Autocatalytic cycle in the pathogenesis of diabetes mellitus: biochemical and pathophysiological aspects of metabolic therapy with natural amino acids on the example of glycine

In this work systematization (classification) of biochemical and physiological processes that cause disorders in the human body during the development of diabetes mellitus is carried out. The development of the disease is considered as the interaction and mutual reinforcement of two groups of parallel processes. The first group has a molecular nature and it is associated with impairment of ROS-regulation system which includes NADPH oxidases, RAGE receptors, mitochondria, cellular peroxireductase system and the immune system. The second group has a pathophysiological nature and it is associated with impairment of microcirculation and liver metabolism. The analysis of diabetes biochemistry based on different published references yields a creation of a block diagram evaluating the disease development over time. Two types of autocatalytic processes were identified: autocatalysis in the cascade of biochemical reactions and "cross-section" catalysis, in which biochemical and pathophysiological processes reinforce each other. The developed model has shown the possibility of using pharmacologically active natural metabolite glycine as a medicine inhibiting the development of diabetes. Despite the fact that glycine is a substitute amino acid the drop in the glycine blood concentration occurs even in the early stages of diabetes development and can aggravate the disease. It is shown that glycine is a potential blocker of key autocatalytic cycles, including biochemical and pathophysiological processes. The analysis of the glycine action based on the developed model is in complete agreement with the results of clinical trials in which glycine has improved blood biochemistry of diabetic patients and thereby it prevents the development of diabetic complications.

1. Marre ML, Piganelli JD. Environmental Factors Contribute to beta Cell Endoplasmic Reticulum Stress and Neo-Antigen Formation in Type 1 Diabetes. Front Endocrinol (Lausanne). 2017;8:262. doi: 10.3389/fendo.2017.00262

2. Montgomery MK, Turner N. Mitochondrial dysfunction and insulin resistance: an update. Endocr Connect. 2015;4(1):R1-R15. doi: 10.1530/EC-14-0092

3. Li C, Liu C, Nissim I, et al. Regulation of glucagon secretion in normal and diabetic human islets by gamma-hydroxybutyrate and glycine. J Biol Chem. 2013;288(6):3938-3951. doi: 10.1074/jbc.M112.385682

4. Дедов И.И., Шестакова М.В., Викулова О.К. Государственный регистр сахарного диабета в Российской Федерации: статус 2014 г. и перспективы развития // Сахарный диабет. – 2015. – Т. 18. – №3. – С. 5-22. [Dedov II, Shestakova MV, Vikulova OK. National register of diabetes mellitus in Russian Federation. Diabetes Mellitus. 2015;18(3):5-22. (In Russ.)] doi: 10.14341/DM201535-22

5. Lustgarten MS, Price LL, Phillips EM, Fielding RA. Serum glycine is associated with regional body fat and insulin resistance in functionally-limited older adults. PLoS One. 2013;8(12):e84034. doi: 10.1371/journal.pone.0084034

6. Palmer ND, Stevens RD, Antinozzi PA, et al. Metabolomic profile associated with insulin resistance and conversion to diabetes in the Insulin Resistance Atherosclerosis Study. J Clin Endocrinol Metab. 2015;100(3):E463-468. doi: 10.1210/jc.2014-2357

7. Wang-Sattler R, Yu Z, Herder C, et al. Novel biomarkers for pre-diabetes identified by metabolomics. Mol Syst Biol. 2012;8:615. doi: 10.1038/msb.2012.43

8. Чуйко М.Р., Ефремова Н.М., Скворцова В.И. Эффективность и безопасность применения глицина и лимонтара в комплексной терапии дисциркуляторной энцефалопатии и энцефалопатии при инсулинзависимом сахарном диабете // Журнал неврологии и психиатрии им. С.С. Корсакова. – 2010. – Т. 110. – №6. – С. 44-48. [Chuyko MR, Efremova NM, Skvortsova VI. Efficacy and safety of glycine and limontar in the complex therapy of discirculatory encephalopathy and encephalopathy in diabetes mellitus type I. Zh Nevrol Psikhiatr Im SS Korsakova. 2010;110(6):44-48. (In Russ.)]

