Генетические аспекты клинической эффективности агонистов глюкагоноподобного пептида 1-го типа

1. Демидова Т.Ю. Сосудистые осложнения сахарного диабета 2 типа за гранью гликемического контроля. Сахарный диабет. 2010;13(3):111-6 [Demidova TYu. Vascular complications of type 2 diabetes mellitus beyond glycemic control]. Diabetes mellitus. 2010;13(3):111-16 (in Russian)].
2. Демидова Т.Ю., Кожевников А.А. Агонисты рецепторов глюкагоноподобного пептида 1: безграничный потенциал применения. Доктор.Ру. 2020;19(2):6-12 [Demidova TYu, Kozhevnikov AA. Glucagon-like peptide 1 receptor agonists: limitless potential applications. Doktor.Ru. 2020;19(2):6-12 (in Russian)]. DOI:10.31550/1727-2378-2020-19-2-6-12
3. Самойлова Ю.Г., Матвеева М.В., Олейник О.А. Исследование антропометрических, метаболических параметров и когнитивных функций у пациентов с ожирением на фоне снижения массы тела при проведении терапии препаратом лираглутид 3 мг. Эндокринология: новости, мнения, обучение. 2022;11(4):21-5 [Samoilova IuG, Matveeva MV, Oleynik OA. Anthropometric, metabolic parameters and cognitive functions investigation in patients with obesity treated with liraglutide 3 mg. Endocrinology: news, opinions, training. 2022;11(4):21-5 (in Russian)]. DOI:10.33029/2304-9529-2022-11-4-00-00
4. Галстян Г.Р., Каратаева Е.А., Юдович Е.А. Эволюция агонистов рецепторов глюкагоноподобного пептида-1 в терапии сахарного диабета 2 типа. Сахарный диабет. 2017;20(4):286-98 [Galstyan GR, Karataeva EA, Yudovich EA. Evolution of glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes. Diabetes Mellitus. 2017;20(4):286-98 (in Russian)].
5. Stoffel M, Espinosa R 3rd, Le Beau MM, Bell GI. Human glucagon-like peptide-1 receptor gene. Localization to chromosome band 6p21 by fluorescence in situ hybridization and linkage of a highly polymorphic simple tandem repeat DNA polymorphism to other markers on chromosome 6. Diabetes. 1993;42(8):1215-8. DOI:10.2337/diab.42.8.1215
6. Tokuyama Y, Matsui K, Egashira T, et al. Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population. Diabetes Res Clin Pract. 2004;66(1):63-9. DOI:10.1016/j.diabres.2004.02.004
7. Sathananthan A, Man CD, Micheletto F, et al. Common genetic variation in GLP1R and insulin secretion in response to exogenous GLP-1 in nondiabetic subjects: a pilot study. Diabetes Care. 2010;33(9):2074-6. DOI:10.2337/dc10-0200
8. Shalaby SM, Zidan HE, Shokry A, et al. Association of incretin receptors genetic polymorphisms with type 2 diabetes mellitus in Egyptian patients. J Gene Med. 2017;19(9-10):10.1002/jgm.2973. DOI:10.1002/jgm.2973 
9. Li W, Li P, Li R, et al. GLP1R Single-Nucleotide Polymorphisms rs3765467 and rs10305492 Affect β Cell Insulin Secretory Capacity and Apoptosis Through GLP-1. DNA Cell Biol. 2020;39(9):1700-10. DOI:10.1089/dna.2020.5424
10. El Eid L, Reynolds CA, Tomas A, Jones B. Biased agonism and polymorphic variation at the GLP-1 receptor: Implications for the development of personalised therapeutics. Pharmacol Res. 2022;184:106411. DOI:10.1016/j.phrs.2022.106411
11. Del Bosque-Plata L, Martínez-Martínez E, Espinoza-Camacho MÁ, Gragnoli C. The Role of TCF7L2 in Type 2 Diabetes. Diabetes. 2021;70(6):1220-8. DOI:10.2337/db20-0573
12. Liu Z, Habener JF. Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem. 2008;283:8723-35. DOI:10.1074/jbc.M706105200
