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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Mini-Review Article

Fathoming the Role of mTOR in Diabetes Mellitus and its Complications

Author(s): Faheem and Shanthi Sivasubrmanian*

Volume 16, Issue 5, 2023

Published on: 27 December, 2022

Article ID: e051022209609 Pages: 10

DOI: 10.2174/1874467215666221005123919

Price: $65

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Abstract

Mechanistic/Mammalian target of rapamycin (mTOR) orchestrates cellular homeostasis by controlling cell growth, proliferation, metabolism, and survival by integrating various growth factors, nutrients and amino acids. Eccentric synchronization of mTOR has been incriminated in various diseases/disorders like cancer, neurodegenerative disorders, and diabetes mellitus and its complications. Recent reports also highlight the role of mTOR in diabetes and its associated complications. This review tries to fathom the role of mTOR signaling in diabetes mellitus and its complications- diabetic cardiomyopathy, diabetic nephropathy, and diabetic retinopathy and highlights mTOR as a putative target for the development of novel anti-diabetic drug candidates.

Keywords: mTOR, diabetes mellitus, insulin resistance, apoptosis, diabetic cardiomyopathy, diabetic nephropathy, diabetic retinopathy.

Graphical Abstract

[1]
International Diabetes Federation - Facts & figures. Available from. https://idf.org/aboutdiabetes/what-is-diabetes/facts-figures.html#:~:text=Almost%201%20in%202%20(240,living%20with%20type%201%20diabetes
[2]
American Diabetes Association. 2. Classification and diagnosis of diabetes: Standards of medical care in diabetes-2019. Diabetes Care, 2019, 42(S1), S13-S28.
[http://dx.doi.org/10.2337/dc19-S002] [PMID: 30559228]
[3]
Williams, J.; Loeffler, M. Global trends in type 2 diabetes, 2007-2017. JAMA, 2019, 322(16), 1542.
[http://dx.doi.org/10.1001/jama.2019.16074] [PMID: 31638662]
[4]
International Diabetes Federation - Complications Available from:. https://www.idf.org/aboutdiabetes/complications.html
[5]
Laplante, M.; Sabatini, D.M. mTOR signaling at a glance. J. Cell Sci., 2009, 122(20), 3589-3594.
[http://dx.doi.org/10.1242/jcs.051011] [PMID: 19812304]
[6]
Kim, D.H.; Sarbassov, D.D.; Ali, S.M.; King, J.E.; Latek, R.R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D.M. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 2002, 110(2), 163-175.
[http://dx.doi.org/10.1016/S0092-8674(02)00808-5] [PMID: 12150925]
[7]
Nojima, H.; Tokunaga, C.; Eguchi, S.; Oshiro, N.; Hidayat, S.; Yoshino, K.; Hara, K.; Tanaka, N.; Avruch, J.; Yonezawa, K. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J. Biol. Chem., 2003, 278(18), 15461-15464.
[http://dx.doi.org/10.1074/jbc.C200665200] [PMID: 12604610]
[8]
Peterson, T.R.; Laplante, M.; Thoreen, C.C.; Sancak, Y.; Kang, S.A.; Kuehl, W.M.; Gray, N.S.; Sabatini, D.M. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell, 2009, 137(5), 873-886.
[http://dx.doi.org/10.1016/j.cell.2009.03.046] [PMID: 19446321]
[9]
Ali, S.M.; Kim, D-H.; Guertin, D.A.; Latek, R.R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D.M.; Sabatini, D.M. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol., 2004, 14(14), 1296-1302.
[http://dx.doi.org/10.1016/j.cub.2004.06.054] [PMID: 15268862]
[10]
