Review Article

Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications

Author(s): Lin Yang, Zhixin Zhang, Doudou Wang, Yu Jiang* and Ying Liu*

Volume 23, Issue 7, 2022

Published on: 21 February, 2022

Page: [692 - 710] Pages: 19

DOI: 10.2174/1389450123666220111115528

Price: $65

Abstract

The mechanistic target of rapamycin (mTOR) is a pivotal regulator of cell metabolism and growth. In the form of two different multi-protein complexes, mTORC1 and mTORC2, mTOR integrates cellular energy, nutrient and hormonal signals to regulate cellular metabolic homeostasis. In type 2 diabetes mellitus (T2DM), pathological conditions and end-organ complications can be attributed to aberrant mTOR. Substantial evidence suggests that two mTOR-mediated signaling schemes, mTORC1-p70S6 kinase 1 (S6K1) and mTORC2-protein kinase B (AKT), play a critical role in insulin sensitivity and that their dysfunction contributes to the development of T2DM. This review summarizes our current understanding of the role of mTOR signaling in T2DM and its associated complications, as well as the potential use of mTOR inhibitors in the treatment of T2DM.

Keywords: mTORC1, mTORC2, type 2 diabetes mellitus, diabetic complications, mTOR inhibitor, pivotal regulator.

Graphical Abstract
[1]
Rahman S, Rahman T, Ismail AA, Rashid AR. Diabetes-associated macrovasculopathy: pathophysiology and pathogenesis. Diabetes Obes Metab 2007; 9(6): 767-80.
[http://dx.doi.org/10.1111/j.1463-1326.2006.00655.x] [PMID: 17924861]
[2]
Cooper ME, Bonnet F, Oldfield M, Jandeleit-Dahm K. Mechanisms of diabetic vasculopathy: an overview. Am J Hypertens 2001; 14(5 Pt 1): 475-86.
[http://dx.doi.org/10.1016/S0895-7061(00)01323-6] [PMID: 11368471]
[3]
Clark CM Jr, Lee DA. Prevention and treatment of the complications of diabetes mellitus. N Engl J Med 1995; 332(18): 1210-7.
[http://dx.doi.org/10.1056/NEJM199505043321807] [PMID: 7700316]
[4]
Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract 2019; 157: 107843.
[http://dx.doi.org/10.1016/j.diabres.2019.107843] [PMID: 31518657]
[5]
Magaway C, Kim E, Jacinto E. Targeting mTOR and metabolism in cancer: Lessons and innovations. Cells 2019; 8(12): E1584.
[http://dx.doi.org/10.3390/cells8121584] [PMID: 31817676]
[6]
Brown EJ, Albers MW, Shin TB, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994; 369(6483): 756-8.
[http://dx.doi.org/10.1038/369756a0] [PMID: 8008069]
[7]
Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994; 78(1): 35-43.
[http://dx.doi.org/10.1016/0092-8674(94)90570-3] [PMID: 7518356]
[8]
Sabers CJ, Martin MM, Brunn GJ, et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 1995; 270(2): 815-22.
[http://dx.doi.org/10.1074/jbc.270.2.815] [PMID: 7822316]
[9]
Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 2000; 19(56): 6680-6.
[http://dx.doi.org/10.1038/sj.onc.1204091] [PMID: 11426655]
[10]
Fan C, Zhao C, Zhang F, et al. Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition. Proc Natl Acad Sci USA 2021; 118(1): e2020102118.
[http://dx.doi.org/10.1073/pnas.2020102118] [PMID: 33443202]
[11]
Liko D, Rzepiela A, Vukojevic V, Zavolan M, Hall MN. Loss of TSC complex enhances gluconeogenesis via upregulation of Dlk1- Dio3 locus miRNAs. Proc Natl Acad Sci USA 2020; 117(3): 1524-32.
[http://dx.doi.org/10.1073/pnas.1918931117] [PMID: 31919282]
[12]
Kim SG, Lee S, Kim Y, et al. Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons. Nat Commun 2021; 12(1): 2695.
[http://dx.doi.org/10.1038/s41467-021-22908-4] [PMID: 33976205]
[13]
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149(2): 274-93.
