 and 2).Moore and James[9]first noticed that acute organophosphate ingestion was associated with hyperglycemia,and hyperglycemia required insulin intervention for blood sugar control(Table 1).Serial studies also demonstrated that organophosphate-mediated acute pancreatic injury might induce hyperglycemia[10,11].In 2008,Montgomeryet al[12]provided epidemiologic data to link chronic exposure to organophosphate with diabetes mellitus(Table 2).Within the 5-year follow-up,the incidence of diabetes mellitus increased in organophosphate users.The study conducted by Liuet al[13]demonstrated that acute exposure to organophosphate led to hyperglycemia,but the effect on the development of diabetes mellitus was only marginal.In a meta-analysis study conducted by Lakshmiet al[14],hyperglycemia was common.A recent study by Pandaet al[15]demonstrated that organophosphate exposure was associated with higher insulin resistance and higher plasma glycated hemoglobin levels.From the clinical study,acute organophosphate exposure was associated with hyperglycemia and then regressed after atropine treatment.From the study published by Leonel Javereset al[16],red blood cell acetylcholinesterase activity decreased within the organophosphate exposure group,and the plasma concentrations of lipase/amylase and insulin increased in the organophosphate-exposed group.Such evidence demonstrated the effect of organophosphate on insulin resistance and direct damage to pancreatic cells in clinical investigations.

Table 1 Published human studies on the association between acute organophosphate exposure and the development of new-onset diabetes mellitus

Table 2 Published human studies on the association between chronic organophosphate exposure and the development of new-onset diabetes mellitus

Clinical studies have shown that acute hyperglycemia develops in acute organophosphate-intoxicated subjects and that such hyperglycemia is associated with poor clinical patient outcomes.However,hyperglycemic status was mostly observed in animals with chronic or subchronic exposure[17,18].Severalin vivostudies demonstrated the acute effect of organophosphate on the variation of blood sugar.Rodrigueset al[19]reported variations in blood sugar after acute organophosphate exposure.For rats receiving a single intraperitoneal injection of malathion,blood glucose increased within 2 h,followed by hypoglycemia 8 h after injection[19].In brain tissue,organophosphates can decrease the storage of glycogen within the brain by activating glycogenolytic enzymes such as glycogen phosphorylase and phosphoglucomutase[20].Glycolytic enzymes,such as phosphofructokinase and hexokinase,might decrease in the acute exposure of organophosphate[21].Collectively,these mechanisms could explain the occurrence of acute hyperglycemia following organophosphate exposure.

MECHANISMS OF NEW-ONSET DIABETES MELLITUS AFTER ORGANOPHOSPHATE EXPOSURE:DYSFUNCTION OF PANCREATIC BETA CELLS

Nagaraju and Rajini[22]reported that rats receiving chronic organophosphate had higher insulin secretion from pancreatic islet cells and associated pancreatic hypertrophy.Insulin plays an important role in activating glucose transporter 9-mediated glucose transport into cells.Therefore,the regulation of insulin secretion is important in mediating the plasma concentration of glucose.Acetylcholinesterase lies within the pancreas either within acinar cells or insulin-secreting beta cells[23,24].In insulin-secreting beta cells,acetylcholine binds to the muscarinic receptors of beta cells and then increases the cytosolic calcium concentration and enhances the efficiency of calcium-mediated exocytosis,which activates insulin-secreting activity[24].Acetylcholinesterase also occurred within the alpha cells of the pancreas.Alpha cellsstimulate insulin secretion in a paracrine manner within the pancreas[25].Bendayan and Gisiger[23]also reported that acetylcholinesterase existed within acinar cells.Acinar cells are commonly regarded as governing lipase,but insulin secretion ability has been noted in several human studies beyond alpha and beta islet cells[26].Case series studies showed that organophosphate overdose could induce pancreatitis and elevation of serum amylase[27].Such clinical studies have provided evidence of organophosphate-mediated pancreatic damage.In addition,the acetylcholinergic receptor also governs the viability of pancreatic cells.The study conducted by Pfitzingeret al[28]demonstrated that cholinergic activation slowed the progression of pancreatic cancer.On the other hand,Zhanget al[29]presented evidence in a type I diabetes mellitus animal model mediated by streptozotocin that an acetylcholinesterase inhibitor protected pancreatic beta cells against apoptosis.Therefore,organophosphates might disrupt insulin secretion directly by dysregulating acetylcholinesterase activity(Figure 1).

