diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM12859diaendo-12859Research ArticleОбзорыReviewРоль пиоглитазона в борьбе с инсулинорезистентностью, атеросклерозом, сердечно-сосудистыми заболеваниями и неалкогольной жировой болезнью печениThe role of pioglitazone in the fight against insulin resistance, atherosclerosis, cardiovascular disease, and non-alcoholic fatty liver diseasehttps://orcid.org/0000-0001-9390-1200ПетунинаН. А.PetuninaN. A.

Петунина Нина Александровна - доктор медицинских наук, профессор, член-корр. РАН; eLibrary SPIN: 9784-3616.

119991, Москва, ул. Трубецкая, д. 8, стр. 2

Nina A. Petunina - MD, PhD, Professor; eLibrary SPIN: 9784-3616

8/2 Trubetskaya, 119991 Moscow

napetunina@mail.ruhttps://orcid.org/0000-0001-7025-8427ГончароваЕ. В.GoncharovaE. V.

Гончарова Екатерина Валерьевна - кандидат медицинских наук, доцент; eLibrary SPIN: 7148-4669.

Москва

Ekaterina V. Goncharova - MD, PhD, associate professor; eLibrary SPIN: 7148-4669.

Moscow

goncharova_ev@list.ruhttps://orcid.org/0000-0001-7923-4894КузинаИ. А.KuzinaI. A.

Кузина Ирина Александровна – ассистент; eLibrary SPIN: 9008-5886.

Москва

Irina A. Kuzina - MD, assistant; eLibrary SPIN: 9008-5886.

Moscow

mia986@mail.ruhttps://orcid.org/0000-0002-6823-2487НедосуговаЛ. В.NedosugovaL. V.

Недосугова Людмила Викторовна - доктор медицинских наук, профессор; eLibrary SPIN: 1853-0215.

Москва

Ludmila V. Nedosugova - MD, PhD, professor; eLibrary SPIN: 1853-0215.

Moscow

profmila@mail.ruhttps://orcid.org/0000-0002-0202-1257МартиросянН. С.MartirosyanN. S.

Мартиросян Нарине Степановна - кандидат медицинских наук, доцент; eLibrary SPIN: 1893-8030.

Москва

Narine S. Martirosyan - MD, PhD, associate professor; eLibrary SPIN: 1893-8030.

Moscow

narinarine@mail.ruhttps://orcid.org/0000-0001-8007-9721ТельноваМ. Э.ТеlnovaM. Е.

Тельнова Милена Эдуардовна - кандидат медицинских наук, доцент; eLibrary SPIN: 1007-4617.

Москва

Milena Е. Теlnova - MD, PhD, associate professor; eLibrary SPIN: 1007-4617.

Moscow

milena.telnova@mail.ruПервый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет)РоссияI.M. Sechenov First Moscow State Medical University (Sechenov University)Russian Federation202230112022255504513Copyright © Петунина Н.А., Гончарова Е.В., Кузина И.А., Недосугова Л.В., Мартиросян Н.С., Тельнова М.Э., 20222022Петунина Н.А., Гончарова Е.В., Кузина И.А., Недосугова Л.В., Мартиросян Н.С., Тельнова М.Э.Petunina N.A., Goncharova E.V., Kuzina I.A., Nedosugova L.V., Martirosyan N.S., Теlnova M.Е.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/12859

Современные стратегии терапии сахарного диабета 2 типа (СД2) предполагают использование патогенетически обоснованных подходов, направленных на достижение оптимального гликемического контроля и его долгосрочное удержание. Своевременное и рациональное применение 9 классов сахароснижающих препаратов, в том числе в составе комбинированной терапии, позволяет добиваться значимых успехов в терапии диабета. Одним из основополагающих принципов лечения СД2 является влияние на инсулинорезистентность. С этой целью используются две группы препаратов: бигуаниды и тиазолидиндионы (глитазоны). Действие глитазонов напрямую связано с повышением чувствительности инсулинозависимых тканей к инсулину и выраженным снижением гиперинсулинемии у пациентов с СД2. Особый интерес представляют пути передачи инсулинового сигнала, механизмы инсулинорезистентности и возможности патогенетической терапии тиазолидиндионами. Пиоглитазон в настоящее время во всем мире является единственным доступным представителем класса тиазолидиндионов, позволяя расширить возможности управления СД через снижение инсулинорезистентности мышечной и жировой ткани и продукции глюкозы печенью. Его применение способно оказывать ряд плейотропных эффектов, в том числе на сердечно-сосудистые заболевания и неалкогольную жировую болезнь печени, что расширяет приоритеты выбора сахароснижающей терапии у пациентов с СД2 на различных этапах терапии.

