Original Article Published on 14 Mar, 2024

Link of Serum Esterase Enzymes with Cognitive Impairment in Diabetic Patients

Esterase & Diabetic Cognitive Dysfunction
Vol. 19 No. 1 : 2024 (161-172)

Mahdavi P Mahdavi P
Mokhtari S Mokhtari S
Iranparvar M Iranparvar M
Amani F Amani F
Mazani M Mazani M
Mostafalou S Mostafalou S

Abstract
Cognitive impairment is one of the main complications of diabetes and patients with cognitive impairment are considered to be in an intermediate stage of decreased cognition with higher risk of developing dementia and Alzheimer's disease. This study aimed at evaluating serum activity of two esterase enzymes including cholinesterase and paraoxonase 1 (PON 1) in diabetic patients and association with cognitive performance and metabolic parameters.  In this cross-sectional study, 128 diabetic patients were enrolled. Cognitive performance was evaluated using the Wechsler Adult Intelligence Scale-Revised (WAIS-R). Body mass index, fasting blood glucose, fasting blood insulin, insulin resistance, serum cholinesterase and paraoxonase 1 activity were measured. Prevalence of cognitive impairment was found to be 77% in the study population. Serum cholinesterase activity was found to be higher in diabetic patients with cognitive impairment than the patients with normal cognitive performance (p < 0.04). Further, a negative correlation was found between cognitive performance and cholinesterase activity, albeit statistically non-significant. Alteration in the activity of cholinesterase enzyme was shown to be associated with cognitive impairment in diabetic patients and future studies are required to find the pathophysiological mechanisms of diabetic cognitive dysfunction.    
Keywords : Alzheimer, arylesterase, cholinesterase, cognitive impairment, diabetes, insulin resistance, paraoxonase 1,
Abstrak
Kecacatan kognitif merupakan salah satu komplikasi utama diabetes, dan pesakit yang mengalami kecacatan kognitif dan dianggap berada dalam peringkat pertengahan penurunan daya kognitif dengan risiko yang lebih tinggi untuk mendapati penyakit demensia dan Alzheimer. Pesakit diabetes juga berisiko lebih tinggi untuk mengalami penyakit Alzheimer. Kajian ini bertujuan untuk menilai aktiviti serum untuk dua enzim esterasa termasuk kolinesterase dan paraoksonase 1 (PON 1) dalam pesakit diabetes serta hubungannya dengan prestasi kognitif dan parameter metabolik. Dalam kajian keratan lintang ini, sejumlah 128 pesakit diabetes telah menyertai. Prestasi kognitif dinilai menggunakan Skala Kecerdasan Dewasa Wechsler yang Dikemaskini (WAIS-R). Indeks jisim badan, glukosa darah puasa, insulin darah puasa, rintangan insulin, dan aktiviti serum kolinesterase dan paraoksonase 1 telah diukur. Kejadian kerosakan kognitif didapati adalah 77% dalam populasi kajian. Aktiviti serum kolinesterase didapati lebih tinggi dalam pesakit diabetes yang mengalami ketakmampuan kognitif berbanding pesakit dengan prestasi kognitif normal (p < 0.04). Selain itu, korelasi negatif didapati antara prestasi kognitif dan aktiviti kolinesterase, walaupun tidak signifikan secara statistik. Perubahan dalam aktiviti enzim kolinesterase telah dikaitkan dengan kerosakan kognitif dalam pesakit diabetes, dan kajian masa depan diperlukan untuk mencari mekanisme patofisiologi dalam disfungsi kognitif diabetes.
Kata Kunci : Alzheimer, aryleterase, kecacatan kognitif, kencing manis, keringtangan insulin, kolinesterase, paraoxonase 1,

Correspondance Address
Associate Professor Dr. Sara Mostafalou. Department of Pharmacology and Toxicology, School of Pharmacy, Ardabil University of Medical Sciences, 5618953141 Ardabil, Iran. Tel: +98 45 33522437/ +98 9307371247 Email: s.mostafalou@gmail.com, s.mostafalou@arums.ac.ir

References
Abdollahi, M., Mostafalou, S., Pournourmohammadi, S., Shadnia, S. 2004. Oxidative stress and cholinesterase inhibition in saliva and plasma of rats following subchronic exposure to malathion. Comp Biochem Physiol C Toxicol Pharmacol 137(1): 29-34.

