Потенциальная роль галанина в терапии сахарного диабета 2 типа

Растущая распространенность сахарного диабета требует оптимизации имеющихся и поиска новых подходов к лечению данного заболевания. Помимо инсулинорезистентности, вызванной дефектами в молекулярных механизмах реализации действия инсулина, необходимо изучать особенности работы других регуляторов, играющих заметную роль в процессе усвоения клетками глюкозы. Галанин, нейропептид из 29 (30 у человека) аминокислот, участвует в большом количестве различных жизненно важных функций, в том числе регуляции энергетического обмена в клетке. Галанин действует посредством взаимодействия с тремя рецепторами, связанными с G-белком, GAL1, GAL2 и GAL3, и передачи сигналов через несколько путей трансдукции, включая ингибирование циклического аденозинмонофосфата (цАМФ)/РКА (GAL1, GAL3) и стимуляцию фосфолипазы C (GAL2). Агонисты и антагонисты подтипов рецепторов галанина GalR1-3 могут использоваться в качестве предполагаемых терапевтических мишеней для лечения различных заболеваний человека. Накапливается все больше данных, доказывающих важную роль пептидного регулятора галанина в этиологии нарушения поглощения глюкозы инсулинозависимыми тканями. В обзоре рассматриваются такие эффекты галанина, как ингибирование синтеза инсулина, активация экспрессии и транслокации к плазматической клеточной мембране переносчика глюкозы GLUT4, увеличение уровня PPAR-g и уменьшение гиперконтрактивности двенадцатиперстной кишки. Приведенные данные подтверждают важность исследований, направленных на поиск эффективного антидиабетического препарата среди синтезированных аналогов галанина.

1. Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011;94(3):311-321. doi: https://doi.org/10.1016Zj.diabres.2011.10.029

2. Taylor R. Insulin resistance and type 2 diabetes. Diabetes. 2012;61(4):778-779. doi: https://doi.org/10.2337/db12-0073

3. Evans H, Baumgartner M, Shine J, Herzog H. Genomic organization and localization of the gene encoding human preprogalanin. Genomics. 1993;18(3):473-477. doi: https://doi.org/10.1016/s0888-7543(11)80002-9

4. Lang R, Gundlach AL, Holmes FE, et al. Physiology, signaling, and pharmacology of galanin peptides and receptors: three decades of emerging diversity. Pharmacol Rev. 2015;67(1):118-175. doi: https://doi.org/10.1124/pr.112.006536

5. Mutt V. Discovery of Galanin. In: Hokfelt T, Bartfai T, Jacobowitz D, Ottoson D. Galanin: A new multifunctional peptide in the neuro-endocrine system. Palgrave, London; 1991. Р, 3-40. https://doi.org/10.1007/978-1-349-12664-4

6. Jacobowitz DM, Kresse A, Skofitsch G. Galanin in the brain: chemoarchitectonics and brain cartography-a historical review. Peptides. 2004;25(3):433-464. doi: https://doi.org/10.1016/j.peptides.2004.02.015

7. Dataset: GeneAtlas U133A, gcrma. Available from: http://biogps.org/#goto=genereport&id=51083

8. Carlton SM, Coggeshall RE. Stereological analysis of galanin and CGRP synapses in the dorsal horn of neuropathic primates. Brain Res. 1996;711(1-2):16-25. doi: https://doi.org/10.1016/0006-8993(95)01303-2

9. Zhang X, Dagerlind A, Bao L, et al. Increased expression of galanin in the rat superior cervical ganglion after pre- and postganglionic nerve lesions. Exp Neurol. 1994;127(1):9-22. doi: https://doi.org/10.1006/exnr.1994.1075

10. Webling KE, Runesson J, Bartfai T, Langel U. Galanin receptors and ligands. Front Endocrinol (Lausanne). 2012;3:146. doi: https://doi.org/10.3389/fendo.2012.00146

11. Fuxe K, Borroto-Escuela DO, Romero-Fernandez W, et al. On the existence and function of galanin receptor heteromers in the central nervous system. Front Endocrinol (Lausanne). 2012;3:127. doi: https://doi.org/10.3389/fendo.2012.00127

12. Díaz Cabiale Z, Parrado C, Fuxe K, et al. Receptor-receptor interactions in central cardiovascular regulation. Focus on neuropeptide/alpha(2)-adrenoreceptor interactions in the nucleus tractussolitarius. J Neural Transm. 2007;114(1):115-125. doi: https://doi.org/10.1007/s00702-006-0559-6

13. Lindskog S, Ahren B, Dunning BE, Sundler F. Galanin-immunoreactive nerves in the mouse and rat pancreas. Cell Tissue Res. 1991;264(2):363-368. doi: https://doi.org/10.1007/BF00313975

14. Adeghate E, Ponery AS. Large reduction in the number of galanin-immunoreactive cells in pancreatic islets of diabetic rats. J Neuroendocrinal. 2001;13(8):706-710. doi: https://doi.org/10.1046/j.1365-2826.2001.00682.x