Inoki, K.; Li, Y.; Zhu, T.; Wu, J.; Guan, K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol., 2002, 4(9), 648-657.
[http://dx.doi.org/10.1038/ncb839] [PMID: 12172553]
[11]
Sancak, Y.; Thoreen, C.C.; Peterson, T.R.; Lindquist, R.A.; Kang, S.A.; Spooner, E.; Carr, S.A.; Sabatini, D.M. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell, 2007, 25(6), 903-915.
[http://dx.doi.org/10.1016/j.molcel.2007.03.003] [PMID: 17386266]
[12]
Long, X.; Lin, Y.; Ortiz-Vega, S.; Yonezawa, K.; Avruch, J. Rheb binds and regulates the mTOR kinase. Curr. Biol., 2005, 15(8), 702-713.
[http://dx.doi.org/10.1016/j.cub.2005.02.053] [PMID: 15854902]
[13]
Um, S.H.; Frigerio, F.; Watanabe, M.; Picard, F.; Joaquin, M.; Sticker, M.; Fumagalli, S.; Allegrini, P.R.; Kozma, S.C.; Auwerx, J.; Thomas, G. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature, 2004, 431(7005), 200-205.
[http://dx.doi.org/10.1038/nature02866] [PMID: 15306821]
[14]
Yu, Y.; Yoon, S.O.; Poulogiannis, G.; Yang, Q.; Ma, X.M.; Villén, J.; Kubica, N.; Hoffman, G.R.; Cantley, L.C.; Gygi, S.P.; Blenis, J. Phosphoproteomic analysis identifies grb10 as an mtorc1 substrate that negatively regulates insulin signaling. Science, 2011, 332, 1322-1326.
[15]
Briaud, I.; Dickson, L.M.; Lingohr, M.K.; McCuaig, J.F.; Lawrence, J.C.; Rhodes, C.J. Insulin receptor substrate-2 proteasomal degradation mediated by a mammalian target of rapamycin (mTOR)-induced negative feedback down-regulates protein kinase B-mediated signaling pathway in β-cells. J. Biol. Chem., 2005, 280(3), 2282-2293.
[http://dx.doi.org/10.1074/jbc.M412179200] [PMID: 15537654]
[16]
Sarbassov, D.D.; Guertin, D.A.; Ali, S.M.; Sabatini, D.M. Phosphorylation and regulation of Akt/PKB by the rictor-MTOR complex. Science, 2005, 307, 1098-1101.
[17]
Cybulski, N.; Polak, P.; Auwerx, J.; Rüegg, M.A.; Hall, M.N. mTOR complex 2 in adipose tissue negatively controls whole-body growth. Proc. Natl. Acad. Sci., 2009, 106(24), 9902-9907.
[http://dx.doi.org/10.1073/pnas.0811321106] [PMID: 19497867]
[18]
Kumar, A.; Lawrence, J.C., Jr; Jung, D.Y.; Ko, H.J.; Keller, S.R.; Kim, J.K.; Magnuson, M.A.; Harris, T.E. Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes, 2010, 59(6), 1397-1406.
[http://dx.doi.org/10.2337/db09-1061] [PMID: 20332342]
[19]
Kim, S.J.; DeStefano, M.A.; Oh, W.J.; Wu, C.; Vega-Cotto, N.M.; Finlan, M.; Liu, D.; Su, B.; Jacinto, E. mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8. Mol. Cell, 2012, 48(6), 875-887.
[http://dx.doi.org/10.1016/j.molcel.2012.09.029] [PMID: 23142081]
[20]
Balcazar, N.; Sathyamurthy, A.; Elghazi, L.; Gould, A.; Weiss, A.; Shiojima, I.; Walsh, K.; Bernal-Mizrachi, E. mTORC1 activation regulates β-cell mass and proliferation by modulation of cyclin D2 synthesis and stability. J. Biol. Chem., 2009, 284(12), 7832-7842.
[http://dx.doi.org/10.1074/jbc.M807458200] [PMID: 19144649]
[21]
Hamada, S.; Hara, K.; Hamada, T.; Yasuda, H.; Moriyama, H.; Nakayama, R.; Nagata, M.; Yokono, K. Upregulation of the mammalian target of rapamycin complex 1 pathway by Ras homolog enriched in brain in pancreatic β-cells leads to increased β-cell mass and prevention of hyperglycemia. Diabetes, 2009, 58(6), 1321-1332.
[http://dx.doi.org/10.2337/db08-0519] [PMID: 19258434]
[22]