Ali, A., Zakeri, A., Nadermohammadi M., Mostafalou, S. 2023. Serum asymmetric dimethylarginine (ADMA) level and cognitive dysfunction in diabetic patients. Int J Diabetes Dev Ctries 43(2): 291-7.

Beltowski, J., Wojcicka, G., Marciniak, A. 2002. Species- and substrate-specific stimulation of human plasma paraoxonase 1 (PON1) activity by high chloride concentration. Acta Biochim Pol 49(4): 927-36.

Castellazzi, M., Trentini, A., Romani, A., Valacchi, G., Bellini, T., Bonaccorsi, G., Fainardi, E., Cavicchio, C., Passaro, A., Zuliani, G., Cervellati, C. 2016. Decreased arylesterase activity of paraoxonase-1 (PON-1) might be a common denominator of neuroinflammatory and neurodegenerative diseases. Int J Biochem Cell Biol 81(Pt B): 356-63.

Ellman, G.L., Courtney, K.D., Andres, V.Jr., Feather-Stone, R.M. 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7: 88-95.

Franzen, M.D. 2002. The wechsler adult intelligence scale-revised and wechsler adult intelligence scale-III. In Reliability and Validity in Neuropsychological Assessment. Boston: Springer US; 55-70.

Frison, E., Proust-Lima, C., Mangin, J.F., Habert, M.O., Bombois, S., Ousset, P.J., Pasquier, F., Hanon, O., Paquet, C., Gabelle, A., Ceccaldi, M., Annweiler, C., Krolak-Salmon, P., Bejot, Y., Belin, C., Wallon, D., Sauvee, M., Beaufils, E., Bourdel-Marchasson, I., Jalenques, I., Chupin, M., Chene, G., Dufouil, C., Memento Cohort Study Group. 2021. Diabetes mellitus and cognition: Pathway analysis in the MEMENTO cohort. Neurology 97(8): e836-48.

Hottman, D.A., Chernick, D., Cheng, S., Wang, Z., Li, L. 2014. HDL and cognition in neurodegenerative disorders. Neurobiol Dis 72 Pt A: 22-36.

Marucci, G., Buccioni, M., Ben, D.D., Lambertucci, C., Volpini, R., Amenta, F. 2021. Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology 190(2021): 108352.

Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C. 1985. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7): 412-9.

Mostafalou, S., Baeeri, M., Bahadar, H., Soltany-Rezaee-Rad, M., Gholami, M., Abdollahi, M. 2015. Molecular mechanisms involved in lead induced disruption of hepatic and pancreatic glucose metabolism. Environ Toxicol Pharmacol 39(1): 16-26.

Mostafalou, S., Eghbal, M.A., Nili-Ahmadabadi, A., Baeeri, M., Abdollahi, M. 2012. Biochemical evidence on the potential role of organophosphates in hepatic glucose metabolism toward insulin resistance through inflammatory signaling and free radical pathways. Toxicol Ind Health 28(9): 840-51.

Mushtaq, G., Greig, N.H., Khan, J.A., Kamal, M.A. 2014. Status of acetylcholinesterase and butyrylcholinesterase in Alzheimer’s disease and type 2 diabetes mellitus. CNS Neurol Disord Drug Targets 13(8): 1432-9.

Ortiz, G.G., Huerta, M., González-Usigli, H.A., Torres-Sánchez, E.D., Delgado-Lara, D.L., Pacheco-Moisés, F.P., Mireles-Ramírez, M.A., Torres-Mendoza, B.M., Moreno-Cih, R.I., Velázquez-Brizuela, I.E. 2022. Cognitive disorder and dementia in type 2 diabetes mellitus. World J Diabetes 13(4): 319-37.