15. Shimosegawa T, Moriizumi S, Koizumi M, et al. Immunohistochemical demonstration of galaninlike immunoreactive nerves in the human pancreas. Gastroenterology. 1992;102(1):263-271. doi: https://doi.org/10.1016/0016-5085(92)91809-i

16. Flynn SP White HS. Regulation of glucose and insulin release following acute and repeated treatment with the synthetic galanin analog NAX-5055. Neuropeptides. 2015;50:35-42. doi: https://doi.org/10.1016Zj.npep.2015.01.001

17. Manabe T, Okada Y, Sawai H, et al. Effect of galanin on plasma glucose, insulin and pancreatic glucagon in dogs. J Int Med Res. 2003;31(2):126-132. doi: https://doi.org/10.1177/147323000303100209

18. Bauer FE, Zintel A, Kenny MJ, et al. Inhibitory effect of galanin on postprandial gastrointestinal motility and gut hormone release in humans. Gastroenterology. 1989;97(2):260-264. doi: https://doi.org/10.1016/0016-5085(89)90059-0

19. Gilbey SG, Stephenson J, O’Halloran DJ, et al. High-dose porcine galanin infusion and effect on intravenous glucose tolerance in humans. Diabetes. 1989;38(9):1114-1116. doi: https://doi.org/10.2337/diab.38.9.1114

20. Ahren B. Effects of galanin and calcitonin gene-related peptide on insulin and glucagon secretion in man. Acta Endocrinol (Copenh). 1990;123:591-597.

21. Smith KE, Walker MW, Artymyshyn R, et al. Cloned human and rat galanin GALR3 receptors. Pharmacology and activation of G-protein inwardly rectifying K+ channels. J Biol Chem. 1998;273(36):23321-23326. doi: https://doi.org/10.1074/jbc.273.36.23321

22. Wang Y, Park S, Bajpayee NS, et al. Augmented glucose-induced insulin release in mice lacking G(o2), but not G(o1) or G(i) proteins. Proc Natl Acad Sci U S A. 2011;108(4):1693-1698. doi: https://doi.org/10.1073/pnas.1018903108

23. Tang G, Wang Y, Park S, et al. Go2 G protein mediates galanin inhibitory effects on insulin release from pancreatic в cells. Proc Natl Acad Sci U S A. 2012;14;109(7):2636-2641. doi: https://doi.org/10.1073/pnas.1200100109

24. Jaldin-Fincati JR, Pavarotti M, Frendo-Cumbo S, et al. Update on GLUT4 vesicle traffic: a cornerstone of insulin action. Trends Endocrinol Metab. 2017;28(8):597-611. doi: https://doi.org/10.1016/j.tem.2017.05.002

25. Alam F, Islam MA, Khalil MI, Gan SH. Metabolic control of type 2 diabetes by targeting the glut4 glucose transporter: intervention approaches. Curr Pharm Des. 2016;22(20):3034-3049. doi: https://doi.org/10.2174/1381612822666160307145801

26. Leto D, Saltiel AR. Regulation of glucose transport by insulin: traffic control of GLUT4. Nat Rev Mol Cell Biol. 2012;13(6):383-396. doi: https://doi.org/10.1038/nrm3351

27. Fang P Shi M, Guo L, et al. Effect of endogenous galanin on glucose transporter 4 expression in cardiac muscle of type 2 diabetic rats. Peptides. 2014;62:159-163. doi: https://doi.org/10.1016/j.peptides.2014.10.001

28. Fang P Shi M, Zhu Y, et al. Central injection of GalR1 agonist M617 facilitates GLUT4 expression in cardiac muscle of type 2 diabetic rats. Exp Gerontol. 2015;65:85-89.

29. Fang P Zhang L, Yu M, et al. Activiatedgalanin receptor 2 attenuates insulin resistance in skeletal muscle of obese mice. Peptides. 2018;99:92-98. doi: https://doi.org/10.1016/j.peptides.2017.11.018

30. Yun R, Dourmashkin JT, Hill J, et al. PVN galanin increases fat storage and promotes obesity by causing muscle to utilize carbohydrate more than fat. Peptides. 2005;26(1 1):2265-2273. doi: https://doi.org/10.1016/j.peptides.2005.04.005

31. Fang P He B, Yu M, et al. Central galanin receptor 2 mediates galanin action to promote systemic glucose metabolism of type 2 diabetic rats. Biochem Pharmacol. 2018;156:241-247. doi: https://doi.org/10.1016/jbcp.2018.08.036

32. Abot A, Lucas A, Bautzova T, et al. Galanin enhances systemic glucose metabolism through enteric Nitric Oxide Synthase-expressed neurons. Mol Metab. 2018;10:100-108. doi: https://doi.org/10.1016/j.molmet.2018.01.020