Figure 1 Postulated molecular mechanisms of new-onset diabetes mellitus after organophosphate pesticide exposure.Organophosphate pesticides are metabolized in the liver to toxic derivatives viacytochrome P450 via a first-pass effect.Paroxonase isoform 1 serves as the enzyme handling hydroxylation and cleavage of the toxic form.The active metabolite might induce new-onset diabetes mellitus via pancreatic beta cell damage and disturb the homeostasis of gluconeogenesis and insulin sensitivity.Organophosphates could directly induce apoptosis of pancreatic beta cells by activating nuclear factor-κappa beta,and therefore,insulin secretion may be hampered.Beyond pancreatic cells,gluconeogenesis within the liver could be activated by reactive oxidative species generation and inflammation induced by microvesicular steatosis,enhanced cyclic adenosine monophosphate generation,excessive catecholamine and abated insulin sensitivity of hepatocytes via insulin receptor substrate-1.Distal organ damage by organophosphates may also disturb the homeostasis of gluconeogenesis.In organophosphate-related acute kidney injury,gluconeogenesis within the proximal tubules is disturbed.Decreased proximal gluconeogenesis exacerbates excessive hepatic gluconeogenesis.In skeletal muscle,sarcopenia mediated by intermediate syndrome might reduce glycogen storage within skeletal muscle,which may induce hyperglycemia.Organophosphates also deposit within adipose tissue and therefore exacerbate adipogenesis by activating peroxisome proliferator-activated receptor-gamma.Excessive adipose tissue might enhance insulin resistance and further hasten the development of new-onset diabetes mellitus.CYP450:Cytochrome P450;PON1:Paroxonase isoform 1;ROS:Reactive oxidative species;AMP:Adenosine monophosphate;IRS-1:Insulin receptor substrate-1;PPAR:Peroxisome proliferator-activated receptor.

MECHANISMS OF NEW-ONSET DIABETES MELLITUS AFTER ORGANOPHOSPHATE EXPOSURE:DYSFUNCTION OF GLUCONEOGENESIS

Organophosphate-mediated gluconeogenesis by disrupted lipolysis

The pathogenesis of diabetes mellitus involves impaired regulation of hepatic gluconeogenesis.Hypersensitive glucose production in response to gluconeogenic stimuli poses organophosphate exposure as a risk factor for prediabetes[30,31].As organophosphates are ingestedviathe intestine,the conversion of organophosphates by cytochrome 450 enhances cholinergic inhibition up to 70%[32].As organophosphate accumulates within hepatocytes,the activation of adenylyl cyclase produces excessive cyclic adenosine monophosphate[31],which increases hepatic glucose production and therefore increases body weight along with adipose tissue[33].In a study conducted by Velmuruganet al[30],acetic acid increased hepatic glucose-6 phosphate and citric acid production after inducing inflammation.Apart from activation of cyclic adenosine monophosphate,the organophosphate itself also increases oxidative stress within hepatocytes by exhausting enzymes that reverse oxidative stress[34],and such oxidative stress may disrupt membranous lipids by activating lipid peroxidation[35].Hepatic injury also occurs in organophosphate intoxication,and therefore,sequential sinusoidal dilatation and microvesicular steatosis impair glycogen synthesis[36].Insulin mediates the suppression of adipose lipolysis physiologically and therefore downregulates gluconeogenesis[37].Inceet al[38]demonstrated that lipid metabolism was disturbed in organophosphate-treated mice,with excessive end-products of lipid peroxidation.As excessive acetylcholinesterase leads to subjects having chronic hypercholinergic status,dietary habits are altered.From the study by Slotkinet al[39],neonatal rats exposed to organophosphate had hyperactive acetylcholine function within the neuron body,and such activity could be ameliorated only by a high-fat diet.