Romani, A., Trentini, A., Flier, W.M.V., Bellini, T., Zuliani, G., Cervellati, C., Teunissen, C.E. 2020. Arylesterase activity of paraoxonase-1 in serum and cerebrospinal fluid of patients with alzheimer’s disease and vascular dementia. Antioxidants (Basel) 9(5): 456.

Shenhar-Tsarfaty, S., Berliner, S., Bornstein, N.M., Soreq, H. 2013. Cholinesterases as biomarkers for parasympathetic dysfunction and inflammation-related disease. J Mol Neurosci 53(3): 298-305.

Shokri, Y., Variji, A., Nosrati, M., Khonakdar-Tarsi, A., Kianmehr, A., Kashi, Z., Bahar, A., Bagheri, A., Mahrooz, A. 2020. Importance of paraoxonase 1 (PON1) as an antioxidant and antiatherogenic enzyme in the cardiovascular complications of type 2 diabetes: Genotypic and phenotypic evaluation. Diabetes Res Clin Pract 161: 108067.

Sridhar, G.R., Thota, H., Allam, A.R., Suresh Babu, C., Siva Prasad, A., Divakar, Ch. 2006. Alzheimer’s disease and type 2 diabetes mellitus: The cholinesterase connection? Lipids Health Dis. 5: 28.
Correspondance Address

Abdollahi, M., Mostafalou, S., Pournourmohammadi, S., Shadnia, S. 2004. Oxidative stress and cholinesterase inhibition in saliva and plasma of rats following subchronic exposure to malathion. Comp Biochem Physiol C Toxicol Pharmacol 137(1): 29-34.

Ali, A., Zakeri, A., Nadermohammadi M., Mostafalou, S. 2023. Serum asymmetric dimethylarginine (ADMA) level and cognitive dysfunction in diabetic patients. Int J Diabetes Dev Ctries 43(2): 291-7.

Beltowski, J., Wojcicka, G., Marciniak, A. 2002. Species- and substrate-specific stimulation of human plasma paraoxonase 1 (PON1) activity by high chloride concentration. Acta Biochim Pol 49(4): 927-36.

Castellazzi, M., Trentini, A., Romani, A., Valacchi, G., Bellini, T., Bonaccorsi, G., Fainardi, E., Cavicchio, C., Passaro, A., Zuliani, G., Cervellati, C. 2016. Decreased arylesterase activity of paraoxonase-1 (PON-1) might be a common denominator of neuroinflammatory and neurodegenerative diseases. Int J Biochem Cell Biol 81(Pt B): 356-63.

Ellman, G.L., Courtney, K.D., Andres, V.Jr., Feather-Stone, R.M. 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7: 88-95.

Franzen, M.D. 2002. The wechsler adult intelligence scale-revised and wechsler adult intelligence scale-III. In Reliability and Validity in Neuropsychological Assessment. Boston: Springer US; 55-70.

Frison, E., Proust-Lima, C., Mangin, J.F., Habert, M.O., Bombois, S., Ousset, P.J., Pasquier, F., Hanon, O., Paquet, C., Gabelle, A., Ceccaldi, M., Annweiler, C., Krolak-Salmon, P., Bejot, Y., Belin, C., Wallon, D., Sauvee, M., Beaufils, E., Bourdel-Marchasson, I., Jalenques, I., Chupin, M., Chene, G., Dufouil, C., Memento Cohort Study Group. 2021. Diabetes mellitus and cognition: Pathway analysis in the MEMENTO cohort. Neurology 97(8): e836-48.

Hottman, D.A., Chernick, D., Cheng, S., Wang, Z., Li, L. 2014. HDL and cognition in neurodegenerative disorders. Neurobiol Dis 72 Pt A: 22-36.

Marucci, G., Buccioni, M., Ben, D.D., Lambertucci, C., Volpini, R., Amenta, F. 2021. Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology 190(2021): 108352.

Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C. 1985. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7): 412-9.