Modern strategies for the treatment of type 2 diabetes mellitus involve the use of pathogenetically based approaches aimed at achieving optimal glycemic control and its long-term retention. Timely and rational use of 9 classes of hypoglycemic drugs, including as part of combination therapy, makes it possible to achieve significant success in diabetes therapy. One of the fundamental principles in the treatment of type 2 diabetes mellitus is the effect on insulin resistance. For this purpose, two groups of drugs are used: biguanides and thiazolidinediones (glitazones). The action of glitazones is directly related to an increase in the sensitivity of insulin-dependent tissues to insulin and a pronounced decrease in hyperinsulinemia in patients with type 2 diabetes. Of particular interest are the pathways of insulin signal transduction, the mechanisms of insulin resistance, and the possibilities of pathogenetic therapy with thiazolidinediones. Pioglitazone is currently the only available member of the thiazolidinedione class in the world, allowing to expand the management of diabetes mellitus by reducing insulin resistance in muscle and adipose tissue and glucose production by the liver. Its use can have a number of pleiotropic effects, including on cardiovascular diseases and non-alcoholic fatty liver disease, which expands the priorities for choosing hypoglycemic therapy in patients with type 2 diabetes at various stages of therapy.

тиазолидиндионыглитазоныпиоглитазонинсулинорезистентностьпути передачи инсулинового сигналаthiazolidinedionesglitazonespioglitazoneinsulin resistanceinsulin signal transmission pathwaysРабота выполнена за счет бюджетного финансирования по месту работы авторовReferencesBanting FG, Best CH, Collip JB, et al. Pancreatic Extracts in the Treatment of Diabetes Mellitus. Can Med Assoc J. 1922;12(3):141-146.Banting FG, Best CH, Collip JB, et al. Pancreatic Extracts in the Treatment of Diabetes Mellitus. Can Med Assoc J. 1922;12(3):141-146.Sanger F. Chemistry of insulin; determination of the structure of insulin opens the way to greater understanding of life processes. Science. 1959;129(3359):1340-1344. doi: https://doi.org/10.1126/science.129.3359.1340Sanger F. Chemistry of insulin; determination of the structure of insulin opens the way to greater understanding of life processes. Science. 1959;129(3359):1340-1344. doi: https://doi.org/10.1126/science.129.3359.1340Freychet P, Roth J, Neville DM Jr. Insulin receptors in the liver: specific binding of (125 I) insulin to the plasma membrane and its relation to insulin bioactivity. Proc Natl Acad Sci U S A. 1971;68(8):1833-1837. doi: https://doi.org/10.1073/pnas.68.8.1833Freychet P, Roth J, Neville DM Jr. Insulin receptors in the liver: specific binding of (125 I) insulin to the plasma membrane and its relation to insulin bioactivity. Proc Natl Acad Sci U S A. 1971;68(8):1833-1837. doi: https://doi.org/10.1073/pnas.68.8.1833Cuatrecasas P. Insulin-Receptor Interactions in Adipose Tissue Cells: Direct Measurement and Properties. Proc Natl Acad Sci. 1971;68(6):1264-1268. doi: https://doi.org/10.1073/pnas.68.6.1264Cuatrecasas P. Insulin-Receptor Interactions in Adipose Tissue Cells: Direct Measurement and Properties. Proc Natl Acad Sci. 1971;68(6):1264-1268. doi: https://doi.org/10.1073/pnas.68.6.1264Ebina Y, Ellis L, Jarnagin K, et al. The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell. 1985;40(4):747-758. doi: https://doi.org/10.1016/0092-8674(85)90334-4Ebina Y, Ellis L, Jarnagin K, et al. The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell. 1985;40(4):747-758. doi: https://doi.org/10.1016/0092-8674(85)90334-4Ullrich A, Bell JR, Chen EY, et al. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature. 1985;313(6005):756-761. doi: https://doi.org/10.1038/313756a0Ullrich A, Bell JR, Chen EY, et al. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature. 1985;313(6005):756-761. doi: https://doi.org/10.1038/313756a0Kasuga M. Structure and function of the insulin receptor-a personal perspective. Proc Jpn Acad Ser B Phys Biol Sci. 2019;95(10):581-589. doi: https://doi.org/10.2183/pjab.95.039Kasuga M. Structure and function of the insulin receptor-a personal perspective. Proc Jpn Acad Ser B Phys Biol Sci. 2019;95(10):581-589. doi: https://doi.org/10.2183/pjab.95.039Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014;6(1):a009191-a009191. doi: https://doi.org/10.1101/cshperspect.a009191Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014;6(1):a009191-a009191. doi: https://doi.org/10.1101/cshperspect.a009191Sun X.J., Rothenberg P., Kahn C.R., et al.. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991;352(6330):73-77. doi: https://doi.org/10.1038/352073a0Sun X.J., Rothenberg P., Kahn C.R., et al.. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991;352(6330):73-77. doi: https://doi.org/10.1038/352073a0Haeusler RA, McGraw TE, Accili D. Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol. 2018;19(1):31-44. doi: https://doi.org/10.1038/nrm.2017.89Haeusler RA, McGraw TE, Accili D. Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol. 2018;19(1):31-44. doi: https://doi.org/10.1038/nrm.2017.89Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev. 2018;98(4):2133-2223. doi: https://doi.org/10.1152/physrev.00063.2017Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev. 2018;98(4):2133-2223. doi: https://doi.org/10.1152/physrev.00063.2017Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-419. doi: https://doi.org/10.1007/BF00280883Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-419. doi: https://doi.org/10.1007/BF00280883Гончарова Е.В., Петунина Н.А., Бокерия О.Л., Архипкин А.А. Метаболический синдром и метаболически здоровое ожирение у молодых мужчин // Consilium Medicum. — 2016. — Т. 18. — №8. — С. 64-67. doi: https://doi.org/10.26442/2075-1753_2016.8.64-67Goncharova EV, Petunina NA, Bokeriia OL, Arkhipkin AA. Metabolic syndrome and metabolically healthy obesity in young men. Consilium Medicum. 2016;18(8):64-67. (In Russ.). doi: https://doi.org/10.26442/2075-1753_2016.8.64-67Tang Q, Li X, Song P, Xu L. Optimal cut-off values for the homeostasis model assessment of insulin resistance (HOMA-IR) and pre-diabetes screening: Developments in research and prospects for the future. Drug Discov Ther. 2015;9(6):380-385. doi: https://doi.org/10.5582/ddt.2015.01207Tang Q, Li X, Song P, Xu L. Optimal cut-off values for the homeostasis model assessment of insulin resistance (HOMA-IR) and pre-diabetes screening: Developments in research and prospects for the future. Drug Discov Ther. 2015;9(6):380-385. doi: https://doi.org/10.5582/ddt.2015.01207Kolterman OG, Gray RS, Griffin J, et al. Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Invest. 1981;68(4):957-969. doi: https://doi.org/10.1172/JCI110350Kolterman OG, Gray RS, Griffin J, et al. Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Invest. 1981;68(4):957-969. doi: https://doi.org/10.1172/JCI110350Olefsky JM, Kolterman OG, Scarlett JA. Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus. Am J Physiol Metab. 1982;243(1):E15-E30. doi: https://doi.org/10.1152/ajpendo.1982.243.1.E15Olefsky JM, Kolterman OG, Scarlett JA. Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus. Am J Physiol Metab. 1982;243(1):E15-E30. doi: https://doi.org/10.1152/ajpendo.1982.243.1.E15Fazakerley DJ, Krycer JR, Kearney AL, et al. Muscle and adipose tissue insulin resistance: malady without mechanism? J Lipid Res. 2019;60(10):1720-1732. doi: https://doi.org/10.1194/jlr.R087510Fazakerley DJ, Krycer JR, Kearney AL, et al. Muscle and adipose tissue insulin resistance: malady without mechanism? J Lipid Res. 2019;60(10):1720-1732. doi: https://doi.org/10.1194/jlr.R087510Cusi K, Maezono K, Osman A, et al. Insulin resistance differentially affects the PI 3-kinase– and MAP kinase–mediated signaling in human muscle. J Clin Invest. 2000;105(3):311-320. doi: https://doi.org/10.1172/JCI7535Cusi K, Maezono K, Osman A, et al. Insulin resistance differentially affects the PI 3-kinase– and MAP kinase–mediated signaling in human muscle. J Clin Invest. 2000;105(3):311-320. doi: https://doi.org/10.1172/JCI7535Melvin A, O’Rahilly S, Savage D. Genetic syndromes of severe insulin resistance. Curr Opin Genet Dev. 2018;50(3):60-67. doi: https://doi.org/10.1016/j.gde.2018.02.002Melvin A, O’Rahilly S, Savage D. Genetic syndromes of severe insulin resistance. Curr Opin Genet Dev. 2018;50(3):60-67. doi: https://doi.org/10.1016/j.gde.2018.02.002Koo SH, Flechner L, Qi L, et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature. 2005;437(7062):1109-1111. doi: https://doi.org/10.1038/nature03967Koo SH, Flechner L, Qi L, et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature. 