13. Shu L, Matveyenko AV, Kerr-Conte J, et al. Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function. Hum Mol Genet. 2009;18:2388-99. DOI:10.1093/hmg/ddp178
14. Pilgaard K, Jensen CB, Schou JH, et al. The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men. Diabetologia. 2009;52(7):1298-307. DOI:10.1007/s00125-009-1307-x
15. Schäfer SA, Tschritter O, Machicao F, et al. Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia. 2007;50(12):2443-50. DOI:10.1007/s00125-007-0753-6
16. De Miguel-Yanes JM, Manning AK, Shrader P, et al. Variants at the endocannabinoid receptor CB1 gene (CNR1) and insulin sensitivity, type 2 diabetes and coronary heart disease. Obesity. 2011;19:2031-7. DOI:10.1038/oby.2011.135
17. De Luis DA, Ovalle HF, Soto GD, et al. Role of genetic variation in the cannabinoid receptor gene (CNR1) (G1359A polymorphism) on weight loss and cardiovascular risk factors after liraglutide treatment in obese patients with diabetes mellitus type 2. J Investig Med. 2014;62:324-7. DOI:10.2310/JIM.0000000000000032
18. Huang G, Buckler-Pena D, Nauta T, et al. Insulin responsiveness of glucose transporter 4 in 3T3-L1 cells depends on the presence of sortilin. MolBiol Cell. 2013;24(19):3115-22. DOI:10.1091/mbc.E12-10-0765
19. Yau B, Blood Z, An Y, et al. Type 2 diabetes-associated single nucleotide polymorphism in Sorcs1 gene results in alternative processing of the Sorcs1 protein in INS1 β-cells. Sci Rep. 2019;9(1):19466. DOI:10.1038/s41598-019-55873-6
20. Goodarzi MO, Lehman DM, Taylor KD, et al. SORCS1: a novel human type 2 diabetes susceptibility gene suggested by the mouse. Diabetes. 2007;56(7):1922-9.
DOI:10.2337/db06-1677
21. Hrovat A, Kravos NA, Goričar K, et al. SORCS1 polymorphism and insulin secretion in obese women with polycystic ovary syndrome. Gynecol Endocrinol. 2016;32(5):395-8. DOI:10.3109/09513590.2015.1126818
22. Takei D, Ishihara H, Yamaguchi S, et al. WFS1 protein modulates the free Ca(2+) concentration in the endoplasmic reticulum. FEBS Lett. 2006;580(24):5635-40. DOI:10.1016/j.febslet.2006.09.007 
23. Rendtorff ND, Lodahl M, Boulahbel H, et al. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment. Am J Med Genet Part A. 2011;155:1298-313. DOI:10.1002/ajmg.a.33970
24. Yamada T, Ishihara H, Tamura A, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet. 2006;15(10):1600-9. DOI:10.1093/hmg/ddl081
25. Schäfer SA, Müssig K, Staiger H, et al. A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion. Diabetologia. 2009;52(6):1075-82. DOI:10.1007/s00125-009-1344-5
26. Song J, Li N, Hu R, et al. Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus. Front Endocrinol (Lausanne). 2022;13:949990. DOI:10.3389/fendo.2022.949990
27. Bojic LA, Telford DE, Fullerton MD, et al. PPARδ activation attenuates hepatic steatosis in Ldlr-/- mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity. J Lipid Res. 2014;55(7):1254-66. DOI:10.1194/jlr.M046037
28. Zarei M, Aguilar-Recarte D, Palomer X, Vázquez-Carrera M. Revealing the role of peroxisome proliferator-activated receptor β/δ in nonalcoholic fatty liver disease. Metabolism. 2021;114:154342. DOI:10.1016/j.metabol.2020.154342
29. Tang L, Lü Q, Cao H, et al. PPARD rs2016520 polymorphism is associated with metabolic traits in a large population of Chinese adults. Gene. 2016;585(2):191-5. DOI:10.1016/j.gene.2016.02.035
30. 't Hart LM, Fritsche A, Nijpels G, et al. The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway. Diabetes. 2013;62(9):3275-81.