9. Cruz M, Maldonado-Bernal C, Mondragón-Gonzalez R, et al. Glycine treatment decreases proinflammatory cytokines and increases interferon-γ in patients with Type 2 diabetes. J Endocrinol Invest. 2014;31(8):694-699. doi: 10.1007/bf03346417

10. Munoz-Carlin Mde L, Rodriguez-Moctezuma JR, Gomez Latorre JG, et al. Effects of glycine on auditory evoked potentials among diabetic patients with auditory pathway neuropathy. Rev Med Chil. 2010;138(10):1246-1252. doi: /S0034-98872010001100006

11. Sekhar RV, McKay SV, Patel SG, et al. Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. Diabetes Care. 2011;34(1):162-167. doi: 10.2337/dc10-1006

12. Gannon MC, Nuttall JA, Nuttall FQ. The metabolic response to ingested glycine. Am J Clin Nutr. 2002;76(6):1302-1307. doi: 10.1093/ajcn/76.6.1302

13. Yan-Do R, Duong E, Manning Fox JE, et al. A Glycine-Insulin Autocrine Feedback Loop Enhances Insulin Secretion From Human beta-Cells and Is Impaired in Type 2 Diabetes. Diabetes. 2016;65(8):2311-2321. doi: 10.2337/db15-1272

14. Lam CK, Chari M, Su BB, et al. Activation of N-methyl-D-aspartate (NMDA) receptors in the dorsal vagal complex lowers glucose production. J Biol Chem. 2010;285(29):21913-21921. doi: 10.1074/jbc.M109.087338

15. Alvarado-Vásquez N, Zamudio P, Cerón E, et al. Effect of glycine in streptozotocin-induced diabetic rats. Comp Biochem Physiol C Toxicol Pharmacol. 2003;134(4):521-527. doi: 10.1016/s1532-0456(03)00046-2

16. Hudson BI, Bucciarelli LG, Wendt T, et al. Blockade of receptor for advanced glycation endproducts: a new target for therapeutic intervention in diabetic complications and inflammatory disorders. Arch Biochem Biophys. 2003;419(1):80-88. doi: 10.1016/j.abb.2003.08.030

17. Sick E, Brehin S, André P, et al. Advanced glycation end products (AGEs) activate mast cells. Br J Pharmacol. 2010;161(2):442-455. doi: 10.1111/j.1476-5381.2010.00905.x

18. Kay AM, Simpson CL, Stewart JA, Jr. The Role of AGE/RAGE Signaling in Diabetes-Mediated Vascular Calcification. J Diabetes Res. 2016;2016:6809703. doi: 10.1155/2016/6809703

19. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res. 2011;21(1):103-115. doi: 10.1038/cr.2010.178

20. Froh M, Thurman RG, Wheeler MD. Molecular evidence for a glycine-gated chloride channel in macrophages and leukocytes. Am J Physiol Gastrointest Liver Physiol. 2002;283(4):G856-863. doi: 10.1152/ajpgi.00503.2001

21. McCarty MF, Barroso-Aranda J, Contreras F. The hyperpolarizing impact of glycine on endothelial cells may be anti-atherogenic. Med Hypotheses. 2009;73(2):263-264. doi: 10.1016/j.mehy.2008.12.021

22. Borggreve SE, de Vries R, Dullaart RPF. Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins. Eur J Clin Invest. 2003;33(12):1051-1069. doi: 10.1111/j.1365-2362.2003.01263.x

23. Yue JT, Mighiu PI, Naples M, et al. Glycine normalizes hepatic triglyceride-rich VLDL secretion by triggering the CNS in high-fat fed rats. Circ Res. 2012;110(10):1345-1354. doi: 10.1161/CIRCRESAHA.112.268276

24. Hammdy N, Salam R, El GNA, Mahmoud E. Mast cell a new player in Type 2 diabetes. Endocrine Abstracts. 2016. doi: 10.1530/endoabs.41.EP476

25. Slatter DA, Bolton CH, Bailey AJ. The importance of lipid-derived malondialdehyde in diabetes mellitus. Diabetologia. 2000;43(5):550-557. doi: 10.1007/s001250051342

26. Looney MR, Matthay MA. Neutrophil sandwiches injure the microcirculation. Nat Med. 2009;15(4):364-366. doi: 10.1038/nm0409-364