Rachdi, L.; Balcazar, N.; Osorio-Duque, F.; Elghazi, L.; Weiss, A.; Gould, A.; Chang-Chen, K.J.; Gambello, M.J.; Bernal-Mizrachi, E. Disruption of Tsc2 in pancreatic β cells induces β cell mass expansion and improved glucose tolerance in a TORC1-dependent manner. Proc. Natl. Acad. Sci., 2008, 105(27), 9250-9255.
[http://dx.doi.org/10.1073/pnas.0803047105] [PMID: 18587048]
[23]
Ni, Q.; Gu, Y.; Xie, Y.; Yin, Q.; Zhang, H.; Nie, A.; Li, W.; Wang, Y.; Ning, G.; Wang, W.; Wang, Q. Raptor regulates functional maturation of murine beta cells. Nat. Commun., 2017, 8(1), 15755.
[http://dx.doi.org/10.1038/ncomms15755] [PMID: 28598424]
[24]
Ardestani, A.; Lupse, B.; Kido, Y.; Leibowitz, G.; Maedler, K. mTORC1 signaling: A double-edged sword in diabetic β cells. Cell Metab., 2018, 27(2), 314-331.
[http://dx.doi.org/10.1016/j.cmet.2017.11.004] [PMID: 29275961]
[25]
Leahy, J.L. Impaired β-cellfunction with chronic hyperglycemia: “Overworked β-cell” hypothesis. Diabetes Rev, 1996, 4, 298-319.
[26]
Dibble, C.C.; Asara, J.M.; Manning, B.D. Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol. Cell. Biol., 2009, 29(21), 5657-5670.
[http://dx.doi.org/10.1128/MCB.00735-09] [PMID: 19720745]
[27]
Liu, P.; Gan, W.; Inuzuka, H.; Lazorchak, A.S.; Gao, D.; Arojo, O.; Liu, D.; Wan, L.; Zhai, B.; Yu, Y.; Yuan, M.; Kim, B.M.; Shaik, S.; Menon, S.; Gygi, S.P.; Lee, T.H.; Asara, J.M.; Manning, B.D.; Blenis, J.; Su, B.; Wei, W. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat. Cell Biol., 2013, 15(11), 1340-1350.
[http://dx.doi.org/10.1038/ncb2860] [PMID: 24161930]
[28]
Julien, L.A.; Carriere, A.; Moreau, J.; Roux, P.P. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol. Cell. Biol., 2010, 30(4), 908-921.
[http://dx.doi.org/10.1128/MCB.00601-09] [PMID: 19995915]
[29]
Yuan, T.; Rafizadeh, S.; Gorrepati, K.D.D.; Lupse, B.; Oberholzer, J.; Maedler, K.; Ardestani, A. Reciprocal regulation of mTOR complexes in pancreatic islets from humans with type 2 diabetes. Diabetologia, 2017, 60(4), 668-678.
[http://dx.doi.org/10.1007/s00125-016-4188-9] [PMID: 28004151]
[30]
Yang, Z.; Liu, F.; Qu, H.; Wang, H.; Xiao, X.; Deng, H. 1, 25(OH)2D3 protects β cell against high glucose-induced apoptosis through mTOR suppressing. Mol. Cell. Endocrinol., 2015, 414, 111-119.
[http://dx.doi.org/10.1016/j.mce.2015.07.023] [PMID: 26213322]
[31]
Jia, G.; Hill, M.A.; Sowers, J.R. Diabetic cardiomyopathy. Circ. Res., 2018, 122(4), 624-638.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.311586] [PMID: 29449364]
[32]
Yancy, C.W.; Jessup, M.; Bozkurt, B.; Butler, J.; Casey, D.E., Jr; Drazner, M.H.; Fonarow, G.C.; Geraci, S.A.; Horwich, T.; Januzzi, J.L.; Johnson, M.R.; Kasper, E.K.; Levy, W.C.; Masoudi, F.A.; McBride, P.E.; McMurray, J.J.V.; Mitchell, J.E.; Peterson, P.N.; Riegel, B.; Sam, F.; Stevenson, L.W.; Tang, W.H.W.; Tsai, E.J.; Wilkoff, B.L. 2013 ACCF/AHA guideline for the management of heart failure. J. Am. Coll. Cardiol., 2013, 62(16), e147-e239.
[http://dx.doi.org/10.1016/j.jacc.2013.05.019] [PMID: 23747642]
[33]
Rubler, S.; Dlugash, J.; Yuceoglu, Y.Z.; Kumral, T.; Branwood, A.W.; Grishman, A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am. J. Cardiol., 1972, 30(6), 595-602.
[http://dx.doi.org/10.1016/0002-9149(72)90595-4] [PMID: 4263660]
[34]
Jia, G.; DeMarco, V.G.; Sowers, J.R. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat. Rev. Endocrinol., 2016, 12(3), 144-153.
[http://dx.doi.org/10.1038/nrendo.2015.216] [PMID: 26678809]