Mostafalou, S., Baeeri, M., Bahadar, H., Soltany-Rezaee-Rad, M., Gholami, M., Abdollahi, M. 2015. Molecular mechanisms involved in lead induced disruption of hepatic and pancreatic glucose metabolism. Environ Toxicol Pharmacol 39(1): 16-26.

Mostafalou, S., Eghbal, M.A., Nili-Ahmadabadi, A., Baeeri, M., Abdollahi, M. 2012. Biochemical evidence on the potential role of organophosphates in hepatic glucose metabolism toward insulin resistance through inflammatory signaling and free radical pathways. Toxicol Ind Health 28(9): 840-51.

Mushtaq, G., Greig, N.H., Khan, J.A., Kamal, M.A. 2014. Status of acetylcholinesterase and butyrylcholinesterase in Alzheimer’s disease and type 2 diabetes mellitus. CNS Neurol Disord Drug Targets 13(8): 1432-9.

Ortiz, G.G., Huerta, M., González-Usigli, H.A., Torres-Sánchez, E.D., Delgado-Lara, D.L., Pacheco-Moisés, F.P., Mireles-Ramírez, M.A., Torres-Mendoza, B.M., Moreno-Cih, R.I., Velázquez-Brizuela, I.E. 2022. Cognitive disorder and dementia in type 2 diabetes mellitus. World J Diabetes 13(4): 319-37.

Romani, A., Trentini, A., Flier, W.M.V., Bellini, T., Zuliani, G., Cervellati, C., Teunissen, C.E. 2020. Arylesterase activity of paraoxonase-1 in serum and cerebrospinal fluid of patients with alzheimer’s disease and vascular dementia. Antioxidants (Basel) 9(5): 456.

Shenhar-Tsarfaty, S., Berliner, S., Bornstein, N.M., Soreq, H. 2013. Cholinesterases as biomarkers for parasympathetic dysfunction and inflammation-related disease. J Mol Neurosci 53(3): 298-305.

Shokri, Y., Variji, A., Nosrati, M., Khonakdar-Tarsi, A., Kianmehr, A., Kashi, Z., Bahar, A., Bagheri, A., Mahrooz, A. 2020. Importance of paraoxonase 1 (PON1) as an antioxidant and antiatherogenic enzyme in the cardiovascular complications of type 2 diabetes: Genotypic and phenotypic evaluation. Diabetes Res Clin Pract 161: 108067.

Sridhar, G.R., Thota, H., Allam, A.R., Suresh Babu, C., Siva Prasad, A., Divakar, Ch. 2006. Alzheimer’s disease and type 2 diabetes mellitus: The cholinesterase connection? Lipids Health Dis. 5: 28.



Abdollahi, M., Mostafalou, S., Pournourmohammadi, S., Shadnia, S. 2004. Oxidative stress and cholinesterase inhibition in saliva and plasma of rats following subchronic exposure to malathion. Comp Biochem Physiol C Toxicol Pharmacol 137(1): 29-34.

Ali, A., Zakeri, A., Nadermohammadi M., Mostafalou, S. 2023. Serum asymmetric dimethylarginine (ADMA) level and cognitive dysfunction in diabetic patients. Int J Diabetes Dev Ctries 43(2): 291-7.

Beltowski, J., Wojcicka, G., Marciniak, A. 2002. Species- and substrate-specific stimulation of human plasma paraoxonase 1 (PON1) activity by high chloride concentration. Acta Biochim Pol 49(4): 927-36.

Castellazzi, M., Trentini, A., Romani, A., Valacchi, G., Bellini, T., Bonaccorsi, G., Fainardi, E., Cavicchio, C., Passaro, A., Zuliani, G., Cervellati, C. 2016. Decreased arylesterase activity of paraoxonase-1 (PON-1) might be a common denominator of neuroinflammatory and neurodegenerative diseases. Int J Biochem Cell Biol 81(Pt B): 356-63.

Ellman, G.L., Courtney, K.D., Andres, V.Jr., Feather-Stone, R.M. 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7: 88-95.