DOI:10.2337/db13-0227
31. Florez JC. Pharmacogenetic perturbations in humans as a tool to generate mechanistic insight. Diabetes. 2013;62(9):3019-21. DOI:10.2337/db13-0871
32. Chedid V, Vijayvargiya P, Carlson P, et al. Allelic variant in the glucagon-like peptide 1 receptor gene associated with greater effect of liraglutide and exenatide on gastric emptying: A pilot pharmacogenetics study. Neurogastroenterol Motil. 2018;30(7):e13313. DOI:10.1111/nmo.13313
33. Yu M, Wang K, Liu H, Cao R. GLP1R variant is associated with response to exenatide in overweight Chinese Type 2 diabetes patients. Pharmacogenomics. 2019;20(4):273-7. DOI:10.2217/pgs-2018-0159
34. Ferreira MC, da Silva MER, Fukui RT, et al. Effect of TCF7L2 polymorphism on pancreatic hormones after exenatide in type 2 diabetes. Diabetol Metab Syndr. 2019;11:10. DOI:10.1186/s13098-019-0401-6
35. Zhou LM, Xu W, Yan XM, et al. Association between SORCS1 rs1416406 and therapeutic effect of exenatide. Zhonghua Yi XueZaZhi. 2017;97(18):1415-9 (in Chinese). DOI:10.3760/cma.j.issn.0376-2491.2017.18.013
36. Pereira MJ, Lundkvist P, Kamble PG, et al. A Randomized Controlled Trial of Dapagliflozin Plus Once-Weekly Exenatide Versus Placebo in Individuals with Obesity and Without Diabetes: Metabolic Effects and Markers Associated with Bodyweight Loss. Diabetes Ther. 2018;9(4):1511-32. DOI:10.1007/s13300-018-0449-6
37. De Luis DA, Diaz Soto G, Izaola O, Romero E. Evaluation of weight loss and metabolic changes in diabetic patients treated with liraglutide, effect of RS 6923761 gene variant of glucagon-like peptide 1 receptor. J Diabetes Complicat. 2015;29:595-8. DOI:10.1016/j.jdiacomp.2015.02.010
38. Jensterle M, Pirš B, Goričar K, et al. Genetic variability in GLP-1 receptor is associated with inter-individual differences in weight lowering potential of liraglutide in obese women with PCOS: a pilot study. Eur J Clin Pharmacol. 2015;71(7):817-24. DOI:10.1007/s00228-015-1868-1
39. Kyriakidou A, Kyriazou AV, Koufakis T, et al. Clinical and Genetic Predictors of Glycemic Control and Weight Loss Response to Liraglutide in Patients with Type 2 Diabetes. J Pers Med. 2022;12(3):424. DOI:10.3390/jpm12030424

________________________________________________

1. Demidova TYu. Vascular complications of type 2 diabetes mellitus beyond glycemic control]. Diabetes mellitus. 2010;13(3):111-16 (in Russian).
2. Demidova TYu, Kozhevnikov AA. Glucagon-like peptide 1 receptor agonists: limitless potential applications. Doktor.Ru. 2020;19(2):6-12 (in Russian).
DOI:10.31550/1727-2378-2020-19-2-6-12
3. Samoilova IuG, Matveeva MV, Oleynik OA. Anthropometric, metabolic parameters and cognitive functions investigation in patients with obesity treated with liraglutide 3 mg. Endocrinology: news, opinions, training. 2022;11(4):21-5 (in Russian). DOI:10.33029/2304-9529-2022-11-4-00-00
4. Galstyan GR, Karataeva EA, Yudovich EA. Evolution of glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes. Diabetes Mellitus. 2017;20(4):286-98 (in Russian).