[35]
Sciarretta, S.; Volpe, M.; Sadoshima, J. Mammalian target of rapamycin signaling in cardiac physiology and disease. Circ. Res., 2014, 114(3), 549-564.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.302022] [PMID: 24481845]
[36]
Zhu, Y.; Pires, K.M.P.; Whitehead, K.J.; Olsen, C.D.; Wayment, B.; Zhang, Y.C.; Bugger, H.; Ilkun, O.; Litwin, S.E.; Thomas, G.; Kozma, S.C.; Abel, E.D. Mechanistic target of rapamycin (Mtor) is essential for murine embryonic heart development and growth. PLoS One, 2013, 8(1), e54221.
[http://dx.doi.org/10.1371/journal.pone.0054221] [PMID: 23342106]
[37]
Wu, Q.Q.; Xiao, Y.; Yuan, Y.; Ma, Z.G.; Liao, H.H.; Liu, C.; Zhu, J.X.; Yang, Z.; Deng, W.; Tang, Q. Mechanisms contributing to cardiac remodelling. Clin. Sci., 2017, 131(18), 2319-2345.
[http://dx.doi.org/10.1042/CS20171167] [PMID: 28842527]
[38]
Levine, B.; Kroemer, G. Autophagy in the pathogenesis of disease. Cell, 2008, 132(1), 27-42.
[http://dx.doi.org/10.1016/j.cell.2007.12.018] [PMID: 18191218]
[39]
Kim, J.; Kundu, M.; Viollet, B.; Guan, K.L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol., 2011, 13(2), 132-141.
[http://dx.doi.org/10.1038/ncb2152] [PMID: 21258367]
[40]
Hosokawa, N.; Hara, T.; Kaizuka, T.; Kishi, C.; Takamura, A.; Miura, Y.; Iemura, S.; Natsume, T.; Takehana, K.; Yamada, N.; Guan, J.L.; Oshiro, N.; Mizushima, N. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell, 2009, 20(7), 1981-1991.
[http://dx.doi.org/10.1091/mbc.e08-12-1248] [PMID: 19211835]
[41]
Inoki, K.; Zhu, T.; Guan, K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell, 2003, 115(5), 577-590.
[http://dx.doi.org/10.1016/S0092-8674(03)00929-2] [PMID: 14651849]
[42]
Gwinn, D.M.; Shackelford, D.B.; Egan, D.F.; Mihaylova, M.M.; Mery, A.; Vasquez, D.S.; Turk, B.E.; Shaw, R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell, 2008, 30(2), 214-226.
[http://dx.doi.org/10.1016/j.molcel.2008.03.003] [PMID: 18439900]
[43]
Guo, R.; Zhang, Y.; Turdi, S.; Ren, J. Adiponectin knockout accentuates high fat diet-induced obesity and cardiac dysfunction: Role of autophagy. Biochim. Biophys. Acta Mol. Basis Dis., 2013, 1832(8), 1136-1148.
[http://dx.doi.org/10.1016/j.bbadis.2013.03.013] [PMID: 23524376]
[44]
Zhang, Y.; Ling, Y.; Yang, L.; Cheng, Y.; Yang, P.; Song, X.; Tang, H.; Zhong, Y.; Tang, L.; He, S.; Yang, S.; Chen, A.; Wang, X. Liraglutide relieves myocardial damage by promoting autophagy via AMPK-mTOR signaling pathway in Zucker diabetic fatty rat. Mol. Cell. Endocrinol., 2017, 448, 98-107.
[http://dx.doi.org/10.1016/j.mce.2017.03.029] [PMID: 28363742]
[45]
Yao, Q.; Ke, Z.; Guo, S.; Yang, X.; Zhang, F.; Liu, X.; Chen, X.; Chen, H.; Ke, H.; Liu, C. Curcumin protects against diabetic cardiomyopathy by promoting autophagy and alleviating apoptosis. J. Mol. Cell. Cardiol., 2018, 124, 26-34.
[http://dx.doi.org/10.1016/j.yjmcc.2018.10.004] [PMID: 30292723]
[46]
Völkers, M.; Doroudgar, S.; Nguyen, N.; Konstandin, M.H.; Quijada, P.; Din, S.; Ornelas, L.; Thuerauf, D.J.; Gude, N.; Friedrich, K.; Herzig, S.; Glembotski, C.C.; Sussman, M.A. PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity. EMBO Mol. Med., 2014, 6(1), 57-65.
[http://dx.doi.org/10.1002/emmm.201303183] [PMID: 24408966]
[47]