Franzen, M.D. 2002. The wechsler adult intelligence scale-revised and wechsler adult intelligence scale-III. In Reliability and Validity in Neuropsychological Assessment. Boston: Springer US; 55-70.

Frison, E., Proust-Lima, C., Mangin, J.F., Habert, M.O., Bombois, S., Ousset, P.J., Pasquier, F., Hanon, O., Paquet, C., Gabelle, A., Ceccaldi, M., Annweiler, C., Krolak-Salmon, P., Bejot, Y., Belin, C., Wallon, D., Sauvee, M., Beaufils, E., Bourdel-Marchasson, I., Jalenques, I., Chupin, M., Chene, G., Dufouil, C., Memento Cohort Study Group. 2021. Diabetes mellitus and cognition: Pathway analysis in the MEMENTO cohort. Neurology 97(8): e836-48.

Hottman, D.A., Chernick, D., Cheng, S., Wang, Z., Li, L. 2014. HDL and cognition in neurodegenerative disorders. Neurobiol Dis 72 Pt A: 22-36.

Marucci, G., Buccioni, M., Ben, D.D., Lambertucci, C., Volpini, R., Amenta, F. 2021. Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology 190(2021): 108352.

Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C. 1985. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7): 412-9.

Mostafalou, S., Baeeri, M., Bahadar, H., Soltany-Rezaee-Rad, M., Gholami, M., Abdollahi, M. 2015. Molecular mechanisms involved in lead induced disruption of hepatic and pancreatic glucose metabolism. Environ Toxicol Pharmacol 39(1): 16-26.

Mostafalou, S., Eghbal, M.A., Nili-Ahmadabadi, A., Baeeri, M., Abdollahi, M. 2012. Biochemical evidence on the potential role of organophosphates in hepatic glucose metabolism toward insulin resistance through inflammatory signaling and free radical pathways. Toxicol Ind Health 28(9): 840-51.

Mushtaq, G., Greig, N.H., Khan, J.A., Kamal, M.A. 2014. Status of acetylcholinesterase and butyrylcholinesterase in Alzheimer’s disease and type 2 diabetes mellitus. CNS Neurol Disord Drug Targets 13(8): 1432-9.

Ortiz, G.G., Huerta, M., González-Usigli, H.A., Torres-Sánchez, E.D., Delgado-Lara, D.L., Pacheco-Moisés, F.P., Mireles-Ramírez, M.A., Torres-Mendoza, B.M., Moreno-Cih, R.I., Velázquez-Brizuela, I.E. 2022. Cognitive disorder and dementia in type 2 diabetes mellitus. World J Diabetes 13(4): 319-37.

Romani, A., Trentini, A., Flier, W.M.V., Bellini, T., Zuliani, G., Cervellati, C., Teunissen, C.E. 2020. Arylesterase activity of paraoxonase-1 in serum and cerebrospinal fluid of patients with alzheimer’s disease and vascular dementia. Antioxidants (Basel) 9(5): 456.

Shenhar-Tsarfaty, S., Berliner, S., Bornstein, N.M., Soreq, H. 2013. Cholinesterases as biomarkers for parasympathetic dysfunction and inflammation-related disease. J Mol Neurosci 53(3): 298-305.

Shokri, Y., Variji, A., Nosrati, M., Khonakdar-Tarsi, A., Kianmehr, A., Kashi, Z., Bahar, A., Bagheri, A., Mahrooz, A. 2020. Importance of paraoxonase 1 (PON1) as an antioxidant and antiatherogenic enzyme in the cardiovascular complications of type 2 diabetes: Genotypic and phenotypic evaluation. Diabetes Res Clin Pract 161: 108067.

Sridhar, G.R., Thota, H., Allam, A.R., Suresh Babu, C., Siva Prasad, A., Divakar, Ch. 2006. Alzheimer’s disease and type 2 diabetes mellitus: The cholinesterase connection? Lipids Health Dis. 5: 28.