27. Sugiyama K, Kanamori H, Tanaka S. Correlation of the Plasma Cholesterol-lowering Effect of Dietary Glycine with the Alteration of Hepatic Phospholipid Composition in Rats. Biosci Biotechnol Biochem. 2014;57(9):1461-1465. doi: 10.1271/bbb.57.1461

28. Podoprigora GI, Nartsissov YR, Aleksandrov PN. Effect of Glycine on Microcirculation in Pial Vessels of Rat Brain. Bull Exp Biol Med. 2005;139(6):675-677. doi: 10.1007/s10517-005-0375-2

29. Podoprigora GI, Nartsissov YR. Effect of Glycine on the Microcirculation in Rat Mesenteric Vessels. Bull Exp Biol Med. 2009;147(3):308-311. doi: 10.1007/s10517-009-0498-y

30. Deng A. Vasodilatory N-Methyl-D-Aspartate Receptors Are Constitutively Expressed in Rat Kidney. J Am Soc Nephrol. 2002;13(5):1381-1384. doi: 10.1097/01.asn.0000013293.11876.4e

31. Podoprigora GI, Blagosklonov O, Angoue O, et al. Assessment of microcirculatory effects of glycine by intravital microscopy in rats. Conf Proc IEEE Eng Med Biol Soc. 2012;2012:2651-2654. doi: 10.1109/EMBC.2012.6346509

32. Yamashina S, Konno A, Wheeler MD, et al. Endothelial cells contain a glycine-gated chloride channel. Nutr Cancer. 2001;40(2):197-204. doi: 10.1207/S15327914NC402_17

33. Meyer KF, Martins JL, Freitas Filho LGd, et al. Glycine reduces tissue lipid peroxidation in hypoxia-reoxygenation-induced necrotizing enterocolitis in rats. Acta Cir Bras. 2006;21(3):161-167. doi: 10.1590/s0102-86502006000300008

34. Selin AA, Lobysheva NV, Nesterov SV, et al. On the regulative role of the glutamate receptor in mitochondria. Biol Chem. 2016;397(5):445-458. doi: 10.1515/hsz-2015-0289

35. Schofield ZV, Woodruff TM, Halai R, et al. Neutrophils--a key component of ischemia-reperfusion injury. Shock. 2013;40(6):463-470. doi: 10.1097/SHK.0000000000000044

36. Gusev EI, Skvortsova VI, Dambinova SA, et al. Neuroprotective effects of glycine for therapy of acute ischaemic stroke. Cerebrovasc Dis. 2000;10(1):49-60. doi: 10.1159/000016025

37. Van den Eynden J, Ali SS, Horwood N, et al. Glycine and glycine receptor signalling in non-neuronal cells. Front Mol Neurosci. 2009;2:9. doi: 10.3389/neuro.02.009.2009

38. Weinberg JM, Bienholz A, Venkatachalam MA. The role of glycine in regulated cell death. Cell Mol Life Sci. 2016;73(11-12):2285-2308. doi: 10.1007/s00018-016-2201-6

39. Selin AA, Lobysheva NV, Vorontsova ON, et al. Mechanism Underlying the Protective Effect of Glycine in Energetic Disturbances in Brain Tissues under Hypoxic Conditions. Bull Exp Biol Med. 2012;153(1):44-47. doi: 10.1007/s10517-012-1638-3

40. Tonshin AA, Lobysheva NV, Yaguzhinsky LS, et al. Effect of the inhibitory neurotransmitter glycine on slow destructive processes in brain cortex slices under anoxic conditions. Biochemistry (Moscow). 2007;72(5):509-517. doi: 10.1134/s0006297907050070

41. Ruiz-Meana M, Pina P, Garcia-Dorado D, et al. Glycine protects cardiomyocytes against lethal reoxygenation injury by inhibiting mitochondrial permeability transition. J Physiol. 2004;558(Pt 3):873-882. doi: 10.1113/jphysiol.2004.068320

42. Wheeler M, Stachlewitz RF, Yamashina S, et al. Glycine-gated chloride channels in neutrophils attenuate calcium influx and superoxide production. FASEB J. 2000;14(3):476-484. doi: 10.1096/fasebj.14.3.476

43. Yan-Do R, MacDonald PE. Impaired «Glycine»-mia in Type 2 Diabetes and Potential Mechanisms Contributing to Glucose Homeostasis. Endocrinology. 2017;158(5):1064-1073. doi: 10.1210/en.2017-00148

44. Jog R, Wang J, Leff T. Hormonal Regulation of Glycine Metabolism And Its Potential Role in Diabetes Susceptibility. FASEB J. 2017;31(1 Supplement):626.

