Цель – оценить влияние агонистов глюкагоноподобного пептида 1-го типа (аГПП-1) на ранние маркеры поражения почек у больных сахарным диабетом (СД) 1-го типа. Материалы и методы. В исследование включено 27 пациентов с СД 1-го типа с нормо- (n=16) и микроальбуминурией (n=11), находившихся на интенсифицированной инсулинотерапии аналогами человеческого инсулина. Пациенты распределены на две группы: 15 пациентов продолжили инсулинотерапию в режиме многократных инъекций на протяжении всего периода наблюдения, 12 пациентам к инсулинотерапии добавлен аГПП-1 (лираглутид) в дозе 1,2 мг 1 раз в сутки в течение 6 мес. До включения в исследование и в динамике через 6 мес у всех пациентов оценивались уровень HbA1c, показатели липидного обмена, классические маркеры поражения почек (альбуминурия, креатинин, скорость клубочковой фильтрации) и биомаркеры поражения почек в плазме (нейтрофильный желатиназо-ассоциированный липокалин – NGAL, молекула почечного повреждения 1-го типа – KIM-1, ци-статин С, остеопонтин) и в моче (нефрин, подоцин, уромодулин, NGAL, KIM-1, коллаген IV типа, цистатин С). Уровень биомаркеров оценивался методом иммуноферментного анализа (ELISA). Результаты. Результаты исследования показали, что в группе, получавшей инсулинотерапию в сочетании с аГПП-1, выявлено статистически значимое снижение экскреции коллагена IV типа, цистатина С, повышение экскреции уромодулина и уменьшение содержания в плазме крови остеопонтина, NGAL и цистатина С. Выводы. Изменение уровня высокочувствительных ренальных биомаркеров свидетельствует о возможном нефропротективном эффекте терапии аГПП-1 у пациентов с СД 1-го типа на ранней стадии поражения почек.
Ключевые слова: сахарный диабет 1-го типа, диабетическая болезнь почек, нефропротективная терапия, инкретины, агонисты рецепторов глюкагоноподобного пептида 1-го типа.
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The purpose of our study is to assess the effects of glucagon-like peptide-1 receptor agonists (GLP-1R agonists) on early markers of kidney damage in patients with type 1 diabetes mellitus (DM). Materials and methods. The study included 27 patients with type 1 diabetes with normo- (n=16) and microalbuminuria (n=11) on intensive insulin injection regimen with insulin analogs. Patients were divided into two groups: 15 patients continued insulin therapy throughout the follow-up period, 12 patients were given 1.2 mg GLP-1R agonist (Liraglutide) once a day in addition to the insulin therapy for
6 months. HbA1c, lipid profile, classic markers of kidney damage (albuminuria, creatinine, glomerular filtration rate); plazma (neutrophilic gelatinase-associated lipoxalin – NGAL, molecule renal damage of type 1 – KIM-1, cystatin C, osteopontin) and urinary kidney biomarkers (nephrin, podocyne, uromodulin, NGAL, KIM-1, collagen type IV, cystatin C) were evaluated prior and in dynamics at 6 months. Kidney biomarkers levels were assessed by the enzyme-linked immunosorbent assay (ELISA). Results. We observed a significant decrease in the urinary excretion of type IV collagen, cystatin C, increased uromodulin excretion and decrease in the plasma levels of osteopontin, NGAL and cystatin C in the group of combined insulin and GLP-1R agonist therapy. Conclusions. Changes in the level of sensitive kidney biomarkers indicate a possible renoprotective effect of GLP-1R agonist therapy in patients with type 1 diabetes at an early stages of kidney damage.
Key words: type 1 diabetes mellitus, diabetic kidney disease, nephroprotective therapy, incretins, glucagon-like peptide type 1 receptor agonists.
Список литературы
1. IDF. IDF Diabetes Atlas; 2018. https://doi:10.1289/image.ehp.v119.i03
2. Дедов И.И., Шестакова М.В., Викулова О.К. Эпидемиология сахарного диабета в Российской Федерации: клинико-статистический анализ по данным Федерального регистра сахарного диабета. Сахарный диабет. 2017;20(1):13-41 [Dedov II, Shestakova MV, Vikulova OK. Epidemiology of diabetes mellitus in Russian Federation: Clinical and statistical report according to the federal diabetes registry. Sakharnyy Diabet = Diabetes Mellit. 2017;20(1):13-41 (In Russ.)].
doi: 10.14341/DM8664
3. Alicic RZ, Rooney MT, Tuttle KR. Diabetic Kidney Disease: Challenges, Progress, and Possibilities. Clin J Am Soc Nephrol. 2017;7;12(12):2032-45. doi: 10.2215/CJN.11491116
4. Salvador J, Andrada P. Extrapancreatic effects of GLP-1 receptor agonists: an open window towards new treatment goals in type 2 diabetes. Med Clin (Barc). 2014;143 Suppl 2:28-34. doi: 10.1016/S0025-7753(14)70106-X
5. Websky K, Reichetzeder C, Hocher B. Physiology and pathophysiology of incretins in the kidney. Curr Opin Nephrol Hypertens. 2014;23(1):54-60. doi: 10.1097/01.mnh.0000437542.77175.a
6. Шестакова М.В., Викулова О.К. Инновации в диагностике и лечении сахарного диабета 2 типа. Врач. 2012;(8):2-6 [Shestakova MV, Vikulova OK. Innovations in the diagnosis and treatment of type 2 diabetes mellitus. Vrach. 2012;(8):2-6 (In Russ.)].