Organophosphate-mediated gluconeogenesis mediated by impaired glycogen storage

Under hyperglycemic conditions,glycogen storage could lower circulating glucose and enhance the anabolism process rather than catabolism.Glycogen phosphorylase,which counteracts glycogen storage,is activated by organophosphates[40].Dichlorvos,as an example,increased the messenger ribonucleic acid expression of glycogen phosphorylase and decreased glycogen storage[41].However,the different organophosphates had diverse actions on glycogen-storing proteins.Malathion,while activating the gluconeogenesis process,decreased glycogen phosphorylase but resulted in compensatory hepatomegaly[42,43].The modulation of organophosphate on glycogen storage could contribute to the gluconeogenesis process.

Organophosphate-mediated gluconeogenesis mediated by altered hormone regulation

Glucagon and catecholamine are the major hormones regulating gluconeogenesis[37].Glucagon and catecholamine could directly enhance hepatic gluconeogenesis by activating cyclic adenosine monophosphateviaphosphorylation of protein kinase A activity[44]and bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2(PFK2/FBPase-2)[45].Glucagon activity also decreased glycogen storage by coupling with the inhibitory G protein[46].Catecholamine,on the other hand,also activates gluconeogenesisviacyclic adenosine monophosphate activity[47].Stressassociated catecholamine release can increase the gluconeogenesis process and therefore insulin resistance,and organophosphate itself activates catecholamine release after inhibiting acetylcholinesterase activity[42].Organophosphate could activate catecholamine release within neurons,and unbalanced catecholamine release might prolong the gluconeogenesis process.

MECHANISMS OF NEW-ONSET DIABETES MELLITUS AFTER ORGANOPHOSPHATE EXPOSURE:INSULIN RESISTANCE MEDIATED BY INFLAMMATION OR DYNAMIC CHANGES IN THE MICROBIOTA

Insulin resistance,excessive gluconeogenesis and insufficient glucose uptake in the presence of insulin place subjects as hyperglycemia status and therefore invoke sequential adipose tissue formation.Physiologically,insulin activates the insulin receptor by tyrosine phosphorylation of insulin receptor substrate-1[48],and serine phosphorylation inhibits the insulin receptor and offsets insulin activity[49].Insulin resistance is common in chronic organophosphate exposure subjects.From thein vivostudy conducted by Nagaraju and Rajini[22],insulin hypertrophy and the increased secretion of insulin were accompanied by circulating insulin-like growth factor 1,free fatty acids,corticosterone,and paraoxonase activity.As organophosphate increases excessive cholinergic activity,insulin resistance is associated with systemic inflammation.From the study reported by Lianget al[50],organophosphates could induce an increase in body weight in experimental mice treated with a high-fat diet.In organophosphate mice treated with a high-fat diet,systemic inflammation mediated by lipopolysaccharide might occur.Systemic inflammation mediated by the intestinal barrier might activate systemic inflammation.In addition,the lipid peroxidation end product malondialdehyde(MDA)increased in organophosphate-treated rats,and the oxidative end product was associated with a higher level of inflammation[38].

Chronic exposure to organophosphate could directly enhance systemic inflammation.In a study by Inceet al[38],organophosphate-treated rats had higher proinflammatory cytokines,such as interferon gamma,interleukin 1 beta,tumor necrosis factor alpha,and nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB),than control rats.Hepatocytes are the major cells confronting proinflammatory cytokines.As NF-κB is activated by inflammatory cytokines,IκB kinase-β might be activated and therefore hamper the downstream action of insulin[51].In addition to IκB kinase-β,JNK signaling was also activated in organophosphate intoxication.When endoplasmic reticulum stress is enhanced after organophosphatemediated excessive oxidative stress,JNK is activated under conditions of proinflammatory cytokine releaseviaNF-κB[52].Based on the evidence above,organophosphates might induce inflammation and produce proinflammatory cytokines mediating insulin resistance.