[http://dx.doi.org/10.1016/j.cell.2012.03.017] [PMID: 22500797]
[14]
Mao Z, Zhang W. Role of mTOR in glucose and lipid metabolism. Int J Mol Sci 2018; 19(7): E2043.
[http://dx.doi.org/10.3390/ijms19072043] [PMID: 30011848]
[15]
Davis OB, Shin HR, Lim CY, et al. NPC1-mTORC1 signaling couples cholesterol sensing to organelle homeostasis and is a targetable pathway in niemann-pick type C. Dev Cell 2021; 56(3): 260-276.e7.
[http://dx.doi.org/10.1016/j.devcel.2020.11.016] [PMID: 33308480]
[16]
Yao L, Xuan Y, Zhang H, et al. Reciprocal REGγ-mTORC1 regulation promotes glycolytic metabolism in hepatocellular carcinoma. Oncogene 2021; 40(3): 677-92.
[http://dx.doi.org/10.1038/s41388-020-01558-8] [PMID: 33230243]
[17]
Hwang SK, Kim HH. The functions of mTOR in ischemic diseases. BMB Rep 2011; 44(8): 506-11.
[http://dx.doi.org/10.5483/BMBRep.2011.44.8.506] [PMID: 21871173]
[18]
Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009; 137(5): 873-86.
[http://dx.doi.org/10.1016/j.cell.2009.03.046] [PMID: 19446321]
[19]
Guertin DA, Stevens DM, Thoreen CC, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 2006; 11(6): 859-71.
[http://dx.doi.org/10.1016/j.devcel.2006.10.007] [PMID: 17141160]
[20]
Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6(11): 1122-8.
[http://dx.doi.org/10.1038/ncb1183] [PMID: 15467718]
[21]
Kaizuka T, Hara T, Oshiro N, et al. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem 2010; 285(26): 20109-16.
[http://dx.doi.org/10.1074/jbc.M110.121699] [PMID: 20427287]
[22]
Nojima H, Tokunaga C, Eguchi S, et al. 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): 15461-4.
[http://dx.doi.org/10.1074/jbc.C200665200] [PMID: 12604610]
[23]
Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007; 25(6): 903-15.
[http://dx.doi.org/10.1016/j.molcel.2007.03.003] [PMID: 17386266]
[24]
Frias MA, Thoreen CC, Jaffe JD, et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 2006; 16(18): 1865-70.
[http://dx.doi.org/10.1016/j.cub.2006.08.001] [PMID: 16919458]
[25]
Pearce LR, Huang X, Boudeau J, et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 2007; 405(3): 513-22.
[http://dx.doi.org/10.1042/BJ20070540] [PMID: 17461779]
[26]
Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol 2005; 15(8): 702-13.
[http://dx.doi.org/10.1016/j.cub.2005.02.053] [PMID: 15854902]
[27]
Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 2003; 13(15): 1259-68.
[http://dx.doi.org/10.1016/S0960-9822(03)00506-2] [PMID: 12906785]
[28]
Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 2010; 141(2): 290-303.
[http://dx.doi.org/10.1016/j.cell.2010.02.024] [PMID: 20381137]
[29]
Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 2011; 334(6056): 678-83.
[http://dx.doi.org/10.1126/science.1207056] [PMID: 22053050]
[30]
Brugarolas J, Lei K, Hurley RL, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18(23): 2893-904.
[http://dx.doi.org/10.1101/gad.1256804] [PMID: 15545625]
[31]
Feng Z, Hu W, de Stanchina E, et al. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res 2007; 67(7): 3043-53.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4149] [PMID: 17409411]
[32]
Brunn GJ, Hudson CC, Sekulić A, et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 1997; 277(5322): 99-101.
[http://dx.doi.org/10.1126/science.277.5322.99] [PMID: 9204908]
[33]
Gingras AC, Gygi SP, Raught B, et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev 1999; 13(11): 1422-37.
[http://dx.doi.org/10.1101/gad.13.11.1422] [PMID: 10364159]
[34]
Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 2005; 123(4): 569-80.
[http://dx.doi.org/10.1016/j.cell.2005.10.024] [PMID: 16286006]
[35]
Ma XM, Yoon SO, Richardson CJ, Jülich K, Blenis J. SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs. Cell 2008; 133(2): 303-13.