45. Hashizume O, Ohnishi S, Mito T, et al. Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. Sci Rep. 2015;5:10434. doi: 10.1038/srep10434

46. Ramen T M. Depletion of Glutathione during Oxidative Stress and Efficacy of N-Acetyl Cysteine: An Old Drug with New Approaches. Med Chem (Los Angeles). 2015;05(01). doi: 10.4172/2161-0444.1000240

47. Ceriello A. The emerging challenge in diabetes: the «metabolic memory». Vascul Pharmacol. 2012;57(5-6):133-138. doi: 10.1016/j.vph.2012.05.005

48. San Martin A, Foncea R, Laurindo FR, et al. Nox1-based NADPH oxidase-derived superoxide is required for VSMC activation by advanced glycation end-products. Free Radic Biol Med. 2007;42(11):1671-1679. doi: 10.1016/j.freeradbiomed.2007.02.002

49. Serban AI, Stanca L, Geicu OI, Dinischiotu A. AGEs-Induced IL-6 Synthesis Precedes RAGE Up-Regulation in HEK 293 Cells: An Alternative Inflammatory Mechanism? Int J Mol Sci. 2015;16(9):20100-20117. doi: 10.3390/ijms160920100

50. Li J, Schmidt AM. Characterization and Functional Analysis of the Promoter of RAGE, the Receptor for Advanced Glycation End Products. J Biol Chem. 1997;272(26):16498-16506. doi: 10.1074/jbc.272.26.16498

51. Huebschmann AG, Regensteiner JG, Vlassara H, Reusch JE. Diabetes and advanced glycoxidation end products. Diabetes Care. 2006;29(6):1420-1432. doi: 10.2337/dc05-2096

52. Bierhaus A, Schiekofer S, Schwaninger M, et al. Diabetes-Associated Sustained Activation of the Transcription Factor Nuclear Factor- κB. Diabetes. 2001;50(12):2792-2808. doi: 10.2337/diabetes.50.12.2792

53. Li C, Jackson RM. Reactive species mechanisms of cellular hypoxia-reoxygenation injury. Am J Physiol Cell Physiol. 2002;282(2):C227-241. doi: 10.1152/ajpcell.00112.2001

54. Tang YH, Vital S, Russell J, et al. Transient ischemia elicits a sustained enhancement of thrombus development in the cerebral microvasculature: effects of anti-thrombotic therapy. Exp Neurol. 2014;261:417-423. doi: 10.1016/j.expneurol.2014.07.004

55. Ghosh S, Pulinilkunnil T, Yuen G, et al. Cardiomyocyte apoptosis induced by short-term diabetes requires mitochondrial GSH depletion. Am J Physiol Heart Circ Physiol. 2005;289(2):H768-776. doi: 10.1152/ajpheart.00038.2005

56. Franco R, Cidlowski JA. Apoptosis and glutathione: beyond an antioxidant. Cell Death Differ. 2009;16(10):1303-1314. doi: 10.1038/cdd.2009.107

57. Badenhorst CP, Erasmus E, van der Sluis R, et al. A new perspective on the importance of glycine conjugation in the metabolism of aromatic acids. Drug Metab Rev. 2014;46(3):343-361. doi: 10.3109/03602532.2014.908903

58. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116(7):1793-1801. doi: 10.1172/JCI29069

59. Nartsissov YR, Tyukina ES, Boronovsky SE, Sheshegova EV. Computer modeling of spatial-time distribution of metabolite concentrations in phantoms of biological objects by example of rat brain pial. Biophysics. 2014;58(5):703-711. doi: 10.1134/s0006350913050102

60. Cho J, Zhang Y, Park SY, et al. Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance. Nat Commun. 2017;8:14477. doi: 10.1038/ncomms14477