MECHANISMS OF NEW-ONSET DIABETES MELLITUS AFTER ORGANOPHOSPHATE EXPOSURE:INSULIN RESISTANCE MEDIATED BY ROS

Excessive oxidative stress is associated with insulin resistance.Polyunsaturated fatty acids are the main source of oxidative stress.Low concentrations of ROS mediate the proliferative signals of insulin by phosphatidylinositol 3-kinase and protein kinase B[53].In acute or chronic organophosphate intoxication,ROS regeneration is common as the exhaustion of endogenous antioxidant species occurs.The MDA level and superoxide dismutase increased in organophosphate intoxication,and reduced glutathione was depleted[5].Possamaiet al[54]showed that both acute and chronic exposure to malathion could generate ROS within the kidney and brain acutely and liver and skeletal muscle chronically.The study performed by Alyet al[55]also demonstrated that the liver serves as the reservoir in chronic organophosphate exposure with the generation of ROS.To enhance the elimination of ROS,adenosine triphosphate is generated from the activated gluconeogenesis process within the liver[56].In addition,ROS also directly disturb insulin receptor signaling.Morinoet al[57]demonstrated that ROS activated serine residues on insulin receptor substrate 1 and therefore inhibited glucose transporter type 4.From the aspect above,the ROS generated by organophosphate could disturb insulin signaling and therefore worsen insulin resistance.

MECHANISMS OF NEW-ONSET DIABETES MELLITUS AFTER ORGANOPHOSPHATE EXPOSURE:DYSFUNCTION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA

Peroxisome proliferator-activated receptor(PPAR)is a transcriptional receptor within the nucleus,and its main action governs the proliferation of peroxisomes within the nucleus.PPARs regulate the metabolism of carbohydrates,lipids and proteins along with insulin sensitivity.The role of organophosphates in lipid metabolism has been demonstrated.Since organophosphate is a highly fat-soluble component,accumulation within adipose tissue could prolong its toxicity and generate oxidative stress within adipose tissue[58].Smithet al[59]demonstrated that diazinon induces adipogenesis within preadipocytes by activating PPAR gamma receptors along with the transcription factor CCAAT-enhancer-binding protein α(C/EBPα).

MECHANISMS OF NEW-ONSET DIABETES MELLITUS AFTER ORGANOPHOSPHATE EXPOSURE:GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST AND DIPEPTIDYL PEPTIDASE-4 INHIBITOR

Incretin secreted from the intestine is important for insulin secretion.As carbohydrates enter the duodenum,the K cells within the duodenum secrete glucose-dependent insulinotropic polypeptides into the brainviathe vagus nerve.Activated vagal tone enhances acetylcholine release to M cells within the distal ileum and therefore increases glucagon-like peptide 1(GLP-1).GLP-1 could therefore increase insulin release and lower blood glucose.Organophosphates might increase the acetylcholine concentration within the neural cleft and therefore downregulate muscarinic receptors.Downregulated muscarinic receptors attenuate GLP-1 release and therefore further insulin release[60].From the study by Rathiset al[61],the GLP-1 response was attenuated in subjects with acute exposure to organophosphate with atropine treatment.Chronic exposure to organophosphate might downregulate the incretinmediated glucose-lowering effect.

MECHANISMS OF NEW-ONSET DIABETES MELLITUS AFTER ORGANOPHOSPHATE EXPOSURE:RENAL HANDLING OF GLUCOSE

From clinical observations,victims of organophosphate exposure had transient glycosuria,which was relevant to euglycemia[62].Based on the evidence,acute tubular necrosis might be noticed in organophosphate intoxication subjects.From the study reported by Kayaet al[63],acute organophosphate intoxication could mediate the vacuolization of tubular epithelial cells and tubular structure approaching atrophy within the proximal tubules.The oxidative stress mediated by organophosphates worsened proximal tubular damage in anin vitrostudy performed by Poovalaet al[64].The activation of the MAPK signaling pathway within nephron precursor cells demonstrated direct nephrotoxicity after activating JNK and caspase-3[65].Proximal tubular cells primarily serve as gluconeogenic cells through the utilization of adenosine triphosphate,and therefore,damaged proximal tubules might impair endogenous gluconeogenesis[66]and are associated with higher mortality and the need for dialysis in critically ill patients[67,68],including organophosphate intoxication subjects[69].Since acute kidney injury and stress-mediated inflammation might contribute to insulin resistance and new-onset diabetes mellitus[70],preserving kidney function during acute kidney injury status through organophosphate intoxication should be important in managing these patients to hamper the development of diabetes mellitus.