[http://dx.doi.org/10.1016/j.cell.2008.02.031] [PMID: 18423201]
[36]
Düvel K, Yecies JL, Menon S, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 2010; 39(2): 171-83.
[http://dx.doi.org/10.1016/j.molcel.2010.06.022] [PMID: 20670887]
[37]
Peterson TR, Sengupta SS, Harris TE, et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011; 146(3): 408-20.
[http://dx.doi.org/10.1016/j.cell.2011.06.034] [PMID: 21816276]
[38]
Ben-Sahra I, Hoxhaj G, Ricoult SJH, Asara JM, Manning BD. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 2016; 351(6274): 728-33.
[http://dx.doi.org/10.1126/science.aad0489] [PMID: 26912861]
[39]
Ben-Sahra I, Howell JJ, Asara JM, Manning BD. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 2013; 339(6125): 1323-8.
[http://dx.doi.org/10.1126/science.1228792] [PMID: 23429703]
[40]
Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13(2): 132-41.
[http://dx.doi.org/10.1038/ncb2152] [PMID: 21258367]
[41]
Settembre C, Zoncu R, Medina DL, et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J 2012; 31(5): 1095-108.
[http://dx.doi.org/10.1038/emboj.2012.32] [PMID: 22343943]
[42]
Martina JA, Chen Y, Gucek M, Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 2012; 8(6): 903-14.
[http://dx.doi.org/10.4161/auto.19653] [PMID: 22576015]
[43]
Zhao J, Zhai B, Gygi SP, Goldberg AL. mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Proc Natl Acad Sci USA 2015; 112(52): 15790-7.
[http://dx.doi.org/10.1073/pnas.1521919112] [PMID: 26669439]
[44]
Rousseau A, Bertolotti A. An evolutionarily conserved pathway controls proteasome homeostasis. Nature 2016; 536(7615): 184-9.
[http://dx.doi.org/10.1038/nature18943] [PMID: 27462806]
[45]
Liu P, Gan W, Chin YR, et al. PtdIns(3,4,5)P3-dependent activation of the mTORC2 kinase complex. Cancer Discov 2015; 5(11): 1194-209.
[http://dx.doi.org/10.1158/2159-8290.CD-15-0460] [PMID: 26293922]
[46]
Zinzalla V, Stracka D, Oppliger W, Hall MN. Activation of mTORC2 by association with the ribosome. Cell 2011; 144(5): 757-68.
[http://dx.doi.org/10.1016/j.cell.2011.02.014] [PMID: 21376236]
[47]
Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14(14): 1296-302.
[http://dx.doi.org/10.1016/j.cub.2004.06.054] [PMID: 15268862]
[48]
Gan X, Wang J, Wang C, et al. PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12. Nat Cell Biol 2012; 14(7): 686-96.
[http://dx.doi.org/10.1038/ncb2507] [PMID: 22609986]
[49]
Thomanetz V, Angliker N, Cloëtta D, et al. Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology. J Cell Biol 2013; 201(2): 293-308.
[http://dx.doi.org/10.1083/jcb.201205030] [PMID: 23569215]
[50]
García-Martínez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008; 416(3): 375-85.
[http://dx.doi.org/10.1042/BJ20081668] [PMID: 18925875]
[51]
Yang G, Murashige DS, Humphrey SJ, James DE. A positive feedback loop between Akt and mTORC2 via SIN1 phosphorylation. Cell Rep 2015; 12(6): 937-43.
[http://dx.doi.org/10.1016/j.celrep.2015.07.016] [PMID: 26235620]
[52]
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307(5712): 1098-101.
[http://dx.doi.org/10.1126/science.1106148] [PMID: 15718470]
[53]
Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 2005; 365(9467): 1333-46.
[http://dx.doi.org/10.1016/S0140-6736(05)61032-X] [PMID: 15823385]
[54]
Manning BD. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 2004; 167(3): 399-403.
[http://dx.doi.org/10.1083/jcb.200408161] [PMID: 15533996]
[55]
Um SH, D’Alessio D, Thomas G. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 2006; 3(6): 393-402.
[http://dx.doi.org/10.1016/j.cmet.2006.05.003] [PMID: 16753575]
[56]
Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 2004; 14(18): 1650-6.
[http://dx.doi.org/10.1016/j.cub.2004.08.026] [PMID: 15380067]
[57]
Wick KR, Werner ED, Langlais P, et al. Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor. J Biol Chem 2003; 278(10): 8460-7.
