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AchE Inhibition leads to Hyperglycemia
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Acetylcholine esterase inhibition leading to type 2 diabetes||non-adjacent||Moderate||Low||Arthur Author (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|All life stages||Moderate|
Key Event Relationship Description
Acetylcholine esterase (AChE) is an enzyme that metabolizes acetylcholine into choline and acetate. Organophosphate pesticides (OPPs) are well establish acetylcholine esterase (AChE) inhibitors (6, 23). Human exposure to OPPs, be it acute high-dose (e.g., a poisoning) or chronic low-dose (e.g., general population), is associated with AChE inhibition and hyperglycemia. These findings are supported by in vitro/ex vivo and in vivo data using a variety of exposure models and different OPPs.
Evidence Supporting this KER
A review by Rahimi and Abdollahi supports the association between OPP exposure and decreased glycogenesis, increased glycogenolysis, and decreased glycolysis (39). Importantly, the authors highlighted that these changes were observed across multiple tissues including brain, hepatic, and muscle. These data suggest that OPP-induced hyperglycemia is the result of global changes to glucose metabolism and storage that point towards an increase in blood glucose. Other reviews have commented on the association between OPP exposure and hyperglycemia in humans (7, 54) and in research animals (7, 18). Overall, the exact mechanism(s) of action remain to be elucidated.
Uncertainties and Inconsistencies
Though some biochemical pathways have been elucidated, the mechanism(s) of action that associate OPP-induced AChE inhibition with hyperglycemia are not fully understood. Further, AChE knock-out mice are normoglycemic relative to wildtype mice (8), suggesting possible compensatory glucose homeostatic mechanism(s) in these transgenic mice.
The in vivo rodent exposure data reviewed highlighted two studies that found that co-exposure to an AChR antagonist prevented OPP-induced hyperglycemia (15, 16). These data are difficult to interpret as they implicate the cholinergic system, a known modulator of pancreatic insulin secretion (27), which modulates blood glucose concentrations.
Though most of the in vivo rodent exposure data is consistent, one study found that exposure to a high dose of malathion (100 mg/kg/day) for >30 days did not cause hyperglycemia (41). However, these must be interpreted with caution as it was a single measurement that was not done under fasting conditions.
Relative to other organic pollutants, most OPPs have short half-lives (14) making it difficult to measure in human serum. This impedes the accurate modeling of human OPP exposure for in vivo and in vitro/ex vivo exposure studies.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Taxonomy: AChE and blood glucose are present in vertebrates and their functional equivalents in invertebrates. However, only human, mouse, and rat data was reviewed.
Life Stage: AChE and blood glucose are present throughout all life stages. However, almost all of the data reviewed was in adults.
Sex Applicability: AChE and blood glucose are present in males and females. However, most of the data reviewed was from male rodents.
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