2005;437(7062):1109-1111. doi: https://doi.org/10.1038/nature03967Brown MS, Goldstein JL. Selective versus Total Insulin Resistance: A Pathogenic Paradox. Cell Metab. 2008;7(2):95-96. doi: https://doi.org/10.1016/j.cmet.2007.12.009Brown MS, Goldstein JL. Selective versus Total Insulin Resistance: A Pathogenic Paradox. Cell Metab. 2008;7(2):95-96. doi: https://doi.org/10.1016/j.cmet.2007.12.009Shimomura I, Matsuda M, Hammer RE, et al. Decreased IRS-2 and Increased SREBP-1c Lead to Mixed Insulin Resistance and Sensitivity in Livers of Lipodystrophic and ob/ob Mice. Mol Cell. 2000;6(1):77-86. doi: https://doi.org/10.1016/S1097-2765(05)00010-9Shimomura I, Matsuda M, Hammer RE, et al. Decreased IRS-2 and Increased SREBP-1c Lead to Mixed Insulin Resistance and Sensitivity in Livers of Lipodystrophic and ob/ob Mice. Mol Cell. 2000;6(1):77-86. doi: https://doi.org/10.1016/S1097-2765(05)00010-9Bi P, Kuang S. Notch signaling as a novel regulator of metabolism. Trends Endocrinol Metab. 2015;26(5):248-255. doi: https://doi.org/10.1016/j.tem.2015.02.006Bi P, Kuang S. Notch signaling as a novel regulator of metabolism. Trends Endocrinol Metab. 2015;26(5):248-255. doi: https://doi.org/10.1016/j.tem.2015.02.006Pajvani UB, Shawber CJ, Samuel VT, et al. Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nat Med. 2011;17(8):961-967. doi: https://doi.org/10.1038/nm.2378Pajvani UB, Shawber CJ, Samuel VT, et al. Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nat Med. 2011;17(8):961-967. doi: https://doi.org/10.1038/nm.2378Pajvani UB, Qiang L, Kangsamaksin T, et al. Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. Nat Med. 2013;19(8):1054-1060. doi: https://doi.org/10.1038/nm.3259Pajvani UB, Qiang L, Kangsamaksin T, et al. Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. Nat Med. 2013;19(8):1054-1060. doi: https://doi.org/10.1038/nm.3259Sohda T, Mizuno K, Imamiya E, et al. Studies on antidiabetic agents. II. Synthesis of 5-[4-(1-methylcyclohexylmethoxy)-benzyl]thiazolidine-2,4-dione (ADD-3878) and its derivatives. Chem Pharm Bull (Tokyo). 1982;30(10):3580-3600. doi: https://doi.org/10.1248/cpb.30.3580Sohda T, Mizuno K, Imamiya E, et al. Studies on antidiabetic agents. II. Synthesis of 5-[4-(1-methylcyclohexylmethoxy)-benzyl]thiazolidine-2,4-dione (ADD-3878) and its derivatives. Chem Pharm Bull (Tokyo). 1982;30(10):3580-3600. doi: https://doi.org/ 10.1248/cpb.30.3580Fujita T, Sugiyama Y, Taketomi S, et al. Reduction of insulin resistance in obese and/or diabetic animals by 5-[4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63,287, ciglitazone), a new antidiabetic agent. Diabetes. 1983;32(9):804-810. doi: https://doi.org/10.2337/diab.32.9.804Fujita T, Sugiyama Y, Taketomi S, et al. Reduction of insulin resistance in obese and/or diabetic animals by 5-[4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63,287, ciglitazone), a new antidiabetic agent. Diabetes. 1983;32(9):804-810. doi: https://doi.org/10.2337/diab.32.9.804Fujiwara T, Yoshioka S, Yoshioka T, et al. Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes. 1988;37(11):1549-1558. doi: https://doi.org/10.2337/diab.37.11.1549Fujiwara T, Yoshioka S, Yoshioka T, et al. Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes. 1988;37(11):1549-1558. doi: https://doi.org/10.2337/diab.37.11.1549Sohda T, Momose Y, Meguro K, et al. Studies on antidiabetic agents. Synthesis and hypoglycemic activity of 5-[4-(pyridylalkoxy)benzyl]-2,4-thiazolidinediones. Arzneimittelforschung. 1990;40(1):37-42.Sohda T, Momose Y, Meguro K, et al. Studies on antidiabetic agents. Synthesis and hypoglycemic activity of 5-[4-(pyridylalkoxy)benzyl]-2,4-thiazolidinediones. Arzneimittelforschung. 1990;40(1):37-42.Lebovitz HE. Insulin resistance and its treatment by thiazolidinediones. Recent Prog Horm Res. 2001;56(1):265-294. doi: https://doi.org/10.1210/rp.56.1.265Lebovitz HE. Insulin resistance and its treatment by thiazolidinediones. Recent Prog Horm Res. 2001;56(1):265-294. doi: https://doi.org/10.1210/rp.56.1.265Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARγ. Annu Rev Biochem. 2008;77(1):289-312. doi: https://doi.org/10.1146/annurev.biochem.77.061307.091829Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARγ. Annu Rev Biochem. 2008;77(1):289-312. doi: https://doi.org/10.1146/annurev.biochem.77.061307.091829Olefsky J, Saltiel A. PPARγ and the treatment of insulin resistance. Trends Endocrinol Metab. 