MECHANISMS OF NEW-ONSET DIABETES MELLITUS AFTER ORGANOPHOSPHATE EXPOSURE:INTERMEDIATE SYNDROME

As described in the previous sections,the major clinical manifestation of cholinergic crisis was the overactivation of the parasympathetic tone with tachycardia,myosis or neurologic complications such as seizures.From a previous study by Liuet al[13],acute organophosphate intoxication was minimally predictive of new-onset diabetes mellitus.Intermediate syndrome by organophosphate could induce myopathy,especially in the proximal skeletal muscle and respiratory muscle[71].Although the direct mechanism is still unknown,necrosis of skeletal muscle and associated myopathy might be an entity in chronic organophosphate intoxication subjects[72].In addition,organophosphate-mediated peripheral motor neuropathy is accompanied by weakness after acute intoxication[73].From a review of the literature,a correlation between organophosphate intoxication and sarcopenia was rare.However,in patients with diabetic neuropathy,sarcopenia was more obvious than in those without neuropathy[74].Persistent muscle weakness in intermediate syndrome might lead to sarcopenic status in organophosphate patients,and sarcopenia alone might enhance the risk of developing diabetes mellitus.In the study by Honget al[75],skeletal muscle mass was negatively associated with the development of type 2 diabetes mellitus.Since skeletal muscle serves as the pool of glucose mediated by insulin,the decreased skeletal mass would reduce glucose disposal and therefore worsen the inflammation of skeletal muscle and insulin resistance[76].

POSSIBLE THERAPEUTIC PERSPECTIVE IN PREVENTING ORGANOPHOSPHATE-MEDIATED NEW-ONSET DIABETES MELLITUS

In acute organophosphate intoxication,the application of atropine is the mandatory therapeutic strategy in treating cholinergic crises.The association between atropine and insulin secretion has been discussed.In 1978,cholinergic blockade by atropine was known to decrease insulin secretion mediated by gastric inhibitory polypeptides and gastrin release[77,78].The action of atropine on gastric inhibitory polypeptides lowered postprandial insulin secretion.From the study published by Schaferet al[79]and Afonsoet al[80],atropine inhibited the release of hepatic insulin-sensitizing substances,which therefore lessened insulin sensitivity during feeding.The parasympathetic nerves directly stimulate postprandial insulin secretion;therefore,atropine might play an inhibitory role in blood sugar control.However,a study by Svenssonet al[81]showed that atropine improved insulin sensitivity in both lean and obese subjects.In the atropine-treated group,glucose uptake was higher than that in the subjects treated with saline alone.In summary,parasympathetic blockade might directly decrease insulin secretion mediated by gastric inhibitory polypeptides and delay intestinal emptying under cellular dehydration conditions[82].However,atropine might improve insulin sensitivity based on the clinical trial mediated by Svenssonet al[81].Since atropine might only be given in the acute intoxication of organophosphate conditions,the acute adverse effect might not be potentiated.

ROLE OF ROS GENERATION IN ORGANOPHOSPHATE-MEDIATED NEWONSET DIABETES MELLITUS

From the evidence mentioned above,the oxidative stress generated by organophosphate increased gluconeogenesis and decreased insulin sensitivity.Therefore,interventions to lessen ROS generation have been proposed to prevent the development of organophosphate-mediated diabetes mellitus.N-Acetylcysteine is a widely used scavenger for ROS due to its regeneration of glutathione.From clinical trials,N-acetylcysteine has been applied to treat acute organophosphate intoxication.From the clinical trial reported by El-Ebiaryet al[83],n-acetylcysteine could achieve less atropine use and shorter hospitalization stays in acute organophosphate intoxication subjects.Falach-Maliket al[84]demonstrated that in diabetes-prone mice treated with a high-fat diet,n-acetylcysteine alleviated glucose intolerance by lessening hepatic steatosis.Charronet al[85]also demonstrated that in high-fat diet-fed maternal mice,n-acetylcysteine supplementation in the maternal stage decreased diabetes mellitus development in offspring.A similar effect was also demonstrated in a type 1 diabetes mellitus animal model under insulin deficiency[86].N-Acetylcysteine also lessened organophosphate-mediated toxicityin vivo.A report from Yurumezet al[87]demonstrated that N-acetylcysteine could rescue antioxidative glutathione,nitrite and nitrate and decrease MDA generation in organophosphate-treated mice.The study conducted by Bayiret al[88]demonstrated that in organophosphate-poisoned mice,nacetylcysteine alone could restore the cholinesterase concentration within erythrocytes,and the liver MDA level was lessened in n-acetylcysteine-treated mice rather than pralidoxime-atropine-treated mice or sham mice.From the aspect of decreasing organophosphate-mediated oxidative stress and the sequential development of diabetes mellitus,a therapeutic strategy for lowering ROS should be considered.