[http://dx.doi.org/10.1074/jbc.M208518200] [PMID: 12493740]
[58]
Elghazi L, Balcazar N, Blandino-Rosano M, et al. Decreased IRS signaling impairs beta-cell cycle progression and survival in transgenic mice overexpressing S6K in beta-cells. Diabetes 2010; 59(10): 2390-9.
[http://dx.doi.org/10.2337/db09-0851] [PMID: 20622167]
[59]
Yoon NA, Diano S. Hypothalamic glucose-sensing mechanisms. Diabetologia 2021; 64(5): 985-93.
[http://dx.doi.org/10.1007/s00125-021-05395-6] [PMID: 33544170]
[60]
Cota D, Proulx K, Smith KA, et al. Hypothalamic mTOR signaling regulates food intake. Science 2006; 312(5775): 927-30.
[http://dx.doi.org/10.1126/science.1124147] [PMID: 16690869]
[61]
Muta K, Morgan DA, Rahmouni K. The role of hypothalamic mTORC1 signaling in insulin regulation of food intake, body weight, and sympathetic nerve activity in male mice. Endocrinology 2015; 156(4): 1398-407.
[http://dx.doi.org/10.1210/en.2014-1660] [PMID: 25574706]
[62]
Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 2002; 8(12): 1376-82.
[http://dx.doi.org/10.1038/nm1202-798] [PMID: 12426561]
[63]
Tavares MR, Lemes SF, de Fante T, et al. Modulation of hypothalamic S6K1 and S6K2 alters feeding behavior and systemic glucose metabolism. J Endocrinol 2020; 244(1): 71-82.
[http://dx.doi.org/10.1530/JOE-19-0364] [PMID: 31557728]
[64]
Caron A, Labbé SM, Lanfray D, et al. Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity. Mol Metab 2015; 5(2): 102-12.
[http://dx.doi.org/10.1016/j.molmet.2015.11.005] [PMID: 26909318]
[65]
Ono H, Pocai A, Wang Y, et al. Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J Clin Invest 2008; 118(8): 2959-68.
[http://dx.doi.org/10.1172/JCI34277] [PMID: 18618016]
[66]
Kocalis HE, Hagan SL, George L, et al. Rictor/mTORC2 facilitates central regulation of energy and glucose homeostasis. Mol Metab 2014; 3(4): 394-407.
[http://dx.doi.org/10.1016/j.molmet.2014.01.014] [PMID: 24944899]
[67]
Chellappa K, Brinkman JA, Mukherjee S, et al. Hypothalamic mTORC2 is essential for metabolic health and longevity. Aging Cell 2019; 18(5): e13014.
[http://dx.doi.org/10.1111/acel.13014] [PMID: 31373126]
[68]
Lillioja S, Mott DM, Howard BV, et al. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med 1988; 318(19): 1217-25.
[http://dx.doi.org/10.1056/NEJM198805123181901] [PMID: 3283552]
[69]
Merz KE, Thurmond DC. Role of skeletal muscle in insulin resistance and glucose uptake. Compr Physiol 2020; 10(3): 785-809.
[http://dx.doi.org/10.1002/cphy.c190029] [PMID: 32940941]
[70]
Um SH, Frigerio F, Watanabe M, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004; 431(7005): 200-5.
[http://dx.doi.org/10.1038/nature02866] [PMID: 15306821]
[71]
Williamson DL, Dungan CM, Mahmoud AM, Mey JT, Blackburn BK, Haus JM. Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics. Am J Physiol Regul Integr Comp Physiol 2015; 309(8): R855-63.
[http://dx.doi.org/10.1152/ajpregu.00285.2015] [PMID: 26269521]
[72]
Frey JW, Jacobs BL, Goodman CA, Hornberger TA. A role for Raptor phosphorylation in the mechanical activation of mTOR signaling. Cell Signal 2014; 26(2): 313-22.
[http://dx.doi.org/10.1016/j.cellsig.2013.11.009] [PMID: 24239769]
[73]
Kleinert M, Parker BL, Fritzen AM, et al. Mammalian target of rapamycin complex 2 regulates muscle glucose uptake during exercise in mice. J Physiol 2017; 595(14): 4845-55.
