İLERİ GLİKASYON ÜRÜNLERİNİN GÜÇLÜ BİR İNDÜKLEYİCİSİ OLAN METİLGLİOKSALIN DİYABET ÜZERİNE ETKİSİ

Abstract

Metilglioksal (MGO), esas olarak glukoz ve fruktoz metabolizmasından türetilen reaktif bir bileşiktir. Bu metabolit güçlü bir ileri glikasyon ürünleri (AGE) öncüsü olması nedeniyle diyabetik komplikasyonlarda rol oynamaktadır. Diyabet dünya çapında en sık görülen hastalıklardan biri olup, DSÖ tarafından epidemik ilan edilmiştir. Diyabet; metabolik bozukluk, nöropati, retinopati, ateroskleroz ve diyabetik nefropati gibi majör komplikasyonlarla; bunların şiddeti/ciddiyeti ise hiperglisemi ile ilişkilidir. Metabolizmada gözlenen bu komplikasyonlar yüksek glukoz/fruktoz tüketimine bağlı olarak tetiklenerek dolaşımdaki AGE seviyelerini arttırır. Ayrıca, indirgen şekerler ve MGO gibi reaktif karbonil türleri, proteinlerin, lipitlerin ve DNA'nın glikasyonuna ve hatta hücrelerde ve dokularda AGE'lerin kademeli olarak birikmesine yol açar. AGE'lerin diyabet komplikasyonlarının patogenezinde yer aldığı ve MGO'nun insülin direncinde ve beta hücre fonksiyon bozukluğunda rol oynadığı son yıllarda yapılan klinik çalışmalarda rapor edilmiştir. Son yıllarda MGO'yu temizleyen ve AGE oluşumunu engelleyen birçok ilaç geliştirilmiş olmasına rağmen, MGO'nun neden olduğu mekanizmaları önleyecek etkili bir strateji bulunmamaktadır. En önemli AGE sınırlayıcı önlem beslenme alışkanlıklarındaki değişikliklere bağlıdır. Bu derlemenin amacı özellikle MGO’nun oluşumu, detoksifikasyonu ve etki mekanizmalarını özetlemekte ve diyabetin patofizyolojisi ve komplikasyonları üzerindeki etkisi hakkındaki bilgileri güncel çalışmalar ışığında değerlendirmektir.

Keywords

• Metilglioksal
• ileri glikasyon ürünleri
• diyabet

EFFECT OF METHYLGLYOXAL, A POWERFUL INDUCER OF ADVANCED GLICATION PRODUCTS, ON DIABETES

Abstract

Methylglyoxal (MGO) is a reactive compound derived mainly from glucose and fructose metabolism. This metabolite has been implicated in diabetic complications as it is a potent advanced glycation products (AGE) precursor. Diabetes is one of the most common diseases worldwide and has been declared epidemic by the WHO. Diabetes is associated with major complications such as metabolic disorders, neuropathy, retinopathy, atherosclerosis and diabetic nephropathy, the severity of which is associated with hyperglycemia. These metabolic complications are triggered by high glucose/fructose consumption, which increases circulating levels of AGEs. Furthermore, reducing sugars and reactive carbonyl species such as MGO lead to glycation of proteins, lipids and DNA, and even to the gradual accumulation of AGEs in cells and tissues. Recent clinical studies have reported that AGEs are involved in the pathogenesis of diabetes complications and that MGO plays a role in insulin resistance and beta cell dysfunction. Although many drugs that clear MGO and prevent the formation of AGEs have been developed in recent years, there is no effective strategy to prevent the mechanisms caused by MGO. The most important AGEs limiting measure depends on changes in dietary habits. The aim of this review is to summarize the formation, detoxification and mechanisms of action of MGO and to provide information on its impact on the pathophysiology and complications of diabetes.

