Butyrylcholinesterase interactions with amylin may protect pancreatic cells in metabolic syndrome

Abstract

The metabolic syndrome (MetS) is a risk factor for type 2 diabetes mellitus (T2DM). However, the mechanisms underlying the transition from MetS to T2DM are unknown. Our goal was to study the potential contribution of butyrylcholinesterase (BChE) to this process. We first determined the hydrolytic activity of BChE in serum from MetS, T2DM and healthy individuals. The ‘Kalow’ variant of BChE (BChE-K), which has been proposed to be a risk factor for T2DM, was genotyped in the last two groups. Our results show that in MetS patients serum BChE activity is elevated compared to T2DM patients and healthy controls (P < 0.001). The BChE-K genotype showed similar prevalence in T2DM and healthy individuals, excluding this genotype as a risk factor for T2DM. However, the activity differences remained unexplained. Previous results from our laboratory have shown BChE to attenuate the formation of β-amyloid fibrils, and protect cultured neurons from their cytotoxicity. Therefore, we next studied the in vitro interactions between recombinant human butyrylcholinesterase and amylin by surface plasmon resonance, Thioflavine T fluorescence assay and cross-linking, and used cultured pancreatic β cells to test protection by BChE from amylin cytotoxicity. We demonstrate that BChE interacts with amylin through its core domain and efficiently attenuates both amylin fibril and oligomer formation. Furthermore, application of BChE to cultured β cells protects them from amylin cytotoxicity. Taken together, our results suggest that MetS-associated BChE increases could protect pancreatic β-cells in vivo by decreasing the formation of toxic amylin oligomers.

Decline in Serum Cholinesterase Activities Predicts 2-Year Major Adverse Cardiac Events

“…Additionally, we did not measure other variables associated with parasympathetic activity such as heart rate variability or heart rate values. However, we demonstrated the close correlation between our biomarkers and parallel physiological variables in past studies (21,22). And lastly, Figure 6 represents the current knowledge about the two cholinesterases (AChE and BChE) and their contribution to the cholinergic status and its effect on the heart and inflammatory profile of MACE patients.…”

“…In past studies, we demonstrated the close correlation between our biomarkers and parallel physiological variables such as resting and recovery heart rate after stress testing (21,22,36).…”

“…To compare the effects of AChE, BChE and cholinergic status changes on cardiovascular risk, we used ATCh as a substrate with or without tetraisopropyl pyrophosphoramide (iso-OMPA, a specific BChE inhibitor), thus identifying AChE alone, mimicking the total impact of ACh hydrolysis and enabling a calculation of BChE contribution. This method has been reliably used in several recent studies (14,(19)(20)(21)(22)(23).…”

Reduced Serum Butyrylcholinesterase Activity Indicates Severe Systemic Inflammation in Critically Ill Patients

“…None of the patients included in our study suffered an ischemic stroke; nevertheless, our results support a hypothesis of a tight correlation between cholinergic activity and the inflammatory response. Inversely, patients with metabolic syndrome have been shown to express increased BChE activities, such that reductions in their BChE might be masked [ 38 ]. The BChE activity was not measured prior to inflammation; therefore, we cannot exclude the possibility that patients with metabolic syndrome might show false elevated BChE activity levels during the systemic inflammatory disease.…”

Cholinesterase Inhibitors

“…For example, BChE was found to have aryl acylamidase activity and was pro posed to attenuate amyloid plaque formation and contrib ute to neurogenesis. In this respect, the K variant of BChE shows weakened protein interactions and lower stability and hydrolytic activity, in spite of an intact active site (Podoly et al, 2009;ShenharTsarfaty et al, 2011).…”