7. Лебедева Н.О., Викулова О.К. Маркеры доклинической диагностики диабетической нефропатии у пациентов с сахарным диабетом
1 типа. Сахарный диабет. 2012;(2):38-45. [Lebedeva NO, Vikulo-
va OK. Pre-clinical markers for diagnosis of diabetic nephropathy in patients with type 1 diabetes mellitus. Sakharnyy Diabet = Diabetes Mellit. 2012;(2):38-45 (In Russ.)]. doi: 10.14341/2072-0351-5517
8. Gemma C, Gerard M, Christian D. Biomarkers in diabetic nephropathy: Present and future. World J Diabetes. 2014;15;5(6):763-76.
doi: 10.4239/wjd.v5.i6.763
9. Hocher B, Reichetzeder C, Alter ML. Renal and cardiac effects of DPP-4 inhibitors – from preclinical development to clinical research. Kidney Blood Press Res. 2012;36(1):65-84. doi: 10.1159/000339028
10. Hendarto H, Inoguchi T, Maeda Y, et al. GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metabolism. 2012;61(10):1422-34.
doi: 10.1016/j.metabol.2012.03.002
11. Chang JT, Liang YJ, Hsu CY, Chen CY, Chen PJ, Yang YF, Chen YL, Pei D, Chang JB, Leu JG. Glucagon-like peptide receptor agonists attenuate advanced glycation end products-induced inflammation in rat mesangial cells. BMC Pharmacol Toxicol. 2017;24;18(1):67.
doi: 10.1186/s40360-017-0172-3
12. Mima A, Hiraoka-Yamomoto J, Li Q, et al. Protective Effects of GLP-1 on Glomerular Endothelium and Its Inhibition by PKC b Activation in Diabetes. Diabetes. 2012;61(11):2967-79. doi:10.2337/db11-1824
13. Zhang H, Zhang X, Hu C, Lu W. Exenatide Reduces Urinary Transforming Growth Factor-ß1 and Type IV Collagen Excretion in Patients with Type 2 Diabetes and Microalbuminuria. Kidney Blood Press Res. 2012;35(6):483-8. doi: 10.1159/000337929
14. Ishibashi Y, Nishino Y, Matsui T, Takeuchi M, Yamagishi SI. Glucagon-like peptide-1 suppresses advanced glycation end product-induced monocyte chemoattractant protein-1 expression in mesangial cells by reducing advanced glycation end product receptor level. Metabolism. 2011;60(9):1271-7. doi: 10.1016/j.metabol.2011.01.010
15. Zeni L, Norden AGW, Cancarini G, Unwin RJ. A more tubulocentric view of diabetic kidney disease. J Nephrol. 2017;30(6):701-17.
doi: 10.1007/s40620-017-0423-9
16. Lou NJ, Ni YH, Jia HY, Deng JT, Jiang L, Zheng FJ, Sun AL. Urinary Microvesicle-Bound Uromodulin: A Potential Molecular Biomarker in Diabetic. Kidney Dis. 2017;2017:3918681. doi: 10.1155/2017/ 3918681
16. Zobel EH, von Scholten BJ, Lindhardt M, Persson F, Hansen TW, Rossing P. Pleiotropic effects of liraglutide treatment on renal risk factors in type 2 diabetes: Individual effects of treatment. J Diabetes Complications. 2017;31(1):162-8. doi: 10.1016/j.jdiacomp.2016. 09.016
17. Mundel P. Podocytes and the quest for precision medicines for kidney diseases. Pflugers Arch. 2017;469(7-8):1029-37. doi: 10.1007/s00424-017-2015-x
18. Gordin D, Forsblom C, Panduru NM, Thomas MC, Bjerre M, Soro-Paavonen A, Tolonen N, Sandholm N, Flyvbjerg A, Harjutsalo V, Groop PH; FinnDiane Study Group. Osteopontin is a strong predictor of incipient diabetic nephropathy, cardio-vascular disease, and all-cause mortality in patients with type 1 diabetes. Diabetes Care. 2014;37(9):2593-600. doi: 10.2337/dc14-0065
19. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-22. doi: 10.1056/NEJMoa1603827
________________________________________________
1. IDF. IDF Diabetes Atlas; 2018. https://doi:10.1289/image.ehp.v119.i03
2. [Dedov II, Shestakova MV, Vikulova OK. Epidemiology of diabetes mellitus in Russian Federation: Clinical and statistical report according to the federal diabetes registry. Sakharnyy Diabet = Diabetes Mellit. 2017;20(1):13-41 (In Russ.)].