Gross, J.L.; de Azevedo, M.J.; Silveiro, S.P.; Canani, L.H.; Caramori, M.L.; Zelmanovitz, T. Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care, 2005, 28(1), 164-176.
[http://dx.doi.org/10.2337/diacare.28.1.164] [PMID: 15616252]
[48]
Lim, A. Diabetic nephropathy - complications and treatment. Int. J. Nephrol. Renovasc. Dis., 2014, 7, 361-381.
[http://dx.doi.org/10.2147/IJNRD.S40172] [PMID: 25342915]
[49]
Lieberthal, W.; Levine, J.S. The role of the mammalian target of rapamycin (mTOR) in renal disease. J. Am. Soc. Nephrol., 2009, 20(12), 2493-2502.
[http://dx.doi.org/10.1681/ASN.2008111186] [PMID: 19875810]
[50]
Gnudi, L.; Coward, R.J.M.; Long, D.A. Diabetic nephropathy: Perspective on novel molecular mechanisms. Trends Endocrinol. Metab., 2016, 27(11), 820-830.
[http://dx.doi.org/10.1016/j.tem.2016.07.002] [PMID: 27470431]
[51]
Molitch, M.E.; DeFronzo, R.A.; Franz, M.J.; Keane, W.F.; Mogensen, C.E.; Parving, H.H.; Steffes, M.W. Nephropathy in diabetes. Diabetes Care, 2004, 27(S1), s79-s83.
[http://dx.doi.org/10.2337/diacare.27.2007.S79] [PMID: 14693934]
[52]
Mori, H.; Inoki, K.; Masutani, K.; Wakabayashi, Y.; Komai, K.; Nakagawa, R.; Guan, K.L.; Yoshimura, A. The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem. Biophys. Res. Commun., 2009, 384(4), 471-475.
[http://dx.doi.org/10.1016/j.bbrc.2009.04.136] [PMID: 19422788]
[53]
Kume, S.; Yamahara, K.; Yasuda, M.; Maegawa, H.; Koya, D. Autophagy: Emerging therapeutic target for diabetic nephropathy. In: Proceedings of the Seminars in nephrology Elsevier, 2014, 34, pp. 9-16.
[http://dx.doi.org/10.1016/j.semnephrol.2013.11.003]
[54]
Inoki, K.; Mori, H.; Wang, J.; Suzuki, T.; Hong, S.; Yoshida, S.; Blattner, S.M.; Ikenoue, T.; Rüegg, M.A.; Hall, M.N.; Kwiatkowski, D.J.; Rastaldi, M.P.; Huber, T.B.; Kretzler, M.; Holzman, L.B.; Wiggins, R.C.; Guan, K.L. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J. Clin. Invest., 2011, 121(6), 2181-2196.
[http://dx.doi.org/10.1172/JCI44771] [PMID: 21606597]
[55]
Yamahara, K.; Kume, S.; Koya, D.; Tanaka, Y.; Morita, Y.; Chin-Kanasaki, M.; Araki, H.; Isshiki, K.; Araki, S.; Haneda, M.; Matsusaka, T.; Kashiwagi, A.; Maegawa, H.; Uzu, T. Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions. J. Am. Soc. Nephrol., 2013, 24(11), 1769-1781.
[http://dx.doi.org/10.1681/ASN.2012111080] [PMID: 24092929]
[56]
Kitada, M.; Ogura, Y.; Monno, I.; Koya, D. Regulating autophagy as a therapeutic target for diabetic nephropathy. Curr. Diab. Rep., 2017, 17(7), 53.
[http://dx.doi.org/10.1007/s11892-017-0879-y] [PMID: 28593583]
[57]
Wu, W.; Hu, W.; Han, W.B.; Liu, Y.L.; Tu, Y.; Yang, H.M.; Fang, Q.J.; Zhou, M.Y.; Wan, Z.Y.; Tang, R.M.; Tang, H.T.; Wan, Y.G. Inhibition of Akt/mTOR/p70S6K signaling activity with huangkui capsule alleviates the early glomerular pathological changes in diabetic nephropathy. Front. Pharmacol., 2018, 9, 443.
[http://dx.doi.org/10.3389/fphar.2018.00443] [PMID: 29881349]
[58]
International Diabetes Federation - Eye health Available from:. https://idf.org/our-activities/care-prevention/eye-health.html
[59]
International Diabetes Federation - World Sight Day. 2019. Available from: https://idf.org/our-activities/care-prevention/eye-health/world-sight-day-2019.html#:~:text=This%20year%20World%20Sight%20Day,the%20theme%20%27Vision%20First%27
[60]
Cai, J.; Boulton, M. The pathogenesis of diabetic retinopathy: Old concepts and new questions. Eye, 2002, 16(3), 242-260.