[http://dx.doi.org/10.1113/JP274203] [PMID: 28464351]
[74]
Bentzinger CF, Romanino K, Cloëtta D, et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab 2008; 8(5): 411-24.
[http://dx.doi.org/10.1016/j.cmet.2008.10.002] [PMID: 19046572]
[75]
Risson V, Mazelin L, Roceri M, et al. Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy. J Cell Biol 2009; 187(6): 859-74.
[http://dx.doi.org/10.1083/jcb.200903131] [PMID: 20008564]
[76]
Bodine SC, Stitt TN, Gonzalez M, et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 2001; 3(11): 1014-9.
[http://dx.doi.org/10.1038/ncb1101-1014] [PMID: 11715023]
[77]
Castets P, Lin S, Rion N, et al. Sustained activation of mTORC1 in skeletal muscle inhibits constitutive and starvation-induced autophagy and causes a severe, late-onset myopathy. Cell Metab 2013; 17(5): 731-44.
[http://dx.doi.org/10.1016/j.cmet.2013.03.015] [PMID: 23602450]
[78]
Li W, Zhang H, Nie A, et al. mTORC1 pathway mediates beta cell compensatory proliferation in 60 % partial-pancreatectomy mice. Endocrine 2016; 53(1): 117-28.
[http://dx.doi.org/10.1007/s12020-016-0861-5] [PMID: 26818915]
[79]
Gu Y, Lindner J, Kumar A, Yuan W, Magnuson MA. Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. Diabetes 2011; 60(3): 827-37.
[http://dx.doi.org/10.2337/db10-1194] [PMID: 21266327]
[80]
Rumala CZ, Liu J, Locasale JW, Corkey BE, Deeney JT, Rameh LE. Exposure of pancreatic beta-cells to excess glucose results in bimodal activation of mTORC1 and mTOR-dependent metabolic acceleration. iScience 2020; 23(2): 100858.
[http://dx.doi.org/10.1016/j.isci.2020.100858] [PMID: 32058969]
[81]
Ding L, Yin Y, Han L, Li Y, Zhao J, Zhang W. TSC1-mTOR signaling determines the differentiation of islet cells. J Endocrinol 2017; 232(1): 59-70.
[http://dx.doi.org/10.1530/JOE-16-0276] [PMID: 27754935]
[82]
Blandino-Rosano M, Barbaresso R, Jimenez-Palomares M, et al. Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing. Nat Commun 2017; 8: 16014.
[http://dx.doi.org/10.1038/ncomms16014] [PMID: 28699639]
[83]
Ni Q, Gu Y, Xie Y, et al. Raptor regulates functional maturation of murine beta cells. Nat Commun 2017; 8: 15755.
[http://dx.doi.org/10.1038/ncomms15755] [PMID: 28598424]
[84]
Mori H, Inoki K, Opland D, et al. Critical roles for the TSC-mTOR pathway in β-cell function. Am J Physiol Endocrinol Metab 2009; 297(5): E1013-22.
[http://dx.doi.org/10.1152/ajpendo.00262.2009] [PMID: 19690069]
[85]
Shigeyama Y, Kobayashi T, Kido Y, et al. Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice. Mol Cell Biol 2008; 28(9): 2971-9.
[http://dx.doi.org/10.1128/MCB.01695-07] [PMID: 18316403]
[86]
Warren KJ, Fang X, Gowda NM, Thompson JJ, Heller NM. The TORC1-activated proteins, p70S6K and GRB10, regulate IL-4 signaling and M2 macrophage polarization by modulating phosphorylation of insulin receptor substrate-2. J Biol Chem 2016; 291(48): 24922-30.
[http://dx.doi.org/10.1074/jbc.M116.756791] [PMID: 27742835]
[87]
Lee JH, Budanov AV, Talukdar S, et al. Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3. Cell Metab 2012; 16(3): 311-21.
[http://dx.doi.org/10.1016/j.cmet.2012.08.004] [PMID: 22958918]
[88]
Tao R, Xiong X, Liangpunsakul S, Dong XC. Sestrin 3 protein enhances hepatic insulin sensitivity by direct activation of the mTORC2-Akt signaling. Diabetes 2015; 64(4): 1211-23.