5. Stoffel M, Espinosa R 3rd, Le Beau MM, Bell GI. Human glucagon-like peptide-1 receptor gene. Localization to chromosome band 6p21 by fluorescence in situ hybridization and linkage of a highly polymorphic simple tandem repeat DNA polymorphism to other markers on chromosome 6. Diabetes. 1993;42(8):1215-8. DOI:10.2337/diab.42.8.1215
6. Tokuyama Y, Matsui K, Egashira T, et al. Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population. Diabetes Res Clin Pract. 2004;66(1):63-9. DOI:10.1016/j.diabres.2004.02.004
7. Sathananthan A, Man CD, Micheletto F, et al. Common genetic variation in GLP1R and insulin secretion in response to exogenous GLP-1 in nondiabetic subjects: a pilot study. Diabetes Care. 2010;33(9):2074-6. DOI:10.2337/dc10-0200
8. Shalaby SM, Zidan HE, Shokry A, et al. Association of incretin receptors genetic polymorphisms with type 2 diabetes mellitus in Egyptian patients. J Gene Med. 2017;19(9-10):10.1002/jgm.2973. DOI:10.1002/jgm.2973 
9. Li W, Li P, Li R, et al. GLP1R Single-Nucleotide Polymorphisms rs3765467 and rs10305492 Affect β Cell Insulin Secretory Capacity and Apoptosis Through GLP-1. DNA Cell Biol. 2020;39(9):1700-10. DOI:10.1089/dna.2020.5424
10. El Eid L, Reynolds CA, Tomas A, Jones B. Biased agonism and polymorphic variation at the GLP-1 receptor: Implications for the development of personalised therapeutics. Pharmacol Res. 2022;184:106411. DOI:10.1016/j.phrs.2022.106411
11. Del Bosque-Plata L, Martínez-Martínez E, Espinoza-Camacho MÁ, Gragnoli C. The Role of TCF7L2 in Type 2 Diabetes. Diabetes. 2021;70(6):1220-8. DOI:10.2337/db20-0573
12. Liu Z, Habener JF. Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem. 2008;283:8723-35. DOI:10.1074/jbc.M706105200
13. Shu L, Matveyenko AV, Kerr-Conte J, et al. Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function. Hum Mol Genet. 2009;18:2388-99. DOI:10.1093/hmg/ddp178
14. Pilgaard K, Jensen CB, Schou JH, et al. The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men. Diabetologia. 2009;52(7):1298-307. DOI:10.1007/s00125-009-1307-x
15. Schäfer SA, Tschritter O, Machicao F, et al. Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia. 2007;50(12):2443-50. DOI:10.1007/s00125-007-0753-6
16. De Miguel-Yanes JM, Manning AK, Shrader P, et al. Variants at the endocannabinoid receptor CB1 gene (CNR1) and insulin sensitivity, type 2 diabetes and coronary heart disease. Obesity. 2011;19:2031-7. DOI:10.1038/oby.2011.135
17. De Luis DA, Ovalle HF, Soto GD, et al. Role of genetic variation in the cannabinoid receptor gene (CNR1) (G1359A polymorphism) on weight loss and cardiovascular risk factors after liraglutide treatment in obese patients with diabetes mellitus type 2. J Investig Med. 2014;62:324-7. DOI:10.2310/JIM.0000000000000032
18. Huang G, Buckler-Pena D, Nauta T, et al. Insulin responsiveness of glucose transporter 4 in 3T3-L1 cells depends on the presence of sortilin. MolBiol Cell. 2013;24(19):3115-22. DOI:10.1091/mbc.E12-10-0765
19. Yau B, Blood Z, An Y, et al. Type 2 diabetes-associated single nucleotide polymorphism in Sorcs1 gene results in alternative processing of the Sorcs1 protein in INS1 β-cells. Sci Rep. 2019;9(1):19466. DOI:10.1038/s41598-019-55873-6
20. Goodarzi MO, Lehman DM, Taylor KD, et al. SORCS1: a novel human type 2 diabetes susceptibility gene suggested by the mouse. Diabetes. 2007;56(7):1922-9.
DOI:10.2337/db06-1677
21. Hrovat A, Kravos NA, Goričar K, et al. SORCS1 polymorphism and insulin secretion in obese women with polycystic ovary syndrome. Gynecol Endocrinol. 2016;32(5):395-8. DOI:10.3109/09513590.2015.1126818
22. Takei D, Ishihara H, Yamaguchi S, et al. WFS1 protein modulates the free Ca(2+) concentration in the endoplasmic reticulum. FEBS Lett. 2006;580(24):5635-40. DOI:10.1016/j.febslet.2006.09.007 
23. Rendtorff ND, Lodahl M, Boulahbel H, et al. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment. Am J Med Genet Part A. 2011;155:1298-313. DOI:10.1002/ajmg.a.33970
24. Yamada T, Ishihara H, Tamura A, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet. 2006;15(10):1600-9. DOI:10.1093/hmg/ddl081
25. Schäfer SA, Müssig K, Staiger H, et al. A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion. Diabetologia. 2009;52(6):1075-82. DOI:10.1007/s00125-009-1344-5
26. Song J, Li N, Hu R, et al. Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus. Front Endocrinol (Lausanne). 2022;13:949990. DOI:10.3389/fendo.2022.949990
27. Bojic LA, Telford DE, Fullerton MD, et al. PPARδ activation attenuates hepatic steatosis in Ldlr-/- mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity. J Lipid Res. 2014;55(7):1254-66. DOI:10.1194/jlr.M046037
28. Zarei M, Aguilar-Recarte D, Palomer X, Vázquez-Carrera M. Revealing the role of peroxisome proliferator-activated receptor β/δ in nonalcoholic fatty liver disease. Metabolism. 2021;114:154342. DOI:10.1016/j.metabol.2020.154342
29. Tang L, Lü Q, Cao H, et al. PPARD rs2016520 polymorphism is associated with metabolic traits in a large population of Chinese adults. Gene. 2016;585(2):191-5. DOI:10.1016/j.gene.2016.02.035
30. 't Hart LM, Fritsche A, Nijpels G, et al. The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway. Diabetes. 2013;62(9):3275-81.