[http://dx.doi.org/10.1038/sj.eye.6700133] [PMID: 12032713]
[61]
Wong, T.Y.; Cheung, C.M.G.; Larsen, M.; Sharma, S.; Simó, R. Diabetic retinopathy. Nat. Rev. Dis. Primers, 2016, 2(1), 1.
[62]
Wilkinson, C.P.; Ferris, F.L., III; Klein, R.E.; Lee, P.P.; Agardh, C.D.; Davis, M.; Dills, D.; Kampik, A.; Pararajasegaram, R.; Verdaguer, J.T.; Lum, F. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology, 2003, 110(9), 1677-1682.
[http://dx.doi.org/10.1016/S0161-6420(03)00475-5] [PMID: 13129861]
[63]
Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature, 2001, 414(6865), 813-820.
[http://dx.doi.org/10.1038/414813a] [PMID: 11742414]
[64]
Simó, R.; Hernández, C. Neurodegeneration in the diabetic eye: New insights and therapeutic perspectives. Trends Endocrinol. Metab., 2014, 25(1), 23-33.
[http://dx.doi.org/10.1016/j.tem.2013.09.005] [PMID: 24183659]
[65]
Tang, J.; Kern, T.S. Inflammation in diabetic retinopathy. Prog. Retin. Eye Res., 2011, 30(5), 343-358.
[http://dx.doi.org/10.1016/j.preteyeres.2011.05.002] [PMID: 21635964]
[66]
Wilkinson-Berka, J.L.; Agrotis, A.; Deliyanti, D. The retinal renin-angiotensin system: Roles of angiotensin II and aldosterone. Peptides, 2012, 36(1), 142-150.
[http://dx.doi.org/10.1016/j.peptides.2012.04.008] [PMID: 22537944]
[67]
Humar, R.; Kiefer, F.N.; Berns, H.; Resink, T.J.; Battegay, E.J. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR) ‐dependent signaling. FASEB J., 2002, 16(8), 771-780.
[http://dx.doi.org/10.1096/fj.01-0658com] [PMID: 12039858]
[68]
Blagosklonny, M.V. TOR-centric view on insulin resistance and diabetic complications: Perspective for endocrinologists and gerontologists. Cell Death Dis., 2013, 4(12), e964-e964.
[http://dx.doi.org/10.1038/cddis.2013.506] [PMID: 24336084]
[69]
Jacot, J.L.; Sherris, D. Potential therapeutic roles for inhibition of the pi3k/akt/mtor pathway in the pathophysiology of diabetic retinopathy. J. Ophthalmol., 2011, 2011, 1-19.
[70]
Poulaki, V.; Qin, W.; Joussen, A.M.; Hurlbut, P.; Wiegand, S.J.; Rudge, J.; Yancopoulos, G.D.; Adamis, A.P. Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1α and VEGF. J. Clin. Invest., 2002, 109(6), 805-815.
[http://dx.doi.org/10.1172/JCI0213776] [PMID: 11901189]
[71]
Wei, J.; Jiang, H.; Gao, H.; Wang, G. Blocking mammalian target of rapamycin (mTOR) attenuates HIF-1α pathways engaged-vascular endothelial growth factor (VEGF) in Diabetic Retinopathy. Cell. Physiol. Biochem., 2016, 40(6), 1570-1577.
[http://dx.doi.org/10.1159/000453207] [PMID: 27997905]
[72]
Zhao, B.W.; Dai, H.Y.; Hao, L.N.; Liu, Y.W. MiR-29 regulates retinopathy in diabetic mice via the AMPK signaling pathway. Eur. Rev. Med. Pharmacol. Sci., 2019, 23(9), 3569-3574.
[PMID: 31114980]
[73]
Chen, H.; Ji, Y.; Yan, X.; Su, G.; Chen, L.; Xiao, J. Berberine attenuates apoptosis in rat retinal Müller cells stimulated with high glucose via enhancing autophagy and the AMPK/mTOR signaling. Biomed. Pharmacother., 2018, 108, 1201-1207.
[http://dx.doi.org/10.1016/j.biopha.2018.09.140] [PMID: 30372821]
[74]
Ran, Z.; Zhang, Y.; Wen, X.; Ma, J. Curcumin inhibits high glucose induced inflammatory injury in human retinal pigment epithelial cells through the ROS PI3K/AKT/mTOR signaling pathway. Mol. Med. Rep., 2019, 19(2), 1024-1031.
[PMID: 30569107]

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