Keywords

• Methylglyoxal
• advanced glycation products
• diabetes

References

1. 1. IDF Diabetes Atlas Report, https://diabetesatlas.org/, 2021, (Erişim Tarihi 21.04.2024)
2. 2. Bellier, J, Nokin, M.J, Lardé, E, Karoyan, P, Peulen, O, Castronovo, V, & Bellahcène, A, Methylglyoxal, a potent inducer of AGEs, connects between diabetes and cancer, Diabetes research and clinical practice, 2019, 148, 200-211.
3. 3. Schalkwijk, C, Stehouwer, C, Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in 343 Diabetes, Its Vascular Complications, and Other Age-Related Diseases, Physiology Review, 2020, 100 (1):407-461.
4. 4. Zheng, J, Guo, H, Ou, J, Liu, P, Huang, C, Wang, M, Xiao, J, Benefits, deleterious effects and mitigation of methylglyoxal in foods: A critical review, Trends in Food Science & Technology, 2021, 107, 201-212.
5. 5. Zhao, Y, Zhu, Y, Wang, P, Sang, S, Dietary genistein reduces methylglyoxal and advanced glycation end product accumulation in obese mice treated with high-fat diet, Journal of agricultural and food chemistry, 2020, 68(28), 7416-7424.
6. 6. Kold-Christensen, R, Johannsen, M, Methylglyoxal Metabolism and Aging-Related Disease: Moving from Correlation toward Causation, Trends Endocrinology and Metabolism, 2019, 31(2):81-92.
7. 7. Bhat, L.R, Vedantham, S, Krishnan, U.M, Rayappan, J.B.B, Methylglyoxal–an emerging biomarker for diabetes mellitus diagnosis and its detection methods, Biosensors and bioelectronics, 2019, 133, 107-124.
8. 8. Gill, V, Kumar, V, Singh, K, Kumar, A, Kim, J.J, Advanced glycation end products (AGEs) may be a striking link between modern diet and health, Biomolecules, 2019, 9(12), 888.