2000;11(9):362-368. doi: https://doi.org/10.1016/S1043-2760(00)00306-4Olefsky J, Saltiel A. PPARγ and the treatment of insulin resistance. Trends Endocrinol Metab. 2000;11(9):362-368. doi: https://doi.org/10.1016/S1043-2760(00)00306-4Chan LSA, Wells RA. Cross-Talk between PPARs and the Partners of RXR: A Molecular Perspective. PPAR Res. 2009;2009(9):1-9. doi: https://doi.org/10.1155/2009/925309Chan LSA, Wells RA. Cross-Talk between PPARs and the Partners of RXR: A Molecular Perspective. PPAR Res. 2009;2009(9):1-9. doi: https://doi.org/10.1155/2009/925309Tan CK, Zhuang Y, Wahli W. Synthetic and natural Peroxisome Proliferator-Activated Receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome. Expert Opin Ther Targets. 2017;21(3):333-348. doi: https://doi.org/10.1080/14728222.2017.1280467Tan CK, Zhuang Y, Wahli W. Synthetic and natural Peroxisome Proliferator-Activated Receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome. Expert Opin Ther Targets. 2017;21(3):333-348. doi: https://doi.org/10.1080/14728222.2017.1280467Usuda D, Kanda T. Peroxisome proliferator-activated receptors for hypertension. World J Cardiol. 2014;6(8):744-754. doi: https://doi.org/10.4330/wjc.v6.i8.744Usuda D, Kanda T. Peroxisome proliferator-activated receptors for hypertension. World J Cardiol. 2014;6(8):744-754. doi: https://doi.org/10.4330/wjc.v6.i8.744Azhar S. Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease. Future Cardiol. 2010;6(5):657-691. doi: https://doi.org/10.2217/fca.10.86Azhar S. Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease. Future Cardiol. 2010;6(5):657-691. doi: https://doi.org/10.2217/fca.10.86Ahmadian M, Suh JM, Hah N, et al. PPARgamma signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19(5):557-566. doi: https://doi.org/10.1038/nm.3159Ahmadian M, Suh JM, Hah N, et al. PPARgamma signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19(5):557-566. doi: https://doi.org/10.1038/nm.3159Ptasinska A, Wang S, Zhang J, et al. Nitric oxide activation of peroxisome proliferator-activated receptor gamma through a p38 MAPK signaling pathway. FASEB J. 2007;21(3):950-961. doi: https://doi.org/10.1096/fj.06-6822comPtasinska A, Wang S, Zhang J, et al. Nitric oxide activation of peroxisome proliferator-activated receptor gamma through a p38 MAPK signaling pathway. FASEB J. 2007;21(3):950-961. doi: https://doi.org/10.1096/fj.06-6822comKliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ. Proc Natl Acad Sci. 1997;94(9):4318-4323. doi: https://doi.org/10.1073/pnas.94.9.4318Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ. Proc Natl Acad Sci. 1997;94(9):4318-4323. doi: https://doi.org/10.1073/pnas.94.9.4318Zhang C, Zhang Y, Zhang C, et al. Pioglitazone increases VEGFR3 expression and promotes activation of M2 macrophages via the peroxisome proliferator-activated receptor γ. Mol Med Rep. 2019;19(4):2740-2748. doi: https://doi.org/10.3892/mmr.2019.9945Zhang C, Zhang Y, Zhang C, et al. Pioglitazone increases VEGFR3 expression and promotes activation of M2 macrophages via the peroxisome proliferator-activated receptor γ. Mol Med Rep. 2019;19(4):2740-2748. doi: https://doi.org/10.3892/mmr.2019.9945Buchanan TA, Xiang AH, Peters RK, et al. Preservation of Pancreatic β-Cell Function and Prevention of Type 2 Diabetes by Pharmacological Treatment of Insulin Resistance in High-Risk Hispanic Women. Diabetes. 2002;51(9):2796-2803. doi: https://doi.org/10.2337/diabetes.51.9.2796Buchanan TA, Xiang AH, Peters RK, et al. Preservation of Pancreatic β-Cell Function and Prevention of Type 2 Diabetes by Pharmacological Treatment of Insulin Resistance in High-Risk Hispanic Women. Diabetes. 2002;51(9):2796-2803. doi: https://doi.org/10.2337/diabetes.51.9.2796Xiang AH, Peters RK, Kjos SL, et al. Effect of pioglitazone on pancreatic β-cell function and diabetes risk in hispanic women with prior gestational diabetes. Diabetes. 2006;55(2):517-522. doi: https://doi.org/10.2337/diabetes.55.02.06.db05-1066Xiang AH, Peters RK, Kjos SL, et al. Effect of pioglitazone on pancreatic β-cell function and diabetes risk in hispanic women with prior gestational diabetes. Diabetes. 2006;55(2):517-522. doi: https://doi.org/10.2337/diabetes.55.02.06.db05-1066Dormandy JA, Betteridge DJ, Schernthaner G, et al. Impact of peripheral arterial disease in patients with diabetes — results from PROactive (PROactive 11). Atherosclerosis. 