DOI:10.2337/db13-0227
31. Florez JC. Pharmacogenetic perturbations in humans as a tool to generate mechanistic insight. Diabetes. 2013;62(9):3019-21. DOI:10.2337/db13-0871
32. Chedid V, Vijayvargiya P, Carlson P, et al. Allelic variant in the glucagon-like peptide 1 receptor gene associated with greater effect of liraglutide and exenatide on gastric emptying: A pilot pharmacogenetics study. Neurogastroenterol Motil. 2018;30(7):e13313. DOI:10.1111/nmo.13313
33. Yu M, Wang K, Liu H, Cao R. GLP1R variant is associated with response to exenatide in overweight Chinese Type 2 diabetes patients. Pharmacogenomics. 2019;20(4):273-7. DOI:10.2217/pgs-2018-0159
34. Ferreira MC, da Silva MER, Fukui RT, et al. Effect of TCF7L2 polymorphism on pancreatic hormones after exenatide in type 2 diabetes. Diabetol Metab Syndr. 2019;11:10. DOI:10.1186/s13098-019-0401-6
35. Zhou LM, Xu W, Yan XM, et al. Association between SORCS1 rs1416406 and therapeutic effect of exenatide. Zhonghua Yi XueZaZhi. 2017;97(18):1415-9 (in Chinese). DOI:10.3760/cma.j.issn.0376-2491.2017.18.013
36. Pereira MJ, Lundkvist P, Kamble PG, et al. A Randomized Controlled Trial of Dapagliflozin Plus Once-Weekly Exenatide Versus Placebo in Individuals with Obesity and Without Diabetes: Metabolic Effects and Markers Associated with Bodyweight Loss. Diabetes Ther. 2018;9(4):1511-32. DOI:10.1007/s13300-018-0449-6
37. De Luis DA, Diaz Soto G, Izaola O, Romero E. Evaluation of weight loss and metabolic changes in diabetic patients treated with liraglutide, effect of RS 6923761 gene variant of glucagon-like peptide 1 receptor. J Diabetes Complicat. 2015;29:595-8. DOI:10.1016/j.jdiacomp.2015.02.010
38. Jensterle M, Pirš B, Goričar K, et al. Genetic variability in GLP-1 receptor is associated with inter-individual differences in weight lowering potential of liraglutide in obese women with PCOS: a pilot study. Eur J Clin Pharmacol. 2015;71(7):817-24. DOI:10.1007/s00228-015-1868-1
39. Kyriakidou A, Kyriazou AV, Koufakis T, et al. Clinical and Genetic Predictors of Glycemic Control and Weight Loss Response to Liraglutide in Patients with Type 2 Diabetes. J Pers Med. 2022;12(3):424. DOI:10.3390/jpm12030424

Е.Л. Головина*1, И.Р. Гришкевич1, О.Е. Ваизова1, Ю.Г. Самойлова1, Д.В. Подчиненова1, М.В. Матвеева1, Д.А. Кудлай2,3

1 ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава России, Томск, Россия;
2 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия;
3 ФГБУ «Государственный научный центр “Институт иммунологии”» ФМБА России, Москва, Россия
*golovina.el@ssmu.ru

________________________________________________

Evgenya L. Golovina*1, Ivan R. Grishkevich1, Olga E. Vaizova1, Iuliia G. Samoilova1, Darja V. Podchinenova1, Mariia V. Matveeva1, Dmitry A. Kudlay2,3

1 Siberian State Medical University, Tomsk, Russia;
2 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia;
3 NRC Institute of Immunology FMBA of Russia, Moscow, Russia
*golovina.el@ssmu.ru