9. 9. Sergi, D, Boulestin, H, Campbell, F.M, Williams, L.M, The role of dietary advanced glycation end products in metabolic dysfunction, Molecular Nutrition & Food Research, 2021, 65(1), 1900934.
10. 10. Dariya, B, Nagaraju, G.P, Advanced glycation end products in diabetes, cancer and phytochemical therapy, Drug Discovery Today, 2020, 25(9), 1614-1623.
11. 11. Dozio, E, Massaccesi, L, Corsi Romanelli, M.M, Glycation and glycosylation in cardiovascular remodeling: focus on advanced glycation end products and O-linked glycosylations as glucose-related pathogenetic factors and disease markers, Journal of clinical medicine, 2021, 10(20), 4792.
12. 12. Singh, R, Rao, H.K, Singh, T.G, Advanced glycated end products (AGEs) in diabetes and its complications: an insight. Plant Archives, 2020, 20(1), 3838-3841.
13. 13. Puddu, A, Sanguineti, R, Maggi, D, Nicolò, M, Traverso, C.E, Cordera, R, Viviani, G.L, Advanced glycation end-products and hyperglycemia increase Angiopoietin-2 production by impairing Angiopoietin-1-Tie-2 system, Journal of Diabetes Research, 2019, 2019.
14. 14. Reddy, V.P, Aryal, P, Darkwah, E.K, Advanced glycation end products in health and disease, Microorganisms, 2022, 10(9), 1848.
15. 15. Moraru, A, Wiederstein, J, Pfaff, D, Fleming, T, Miller, A.K, Nawroth, P, Teleman, A.A, Elevated levels of the reactive metabolite methylglyoxal recapitulate progression of type 2 diabetes, Cell Metabolism, 2018, 27, 1–9. https://doi.org/10.1016/j.cmet.2018.02.003.
16. 16. Yusufoğlu B, Potansiyel Glikasyon Ürünlerinin Azaltılmasına Yönelik Yeni Fonksiyonel Gıdalar Geliştirilmesi ve in vitro yöntemle Biyoerişilebilirliklerinin Tayini, Yıldız Teknik Üniversitesi, Fen Bilimleri Enstitüsü, Kimya Ana Bilim Dalı, Biyokimya Bilim Dalı Doktora Tezi, İstanbul, Türkiye, 2022, 124s.
17. 17. Vıcıl, S, Ulutaş, E, Metilglioksal ve İleri Glikasyon Son Ürünleri, Bozok Veterinary Sciences, 2020, 1(1-2), 74-79.
18. 18. Toydemir, S, Yusufoğlu, B, Effect of processed foods on advanced glycation end products: Cancer cases, ITU Journal of Food Science and Technology, 2024, 2(1), 9-18.
19. 19. Rabbani, N, Thornalley, P.J, Glyoxalase in diabetes, obesity and related disorders, In Seminars in cell & developmental biology, Academic Press, 2011, 22(3):309-317.
20. 20. Schalkwijk, C.G, Micali, L.R, Wouters, K, Advanced glycation endproducts in diabetes-related macrovascular complications: Focus on methylglyoxal, Trends in Endocrinology & Metabolism, 2023, 34(1), 49-60.
21. 21. Matafome, P, Sena, C, Seiça, R, Methylglyoxal, obesity, and diabetes, Endocrine, 201343, 472-484.
22. 22. Nasirzadeh, M, Alizadeh, M, Kheirouri, S, Taheraghdam, A, Correlation of high glycemic index diets with the occurrence of Parkinson's disease and involvement of glycation end products: A case-control study, Neurology Asia, 2021, 26(1).
23. 23. AGE Database Introduction, https://lemchem.file3.wcms.tu-dresden.de/ ,Erişim Tarihi: 23 Nisan 2024.
24. 24. Alomar, F.A, Methylglyoxal in COVİD-19-induced hyperglycemşa and new-onset diabetes, European Review for Medical & Pharmacological Sciences, 2022, 26(21).
25. 25. Yang, Z, Zhang, W, Lu, H, Cai, S, Methylglyoxal in the brain: from glycolytic metabolite to signalling molecule. Molecules, 2022, 27(22), 7905.
26. 26. Shah, S.Z.H, Rashid, A, Majeed, A, Determination of Glyoxalase-1 levels and Identification of Genetic Variants in GLO1 Gene in Patients of Diabetic Nephropathy. Pakistan Journal of Medical Sciences, 2024, 40(4).
27. 27. Matafome, P, Rodrigues, T, Sena, C, Seiça, R, Methylglyoxal in metabolic disorders: facts, myths, and promises, Medicinal Research Reviews. 2017, 37, 368–403. https://doi.org/10.1002/med.21410.
28. 28. Ramasubbu, K, Devi Rajeswari, V, Impairment of insulin signaling pathway PI3K/Akt/mTOR and insulin resistance induced AGEs on diabetes mellitus and neurodegenerative diseases: a perspective review, Molecular and Cellular Biochemistry, 2023, 478(6), 1307-1324.
29. 29. Yao, Y, Li, X, Yang, X, Mou, H, Wei, L, Dihydromyricetin promotes GLP-1 release and glucose uptake by STC-1 cells and enhances the effects of metformin upon STC-1 cells and diabetic mouse model, Tissue and Cell, 2023, 82, 102108.
30. 30. Peter, A, Schleicher, E, Kliemank, E, Szendroedi, J, Königsrainer, A, Häring, H.U, Fleming, T, Accumulation of Non-Pathological Liver Fat Is Associated with the Loss of Glyoxalase I Activity in Humans. Metabolites, 2024, 14(4), 209.
31. 31. Anaga, N, Lekshmy, K, Purushothaman, J, Catechin mitigates impairment in insulin secretion and beta cell damage in methylglyoxal-induced pancreatic beta cells. Molecular Biology Reports, 2024, 51(1), 434.
32. 32. Dhar, A, Desai, K.M, Wu, L, Alagebrium attenuates acute methylglyoxal‐induced glucose intolerance in Sprague‐Dawley rats, British journal of pharmacology, 2010, 159(1), 166-175.