2009;202(1):272-281. doi: https://doi.org/10.1016/j.atherosclerosis.2008.03.002Dormandy JA, Betteridge DJ, Schernthaner G, et al. Impact of peripheral arterial disease in patients with diabetes — results from PROactive (PROactive 11). Atherosclerosis. 2009;202(1):272-281. doi: https://doi.org/10.1016/j.atherosclerosis.2008.03.002Erdmann E, Dormandy JA, Charbonnel B, et al. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction. J Am Coll Cardiol. 2007;49(17):1772-1780. doi: https://doi.org/10.1016/j.jacc.2006.12.048Erdmann E, Dormandy JA, Charbonnel B, et al. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction. J Am Coll Cardiol. 2007;49(17):1772-1780. doi: https://doi.org/10.1016/j.jacc.2006.12.048Wilcox R, Bousser M-G, Betteridge DJ, et al. PROspective pioglitazone clinical trial in macrovascular events 04). Stroke. 2007;38(3):865-873. doi: https://doi.org/10.1161/01.STR.0000257974.06317.49Wilcox R, Bousser M-G, Betteridge DJ, et al. PROspective pioglitazone clinical trial in macrovascular events 04). Stroke. 2007;38(3):865-873. doi: https://doi.org/10.1161/01.STR.0000257974.06317.49de Jong M, van der Worp HB, van der Graaf Y, et al. Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials. Cardiovasc Diabetol. 2017;16(1):134. doi: https://doi.org/10.1186/s12933-017-0617-4de Jong M, van der Worp HB, van der Graaf Y, et al. Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials. Cardiovasc Diabetol. 2017;16(1):134. doi: https://doi.org/10.1186/s12933-017-0617-4DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53(7):1270-1287. doi: https://doi.org/10.1007/s00125-010-1684-1DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53(7):1270-1287. doi: https://doi.org/10.1007/s00125-010-1684-1Inzucchi SE, Furie KL. The IRIS (Insulin Resistance Intervention after Stroke) trial: A new perspective on pioglitazone. J Diabetes. 2016 Sep;8(5):607-9. doi: 10.1111/1753-0407.12399. Epub 2016 Jun 8. PMID: 27125599.Inzucchi SE, Furie KL. The IRIS (Insulin Resistance Intervention after Stroke) trial: A new perspective on pioglitazone. J Diabetes. 2016 Sep;8(5):607-9. doi: 10.1111/1753-0407.12399. Epub 2016 Jun 8. PMID: 27125599.Yaghi S, Furie KL, Viscoli CM, et al. Pioglitazone prevents stroke in patients with a recent transient ischemic attack or ischemic stroke. Circulation. 2018;137(5):455-463. doi: https://doi.org/10.1161/CIRCULATIONAHA.117.030458Yaghi S, Furie KL, Viscoli CM, et al. Pioglitazone prevents stroke in patients with a recent transient ischemic attack or ischemic stroke. Circulation. 2018;137(5):455-463. doi: https://doi.org/10.1161/CIRCULATIONAHA.117.030458Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med. 2016;374(14):1321-1331. doi: https://doi.org/10.1056/NEJMoa1506930Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med. 2016;374(14):1321-1331. doi: https://doi.org/10.1056/NEJMoa1506930Tanaka R, Yamashiro K, Okuma Y, et al. Effects of pioglitazone for secondary stroke prevention in patients with impaired glucose tolerance and newly diagnosed diabetes: the J-SPIRIT study. J Atheroscler Thromb. 2015;22(12):1305-1316. doi: https://doi.org/10.5551/jat.30007Tanaka R, Yamashiro K, Okuma Y, et al. Effects of pioglitazone for secondary stroke prevention in patients with impaired glucose tolerance and newly diagnosed diabetes: the J-SPIRIT study. J Atheroscler Thromb. 2015;22(12):1305-1316. doi: https://doi.org/10.5551/jat.30007Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279-1289. doi: https://doi.org/10.1016/S0140-6736(05)67528-9Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279-1289. doi: https://doi.org/10.1016/S0140-6736(05)67528-9Takagi T, Okura H, Kobayashi Y, et al. A prospective, multicenter, randomized trial to assess efficacy of pioglitazone on in-stent neointimal suppression in type 2 diabetes. JACC Cardiovasc Interv. 2009;2(6):524-531. doi: https://doi.org/10.1016/j.jcin.2009.04.007Takagi T, Okura H, Kobayashi Y, et al. A prospective, multicenter, randomized trial to assess efficacy of pioglitazone on in-stent neointimal suppression in type 2 diabetes. JACC Cardiovasc Interv. 2009;2(6):524-531. doi: https://doi.org/10.1016/j.jcin.2009.04.007Berlie HD, Kalus JS, Jaber LA. Thiazolidinediones and the risk of edema: A meta-analysis. Diabetes Res Clin Pract. 2007;76(2):279-289. doi: https://doi.org/10.1016/j.diabres.2006.09.010Berlie HD, Kalus JS, Jaber LA. Thiazolidinediones and the risk of edema: A meta-analysis. Diabetes Res Clin Pract. 