doi: 10.14341/DM8664
3. Alicic RZ, Rooney MT, Tuttle KR. Diabetic Kidney Disease: Challenges, Progress, and Possibilities. Clin J Am Soc Nephrol. 2017;7;12(12):2032-45. doi: 10.2215/CJN.11491116
4. Salvador J, Andrada P. Extrapancreatic effects of GLP-1 receptor agonists: an open window towards new treatment goals in type 2 diabetes. Med Clin (Barc). 2014;143 Suppl 2:28-34. doi: 10.1016/S0025-7753(14)70106-X
5. Websky K, Reichetzeder C, Hocher B. Physiology and pathophysiology of incretins in the kidney. Curr Opin Nephrol Hypertens. 2014;23(1):54-60. doi: 10.1097/01.mnh.0000437542.77175.a
6. [Shestakova MV, Vikulova OK. Innovations in the diagnosis and treatment of type 2 diabetes mellitus. Vrach. 2012;(8):2-6 (In Russ.)].
7. [Lebedeva NO, Vikulova OK. Pre-clinical markers for diagnosis of diabetic nephropathy in patients with type 1 diabetes mellitus. Sakharnyy Diabet = Diabetes Mellit. 2012;(2):38-45 (In Russ.)]. doi: 10.14341/2072-0351-5517
8. Gemma C, Gerard M, Christian D. Biomarkers in diabetic nephropathy: Present and future. World J Diabetes. 2014;15;5(6):763-76.
doi: 10.4239/wjd.v5.i6.763
9. Hocher B, Reichetzeder C, Alter ML. Renal and cardiac effects of DPP-4 inhibitors – from preclinical development to clinical research. Kidney Blood Press Res. 2012;36(1):65-84. doi: 10.1159/000339028
10. Hendarto H, Inoguchi T, Maeda Y, et al. GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metabolism. 2012;61(10):1422-34.
doi: 10.1016/j.metabol.2012.03.002
11. Chang JT, Liang YJ, Hsu CY, Chen CY, Chen PJ, Yang YF, Chen YL, Pei D, Chang JB, Leu JG. Glucagon-like peptide receptor agonists attenuate advanced glycation end products-induced inflammation in rat mesangial cells. BMC Pharmacol Toxicol. 2017;24;18(1):67.
doi: 10.1186/s40360-017-0172-3
12. Mima A, Hiraoka-Yamomoto J, Li Q, et al. Protective Effects of GLP-1 on Glomerular Endothelium and Its Inhibition by PKC b Activation in Diabetes. Diabetes. 2012;61(11):2967-79. doi:10.2337/db11-1824
13. Zhang H, Zhang X, Hu C, Lu W. Exenatide Reduces Urinary Transforming Growth Factor-ß1 and Type IV Collagen Excretion in Patients with Type 2 Diabetes and Microalbuminuria. Kidney Blood Press Res. 2012;35(6):483-8. doi: 10.1159/000337929
14. Ishibashi Y, Nishino Y, Matsui T, Takeuchi M, Yamagishi SI. Glucagon-like peptide-1 suppresses advanced glycation end product-induced monocyte chemoattractant protein-1 expression in mesangial cells by reducing advanced glycation end product receptor level. Metabolism. 2011;60(9):1271-7. doi: 10.1016/j.metabol.2011.01.010
15. Zeni L, Norden AGW, Cancarini G, Unwin RJ. A more tubulocentric view of diabetic kidney disease. J Nephrol. 2017;30(6):701-17.
doi: 10.1007/s40620-017-0423-9
16. Lou NJ, Ni YH, Jia HY, Deng JT, Jiang L, Zheng FJ, Sun AL. Urinary Microvesicle-Bound Uromodulin: A Potential Molecular Biomarker in Diabetic. Kidney Dis. 2017;2017:3918681. doi: 10.1155/2017/ 3918681
16. Zobel EH, von Scholten BJ, Lindhardt M, Persson F, Hansen TW, Rossing P. Pleiotropic effects of liraglutide treatment on renal risk factors in type 2 diabetes: Individual effects of treatment. J Diabetes Complications. 2017;31(1):162-8. doi: 10.1016/j.jdiacomp.2016. 09.016
17. Mundel P. Podocytes and the quest for precision medicines for kidney diseases. Pflugers Arch. 2017;469(7-8):1029-37. doi: 10.1007/s00424-017-2015-x
18. Gordin D, Forsblom C, Panduru NM, Thomas MC, Bjerre M, Soro-Paavonen A, Tolonen N, Sandholm N, Flyvbjerg A, Harjutsalo V, Groop PH; FinnDiane Study Group. Osteopontin is a strong predictor of incipient diabetic nephropathy, cardio-vascular disease, and all-cause mortality in patients with type 1 diabetes. Diabetes Care. 2014;37(9):2593-600. doi: 10.2337/dc14-0065
19. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-22. doi: 10.1056/NEJMoa1603827