33. 33. Dhar, A, Dhar, I, Jiang, B, Desai, K.M, Wu, L, Chronic methylglyoxal infusion by minipump causes pancreatic β-cell dysfunction and induces type 2 diabetes in Sprague-Dawley rats. Diabetes, 2011, 60(3), 899-908.
34. 34. Guo, Q, Mori, T, Jiang, Y, Hu, C, Osaki, Y, Yoneki, Y, Sun, Y, Hosoya, T, Kawamata, A, Ogawa, S, Nakayama, M, Miyata, T, Ito, S, Methylglyoxal contributes to the development of insulin resistance and salt sensitivity in Sprague–Dawley rats, Journal Hypertension. 2009, 27, 1664–1671. https://doi.org/10.1097/HJH.0b013e32832c419a.
35. 35. Lin, J.A, Wu, C.H, Yen, G.C, Methylglyoxal displays colorectal cancer-promoting properties in the murine models of azoxymethane and CT26 isografts, Free Radical Biology and Medicine, 2018, 115, 436-446.
36. 36. Oliveira, J.S, de Almeida, C, de Souza, Â.M, da Cruz, L.D, Alfenas, R.C, Effect of dietary advanced glycation end-products restriction on type 2 diabetes mellitus control: a systematic review, Nutrition Reviews, 2022, 80(2), 294-305.
37. 37. Sena, C. M, Matafome, P, Crisóstomo, J, Rodrigues, L, Fernandes, R, Pereira, P, Seica, R.M, Methylglyoxal promotes oxidative stress and endothelial dysfunction, Pharmacological Research, 2012, 65(5), 497-506.
38. 38. Averill-Bates, D.A, The antioxidant glutathione. In Vitamins and hormones, Academic Press, 2023, Vol. 121, pp. 109-141.
39. 39. Alzayadneh, E.M, Shatanawi, A, Caldwell, R.W, Caldwell, R.B, Methylglyoxal-Modified Albumin Effects on Endothelial Arginase Enzyme and Vascular Function, Cells, 2023, 12(5), 795.
40. 40. Kamiya, E, Morita, A, Mori, A, Sakamoto, K, Nakahara, T, The process of methylglyoxal-induced retinal capillary endothelial cell degeneration in rats, Microvascular Research, 2023, 146, 104455.
41. 41. Liccardo, M, Sapio, L, Perrella, S, Sirangelo, I, Iannuzzi, C, Genistein Prevents Apoptosis and Oxidative Stress Induced by Methylglyoxal in Endothelial Cells, Molecules, 2024, 29(8), 1712.
42. 42. Khan, M.Y, Alouffi, S, Khan, M.S, Husain, F.M, Akhter, F, Ahmad, S, The neoepitopes on methylglyoxal (MG) glycated LDL create autoimmune response; autoimmunity detection in T2DM patients with varying disease duration, Cellular Immunology, 2020, 351, 104062.
43. 43. American Diabetes Association, Classification and diagnosis of diabetes: standards of medical care in diabetes 2018, Diabetes Care, 2018, https://doi.org/10.2337/dc18-S002.
44. 44. Lai, S.W.T, Hernandez-Castillo, C, Gonzalez, E.D.J.L, Zoukari, T, Talley, M, Paquin, N, Shuck, S.C, Methylglyoxal adducts are prognostic biomarkers for diabetic kidney disease in patients with type 1 diabetes, Diabetes, 2024, 73(4), 611-617.
45. 45. Ferreira, S.S, Domingues, M.R, Barros, C, Santos, S.A, Silvestre, A.J, Silva, A.M, Nunes, F.M, Major anthocyanins in elderberry effectively trap methylglyoxal and reduce cytotoxicity of methylglyoxal in HepG2 cell line, Food Chemistry, 2022, 10, 16, 100468.
46. 46. Tu, A.T, Lin, J.A, Lee, C.H, Chen, Y.A, Wu, J.T, Tsai, M.S, Hsieh, C.W, Reduction of 3-deoxyglucosone by epigallocatechin gallate results partially from an addition reaction: The possible mechanism of decreased 5-hydroxymethylfurfural in epigallocatechin gallate-treated black garlic, Molecules, 2021, 26(16), 4746.
47. 47. Hashemzaei, M, Tabrizian, K, Alizadeh, Z, Pasandideh, S, Rezaee, R, Mamoulakis, C, Shahraki, J, Resveratrol, curcumin and gallic acid attenuate glyoxal-induced damage to rat renal cells, Toxicology Reports, 2020, 7, 1571-1577.
48. 48. Dalbanjan, N.P, Kadapure, A.J, Huded, P, Chachadi, V.B, Nayaka, S, SK, P.K, Assessıng The In Vıtro Antı-Glycatıon Effıcacy Of Vıtamıns A, C, D, E, 2022, 61-66.
49. 49. İnceören, N, Emen, S, Toptancı, B.Ç, Kızıl, G, Kızıl, M, In vitro inhibition of advanced glycation end product formation by ethanol extract of milk thistle (Silybum marianum L.) seed, South African Journal of Botany, 2022, 149, 682-692.
50. 50. Elewa, H.A, Zalat, Z.A.K, Keshk, W.A, Werida, R.H, Role of alpha-lipoic acid in protection from cardiovascular events in patients with hemodialysis, Journal of Bioscience Applied Research, 2020, 6(3), 121-132.
51. 51. Liu, P, Yin, Z, Chen, M, Huang, C, Wu, Z, Huang, J, Zheng, J, Cytotoxicity of adducts formed between quercetin and methylglyoxal in PC-12 cells, Food Chemistry, 2021, 352, 129424.
52. 52. Cha, S.H, Hwang, Y, Heo, S.J, Jun, H.S, Indole-4-carboxaldehyde isolated from seaweed, Sargassum thunbergii, attenuates methylglyoxal-induced hepatic inflammation, Marine drugs, 2019, 17(9), 486.
53. 53 Fecka, I, Bednarska, K, Kowalczyk, A, In Vitro Antiglycation and Methylglyoxal Trapping Effect of Peppermint Leaf (Mentha× piperita L.) and Its Polyphenols, Molecules, 2023, 28(6), 2865.