[http://dx.doi.org/10.2337/db14-0539] [PMID: 25377878]
[89]
Umemura A, Park EJ, Taniguchi K, et al. Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition. Cell Metab 2014; 20(1): 133-44.
[http://dx.doi.org/10.1016/j.cmet.2014.05.001] [PMID: 24910242]
[90]
Javary J, Allain-Courtois N, Saucisse N, et al. Liver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling. Gut 2018; 67(12): 2192-203.
[http://dx.doi.org/10.1136/gutjnl-2017-314208] [PMID: 29074727]
[91]
Hagiwara A, Cornu M, Cybulski N, et al. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab 2012; 15(5): 725-38.
[http://dx.doi.org/10.1016/j.cmet.2012.03.015] [PMID: 22521878]
[92]
Yuan M, Pino E, Wu L, Kacergis M, Soukas AA. Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2. J Biol Chem 2012; 287(35): 29579-88.
[http://dx.doi.org/10.1074/jbc.M112.386854] [PMID: 22773877]
[93]
Khan MW, Biswas D, Ghosh M, Mandloi S, Chakrabarti S, Chakrabarti P. mTORC2 controls cancer cell survival by modulating gluconeogenesis. Cell Death Discov 2015; 1: 15016.
[http://dx.doi.org/10.1038/cddiscovery.2015.16] [PMID: 27551450]
[94]
Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 2010; 468(7327): 1100-4.
[http://dx.doi.org/10.1038/nature09584] [PMID: 21179166]
[95]
Nazio F, Strappazzon F, Antonioli M, et al. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol 2013; 15(4): 406-16.
[http://dx.doi.org/10.1038/ncb2708] [PMID: 23524951]
[96]
Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 2014; 15(3): 155-62.
[http://dx.doi.org/10.1038/nrm3757] [PMID: 24556838]
[97]
Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 2015; 125(1): 25-32.
[http://dx.doi.org/10.1172/JCI73939] [PMID: 25654547]
[98]
Porstmann T, Santos CR, Griffiths B, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008; 8(3): 224-36.
[http://dx.doi.org/10.1016/j.cmet.2008.07.007] [PMID: 18762023]
[99]
Han J, Li E, Chen L, et al. The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 2015; 524(7564): 243-6.
[http://dx.doi.org/10.1038/nature14557] [PMID: 26147081]
[100]
Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 2010; 140(6): 900-17.
[http://dx.doi.org/10.1016/j.cell.2010.02.034] [PMID: 20303879]
[101]
Ahmed B, Sultana R, Greene MW. Adipose tissue and insulin resistance in obese. Biomed Pharmacother 2021; 137: 111315.
[http://dx.doi.org/10.1016/j.biopha.2021.111315] [PMID: 33561645]
[102]
Polak P, Cybulski N, Feige JN, Auwerx J, Rüegg MA, Hall MN. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab 2008; 8(5): 399-410.
[http://dx.doi.org/10.1016/j.cmet.2008.09.003] [PMID: 19046571]
[103]
Shi Y, Li F, Wang S, et al. miR-196b-5p controls adipocyte differentiation and lipogenesis through regulating mTORC1 and TGF-β signaling. FASEB J 2020; 34(7): 9207-22.
[http://dx.doi.org/10.1096/fj.201901562RR] [PMID: 32469097]
[104]
Carnevalli LS, Masuda K, Frigerio F, et al. S6K1 plays a critical role in early adipocyte differentiation. Dev Cell 2010; 18(5): 763-74.
[http://dx.doi.org/10.1016/j.devcel.2010.02.018] [PMID: 20493810]
[105]
Le Bacquer O, Petroulakis E, Paglialunga S, et al. Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2. J Clin Invest 2007; 117(2): 387-96.
[http://dx.doi.org/10.1172/JCI29528] [PMID: 17273556]
[106]
Xiang X, Lan H, Tang H, et al. Tuberous sclerosis complex 1-mechanistic target of rapamycin complex 1 signaling determines brown-to-white adipocyte phenotypic switch. Diabetes 2015; 64(2): 519-28.
[http://dx.doi.org/10.2337/db14-0427] [PMID: 25213336]
[107]
Kumar A, Lawrence JC Jr, Jung DY, et al. Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 2010; 59(6): 1397-406.