33. Khan AH, Pessin JE. Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Diabetologia. 2002;45(11):1475-1483. doi: https://doi.org/10.1007/s00125-002-0974-7

34. Denley A, Carroll JM, Brierley GV, et al. Differential activation of insulin receptor substrates 1 and 2 by insulin-likegrowth factor-activated insulin receptors. Jr Mol Cell Biol. 2007;27(10):3569-3577. doi: https://doi.org/10.1128/MCB.01447-06

35. Tonks KT, Ng Y, Miller S, et al. Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects. Diabetologia. 2013;56(4):875-885. doi: https://doi.org/10.1007/s00125-012-2811-y

36. Thong FS, Bilan PJ, Klip A. The Rab GTPase-activating protein AS160integrates Akt, protein kinase C, and AMP-activated protein kinase signals regulatingGLUT4 traffic. Diabetes. 2007;56(2): 414-423. doi: https://doi.org/10.2337/db06-0900

37. Rashid AJ, O’Dowd BF, Verma V, George SR. Neuronal Gq/11-coupled dopamine receptors: an uncharted role for dopamine. Trends PharmacolSci. 2007;28(1 1):551-555. doi: https://doi.org/10.1016/jtips.2007.10.001

38. Fang P, Yu M, He B, et al. Central injection of GALR1 agonist M617 attenuates diabetic rat skeletal muscle insulin resistance through the Akt/AS160/GLUT4 pathway. Mech Ageing Dev. 2017;162:122-128. doi: https://doi.org/10.1016/j.mad.2016.03.013

39. Bu L, Yao Q, Liu Z, et al. Combined galanin with insulin improves insulin sensitivity of diabetic rat muscles. J Endocrinol. 2014;221(1):157-165. doi: https://doi.org/10.1530/JOE-13-0444

40. Mirza AZ, Althagafi II, Shamshad H. Role of PPAR receptor in different diseases and their ligands: Physiological importance and clinical implications. Eur J Med Chem. 2019;15:166:502-513. doi: https://doi.org/10.1016/j.ejmech.2019.01.067

41. Kersten S, Desvergne B, Wahli W, Roles of PPARs in health and disease. Nature. 2000;25;405(6785):421-424. doi: https://doi.org/10.1038/35013000

42. Hsueh WA, Law R. The central role of fat and effect of peroxisome proliferator-activated receptorgamma on progression of insulin resistance and cardiovascular disease. Am J Cardiol. 2003;92(4A):3J-9J. doi: https://doi.org/10.1016/s0002-9149(03)00610-6

43. Kim A, Park T. Diet-induced obesity regulates the galanin-mediated signaling cascade in the adipose tissue of mice. Mol Nutr Food Res. 2010;54(9):1361-1370. doi: https://doi.org/10.1002/mnfr.200900317

44. Celi F, Bini V, Papi F, et al. Circulating acylated and total ghrelin and galanin inchildren with insulin-treated type 1 diabetes: relationship to insulin therapy, metaboliccontrol and pubertal development. Clin Endocrinol (Oxf). 2005;63(2):139-145. doi: https://doi.org/10.1111/j.1365-2265.2005.02313.x

45. Alotibi MN, Alnoury AM, Alhozali AM. Serum nesfatin-1 and galanin concentrations in the adult with metabolic syndrome. Relationships to insulin resistance and obesity. Saudi Med J. 2019;40(1):19-25. doi: https://doi.org/10.15537/smj.2019.L22825

46. Acar S, Paketji A, Kume T, et al. Positive correlation of galanin with insulin resistance and triglyceride levels in obese children. Turk J Med Sci. 2018;48(3):560-568. doi: https://doi.org/10.3906/sag-1710-68

47. Fang P, Shi M, Zhu Y, et al. Type 2 diabetes mellitus as a disorder of galanin resistance. Exp Gerontol. 2016;73:72-77. doi: https://doi.org/10.1016/j.exger.2015.11.007

48. Weber C. Neurogastroenterology: improving glucose tolerance via the gut-brain axis. Nat Rev Gastroenterol Hepatol. 2016;13(1):4. doi: https://doi.org/10.1038/nrgastro.2015.204

49. Fournel A, Drougard A, Duparc T, et al. Apelin targets gut contraction to control glucose metabolism via the brain. Gut. 2017;66(2):258-269. doi: https://doi.org/10.1136/gutjnl-2015-310230

50. Fournel A, Marlin A, Abot A, et al. Glucosensing in the gastrointestinal tract: impact on glucose metabolism. Am J Physiol Gastrointest Liver Physiol. 2016;310(9):G645-G658. doi: https://doi.org/10.1152/ajpgi.00015.2016

51. Chandrasekharan B, Srinivasan S. Diabetes and the enteric nervous system. Neurogastroenterol Motil. 2007;19(12):951-960. doi: https://doi.org/10.1111/j.1365-2982.2007.01023.x