2007;76(2):279-289. doi: https://doi.org/10.1016/j.diabres.2006.09.010Basu A, Jensen MD, McCann F, et al. Effects of pioglitazone versus glipizide on body fat distribution, body water content, and hemodynamics in type 2 diabetes. Diabetes Care. 2006;29(3):510-514. doi: https://doi.org/10.2337/diacare.29.03.06.dc05-2004Basu A, Jensen MD, McCann F, et al. Effects of pioglitazone versus glipizide on body fat distribution, body water content, and hemodynamics in type 2 diabetes. Diabetes Care. 2006;29(3):510-514. doi: https://doi.org/10.2337/diacare.29.03.06.dc05-2004DeFronzo RA, Inzucchi S, Abdul-Ghani M, et al. Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes. Diab Vasc Dis Res. 2019;16(2):133-143. doi: https://doi.org/10.1177/1479164118825376DeFronzo RA, Inzucchi S, Abdul-Ghani M, et al. Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes. Diab Vasc Dis Res. 2019;16(2):133-143. doi: https://doi.org/10.1177/1479164118825376Hurren KM, Dunham MW. Are thiazolidinediones a preferred drug treatment for type 2 diabetes? Expert Opin Pharmacother. 2021;22(2):131-133. doi: https://doi.org/10.1080/14656566.2020.1853100Hurren KM, Dunham MW. Are thiazolidinediones a preferred drug treatment for type 2 diabetes? Expert Opin Pharmacother. 2021;22(2):131-133. doi: https://doi.org/10.1080/14656566.2020.1853100Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol. 2010;10(5):365-376. doi: https://doi.org/10.1038/nri2748Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol. 2010;10(5):365-376. doi: https://doi.org/10.1038/nri2748Li AC, Brown KK, Silvestre MJ, et al. Peroxisome proliferator–activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor–deficient mice. J Clin Invest. 2000;106(4):523-531. doi: https://doi.org/10.1172/JCI10370Li AC, Brown KK, Silvestre MJ, et al. Peroxisome proliferator–activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor–deficient mice. J Clin Invest. 2000;106(4):523-531. doi: https://doi.org/10.1172/JCI10370Law RE, Goetze S, Xi X-P, et al. Expression and Function of PPARγ in Rat and Human Vascular Smooth Muscle Cells. Circulation. 2000;101(11):1311-1318. doi: https://doi.org/10.1161/01.CIR.101.11.1311Law RE, Goetze S, Xi X-P, et al. Expression and Function of PPARγ in Rat and Human Vascular Smooth Muscle Cells. Circulation. 2000;101(11):1311-1318. doi: https://doi.org/10.1161/01.CIR.101.11.1311Sugawara A, Takeuchi K, Uruno A, et al. Transcriptional suppression of type 1 angiotensin ii receptor gene expression by peroxisome proliferator-activated receptor-γ in vascular smooth muscle cells*. Endocrinology. 2001;142(7):3125-3134. doi: https://doi.org/10.1210/endo.142.7.8272Sugawara A, Takeuchi K, Uruno A, et al. Transcriptional suppression of type 1 angiotensin ii receptor gene expression by peroxisome proliferator-activated receptor-γ in vascular smooth muscle cells*. Endocrinology. 2001;142(7):3125-3134. doi: https://doi.org/10.1210/endo.142.7.8272Hirano M, Nakamura T, Kitta Y, et al. Rapid improvement of carotid plaque echogenicity within 1 month of pioglitazone treatment in patients with acute coronary syndrome. Atherosclerosis. 2009;203(2):483-488. doi: https://doi.org/10.1016/j.atherosclerosis.2008.07.023Hirano M, Nakamura T, Kitta Y, et al. Rapid improvement of carotid plaque echogenicity within 1 month of pioglitazone treatment in patients with acute coronary syndrome. Atherosclerosis. 2009;203(2):483-488. doi: https://doi.org/10.1016/j.atherosclerosis.2008.07.023Mazzone T, Meyer PM, Feinstein SB, et al. Effect of Pioglitazone Compared With Glimepiride on Carotid Intima-Media Thickness in Type 2 Diabetes: A Randomized Trial. JAMA. 2006;296(21):2572-2581. doi: https://doi.org/10.1001/jama.296.21.joc60158Mazzone T, Meyer PM, Feinstein SB, et al. Effect of Pioglitazone Compared With Glimepiride on Carotid Intima-Media Thickness in Type 2 Diabetes: A Randomized Trial. JAMA. 2006;296(21):2572-2581. doi: https://doi.org/10.1001/jama.296.21.joc60158Nissen SE, Nicholls SJ, Wolski K, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299(13):1561-1573. doi: https://doi.org/10.1001/jama.299.13.1561Nissen SE, Nicholls SJ, Wolski K, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299(13):1561-1573. doi: https://doi.org/10.1001/jama.299.13.1561Schneider CA, Ferrannini E, Defronzo R, et al. Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease. J Am Soc Nephrol. 2008;19(1):182-187. doi: https://doi.org/10.1681/ASN.2007060678Schneider CA, Ferrannini E, Defronzo R, et al. Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease. J Am Soc Nephrol. 2008;19(1):182-187. doi: https://doi.org/10.1681/ASN.2007060678Schernthaner G, Matthews DR, Charbonnel B, et al. Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial. J Clin Endocrinol Metab. 2004;89(12):6068-6076. doi: https://doi.org/10.1210/jc.2003-030861Schernthaner G, Matthews DR, Charbonnel B, et al. Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial. J Clin Endocrinol Metab. 2004;89(12):6068-6076. doi: https://doi.org/10.1210/jc.2003-030861Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2022;142(7):3125-3134. doi: https://doi.org/10.1007/s00125-022-05787-2Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2022;142(7):3125-3134. doi: https://doi.org/10.1007/s00125-022-05787-2Davies MJ, Aroda VR, Collins BS, et al. EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402. doi: https://doi.org/10.1016/j.jhep.2015.11.004Davies MJ, Aroda VR, Collins BS, et al. EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402. doi: https://doi.org/10.1016/j.jhep.2015.11.004Cusi K, Isaacs S, Barb D, et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings. Endocr Pract. 2022;28(5):528-562. doi: https://doi.org/10.1016/j.eprac.2022.03.010Cusi K, Isaacs S, Barb D, et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings. Endocr Pract. 2022;28(5):528-562. doi: https://doi.org/10.1016/j.eprac.2022.03.010Bugianesi E, Vanni E, Marchesini G. NASH and the risk of cirrhosis and hepatocellular carcinoma in type 2 diabetes. Curr Diab Rep. 2007;7(3):175-180. doi: https://doi.org/10.1007/s11892-007-0029-zBugianesi E, Vanni E, Marchesini G. NASH and the risk of cirrhosis and hepatocellular carcinoma in type 2 diabetes. Curr Diab Rep. 2007;7(3):175-180. doi: https://doi.org/10.1007/s11892-007-0029-zVan Wagner LB, Rinella ME. The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis. Therap Adv Gastroenterol. 2011;4(4):249-263. doi: https://doi.org/10.1177/1756283X11403809Van Wagner LB, Rinella ME. The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis. Therap Adv Gastroenterol. 2011;4(4):249-263. doi: https://doi.org/10.1177/1756283X11403809Belfort R, Harrison SA, Brown K, et al. A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis. N Engl J Med. 2006;355(22):2297-2307. doi: https://doi.org/10.1056/NEJMoa060326Belfort R, Harrison SA, Brown K, et al. A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis. N Engl J Med. 2006;355(22):2297-2307. doi: https://doi.org/10.1056/NEJMoa060326Sanyal AJ, Chalasani N, Kowdley KV., et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675-1685. doi: https://doi.org/10.1056/NEJMoa0907929Sanyal AJ, Chalasani N, Kowdley KV., et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675-1685. doi: https://doi.org/10.1056/NEJMoa0907929Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus. Ann Intern Med. 2016;165(5):305-315. doi: https://doi.org/10.7326/M15-1774Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus. Ann Intern Med. 2016;165(5):305-315. doi: https://doi.org/10.7326/M15-1774Rakoski MO, Singal AG, Rogers MAM, Conjeevaram H. Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2010;32(10):1211-1221. doi: https://doi.org/10.1111/j.1365-2036.2010.04467.xRakoski MO, Singal AG, Rogers MAM, Conjeevaram H. Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2010;32(10):1211-1221. doi: https://doi.org/10.1111/j.1365-2036.2010.04467.xMahady SE, Webster AC, Walker S, et al. The role of thiazolidinediones in non-alcoholic steatohepatitis – A systematic review and meta analysis. J Hepatol. 2011;55(6):1383-1390. doi: https://doi.org/10.1016/j.jhep.2011.03.016Mahady SE, Webster AC, Walker S, et al. The role of thiazolidinediones in non-alcoholic steatohepatitis – A systematic review and meta analysis. J Hepatol. 2011;55(6):1383-1390. doi: https://doi.org/10.1016/j.jhep.2011.03.016Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297-2307. doi: https://doi.org/10.1056/NEJMoa060326Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297-2307. doi: https://doi.org/10.1056/NEJMoa060326Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135(4):1176-1184. doi: https://doi.org/10.1053/j.gastro.2008.06.047Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135(4):1176-1184. doi: https://doi.org/10.1053/j.gastro.2008.06.047

The authors declare that there are no conflicts of interest present.