[http://dx.doi.org/10.2337/db09-1061] [PMID: 20332342]
[108]
Allu PKR, Paulo E, Bertholet AM, et al. Role of mTORC2 in biphasic regulation of brown fat metabolism in response to mild and severe cold. J Biol Chem 2021; 296: 100632.
[http://dx.doi.org/10.1016/j.jbc.2021.100632] [PMID: 33865855]
[109]
Hung CM, Calejman CM, Sanchez-Gurmaches J, et al. Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease. Cell Rep 2014; 8(1): 256-71.
[http://dx.doi.org/10.1016/j.celrep.2014.06.007] [PMID: 25001283]
[110]
Tang Y, Wallace M, Sanchez-Gurmaches J, et al. Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism. Nat Commun 2016; 7: 11365.
[http://dx.doi.org/10.1038/ncomms11365] [PMID: 27098609]
[111]
Yao Y, Suraokar M, Darnay BG, et al. BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation. Sci Signal 2013; 6(257): ra2.
[http://dx.doi.org/10.1126/scisignal.2003295] [PMID: 23300339]
[112]
Cao Z, Cooper ME. Pathogenesis of diabetic nephropathy. J Diabetes Investig 2011; 2(4): 243-7.
[http://dx.doi.org/10.1111/j.2040-1124.2011.00131.x] [PMID: 24843491]
[113]
Gödel M, Hartleben B, Herbach N, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest 2011; 121(6): 2197-209.
[http://dx.doi.org/10.1172/JCI44774] [PMID: 21606591]
[114]
Kogot-Levin A, Hinden L, Riahi Y, et al. Proximal tubule mTORC1 is a central player in the pathophysiology of diabetic nephropathy and its correction by SGLT2 inhibitors. Cell Rep 2020; 32(4): 107954.
[http://dx.doi.org/10.1016/j.celrep.2020.107954] [PMID: 32726619]
[115]
Nagai K, Matsubara T, Mima A, et al. Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy. Kidney Int 2005; 68(2): 552-61.
[http://dx.doi.org/10.1111/j.1523-1755.2005.00433.x] [PMID: 16014032]
[116]
Inoki K, Mori H, Wang J, et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest 2011; 121(6): 2181-96.
[http://dx.doi.org/10.1172/JCI44771] [PMID: 21606597]
[117]
Yang Y, Wang J, Qin L, et al. Rapamycin prevents early steps of the development of diabetic nephropathy in rats. Am J Nephrol 2007; 27(5): 495-502.
[http://dx.doi.org/10.1159/000106782] [PMID: 17671379]
[118]
Wittmann S, Daniel C, Stief A, Vogelbacher R, Amann K, Hugo C. Long-term treatment of sirolimus but not cyclosporine ameliorates diabetic nephropathy in the rat. Transplantation 2009; 87(9): 1290-9.
[http://dx.doi.org/10.1097/TP.0b013e3181a192bd] [PMID: 19424027]
[119]
Lloberas N, Cruzado JM, Franquesa M, et al. Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats. J Am Soc Nephrol 2006; 17(5): 1395-404.
[http://dx.doi.org/10.1681/ASN.2005050549] [PMID: 16597691]
[120]
Stridh S, Palm F, Takahashi T, Ikegami-Kawai M, Hansell P. Inhibition of mTOR activity in diabetes mellitus reduces proteinuria but not renal accumulation of hyaluronan. Ups J Med Sci 2015; 120(4): 233-40.
[http://dx.doi.org/10.3109/03009734.2015.1062442] [PMID: 26175092]
[121]
Proud CG. Ras, PI3-kinase and mTOR signaling in cardiac hypertrophy. Cardiovasc Res 2004; 63(3): 403-13.
[http://dx.doi.org/10.1016/j.cardiores.2004.02.003] [PMID: 15276465]
[122]
Davogustto GE, Salazar RL, Vasquez HG, et al. Metabolic remodeling precedes mTORC1-mediated cardiac hypertrophy. J Mol Cell Cardiol 2021; 158: 115-27.
[http://dx.doi.org/10.1016/j.yjmcc.2021.05.016] [PMID: 34081952]
[123]
Völkers M, Toko H, Doroudgar S, et al. Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1. Proc Natl Acad Sci USA 2013; 110(31): 12661-6.