FUTURE PERSPECTIVES ON THE PREVENTION OF ORGANOPHOSPHATE-MEDIATED NEW-ONSET DIABETES MELLITUS:RISK FACTOR STRATIFICATION

Since the development of diabetes mellitus is common in organophosphate-exposed subjects,risk stratification should be emphasized.The specific brand of organophosphate pesticide could influence the development of diabetes mellitus.Juntarawijit and Juntarawijit[89]noticed that endosulfan,mevinphos,carbamate and one fungicide(benlates)contributed to the development of diabetes mellitus in the Thai population.Apart from the specific insecticides,the environmental heavy metal content might play a synergistic role in the development of diabetes mellitus.From the study by Velmuruganet al[90],arsenics could synergize with organophosphate-mediated diabetes mellitus.At the same time,genetic polymorphisms should play a role in the development of organophosphate-induced diabetes mellitus.As the previous section mentioned,organophosphates could be metabolized by hepatic cytochrome p450,and metabolites might generate genotoxicity if the polymorphism existed within the subjects[91].The first pass effect of cytochrome p450 generates toxic oxon organophosphate,which would be further oxidatively cleaved by cytochrome or hydroxylated by paraoxonase-1[92,93].From the study by Al-Hakeemet al[94],the polymorphism in paraoxonase-1 with glutamine 192 to arginine made the subject vulnerable to gestational diabetes mellitus.The evidence shows a link between the polymorphism and organophosphate-mediated diabetes mellitus.In addition to diabetes mellitus development,lipid metabolism might be altered by paraoxonase-1 polymorphisms.The study conducted by Onat andet al[95]Leonel Javereset al[96]demonstrated that the paraoxonase-1 polymorphism with the rs662 genotype was associated with ApoA1 and ApoB,which also reflected dyslipidemia in metabolic syndrome.Finally,personal protective equipment plays an important role in moderating the organophosphate metabolites associated with insulin resistance.Seesen conducted a study analyzing urinary organophosphate metabolites in pesticide sprayers and nonfarm workers[97].In this study,the pesticide sprayer had a higher incidence of insulin resistance,and the only different organophosphate metabolite was diethylthiophosphate.No correlation was identified between diethylthiophosphate and the severity of insulin resistance.However,personal protection equipment lowered organophosphate metabolite generation.Personal protective equipment might play a preventive role in alleviating insulin resistance in organophosphate intoxication subjects.

CONCLUSION

Organophosphate pesticides have been linked to both acute and chronic intoxication.In acute intoxication,organophosphate-mediated cholinergic crisis might sequentially be followed by intermediate syndrome.Intermediate syndrome might hamper chronic muscle wasting and sarcopenia,therefore increasing the risk of diabetes mellitus.With chronic exposure to organophosphates,diabetes mellitus might develop by direct damage to the pancreas and insulin resistance mediated by lipolysis,oxidative stress and chronic inflammation.Distal organ damage,such as acute kidney injury,might worsen possible organophosphate-mediated diabetes mellitus.The standard therapeutic strategy for cholinergic crisis may play a controversial role in managing organophosphate-mediated diabetes mellitus.However,reducing ROS might be a possible therapeutic strategy.In addition,elucidating the possible genetic polymorphisms to predict the development of diabetes mellitus with organophosphate intoxication might be essential.