[http://dx.doi.org/10.1073/pnas.1301455110] [PMID: 23842089]
[124]
Kanamori H, Takemura G, Goto K, et al. Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes. Autophagy 2015; 11(7): 1146-60.
[http://dx.doi.org/10.1080/15548627.2015.1051295] [PMID: 26042865]
[125]
Zhai P, Sciarretta S, Galeotti J, Volpe M, Sadoshima J. Differential roles of GSK-3β during myocardial ischemia and ischemia/reperfusion. Circ Res 2011; 109(5): 502-11.
[http://dx.doi.org/10.1161/CIRCRESAHA.111.249532] [PMID: 21737790]
[126]
Matsui Y, Takagi H, Qu X, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 2007; 100(6): 914-22.
[http://dx.doi.org/10.1161/01.RES.0000261924.76669.36] [PMID: 17332429]
[127]
Völkers M, Konstandin MH, Doroudgar S, et al. Mechanistic target of rapamycin complex 2 protects the heart from ischemic damage. Circulation 2013; 128(19): 2132-44.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003638] [PMID: 24008870]
[128]
Janghorbani M, Feskanich D, Willett WC, Hu F. Prospective study of diabetes and risk of hip fracture: the Nurses’ Health Study. Diabetes Care 2006; 29(7): 1573-8.
[http://dx.doi.org/10.2337/dc06-0440] [PMID: 16801581]
[129]
Zhang Y, Vasheghani F, Li YH, et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann Rheum Dis 2015; 74(7): 1432-40.
[http://dx.doi.org/10.1136/annrheumdis-2013-204599] [PMID: 24651621]
[130]
Ribeiro M, López de Figueroa P, Nogueira-Recalde U, et al. Diabetes-accelerated experimental osteoarthritis is prevented by autophagy activation. Osteoarthritis Cartilage 2016; 24(12): 2116-25.
[http://dx.doi.org/10.1016/j.joca.2016.06.019] [PMID: 27390029]
[131]
Feng X, Pan J, Li J, et al. Metformin attenuates cartilage degeneration in an experimental osteoarthritis model by regulating AMPK/mTOR. Aging (Albany NY) 2020; 12(2): 1087-103.
[http://dx.doi.org/10.18632/aging.102635] [PMID: 31945013]
[132]
Cai ZY, Yang B, Shi YX, et al. High glucose downregulates the effects of autophagy on osteoclastogenesis via the AMPK/mTOR/ULK1 pathway. Biochem Biophys Res Commun 2018; 503(2): 428-35.
[http://dx.doi.org/10.1016/j.bbrc.2018.04.052] [PMID: 29649480]
[133]
Wei J, Jiang H, Gao H, Wang G. Blocking mammalian target of rapamycin (mTOR) attenuates HIF-1alpha pathways engaged-vascular endothelial growth factor (VEGF) in diabetic retinopathy. Cell Physiol Biochem 2016; 40(6): 1570-7.
[http://dx.doi.org/10.1159/000453207] [PMID: 27997905]
[134]
Lopes de FJM, Duarte DA, Montemurro C, Papadimitriou A, Consonni SR, Lopes de Faria JB. Defective autophagy in diabetic retinopathy. Invest Ophthalmol Vis Sci 2016; 57(10): 4356-66.
[http://dx.doi.org/10.1167/iovs.16-19197] [PMID: 27564518]
[135]
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): 1024-31.
[http://dx.doi.org/10.3892/mmr.2018.9749] [PMID: 30569107]
[136]
Elsherbiny NM, Abdel-Mottaleb Y, Elkazaz AY, et al. Carbamazepine alleviates retinal and optic nerve neural degeneration in diabetic mice via nerve growth factor-induced PI3K/Akt/mTOR activation. Front Neurosci 2019; 13: 1089.
[http://dx.doi.org/10.3389/fnins.2019.01089] [PMID: 31736682]
[137]
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: 1201-7.
[http://dx.doi.org/10.1016/j.biopha.2018.09.140] [PMID: 30372821]
[138]
Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP. mTOR kinase structure, mechanism and regulation. Nature 2013; 497(7448): 217-23.
[http://dx.doi.org/10.1038/nature12122] [PMID: 23636326]
[139]
Lamming DW, Ye L, Katajisto P, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 2012; 335(6076): 1638-43.
[http://dx.doi.org/10.1126/science.1215135] [PMID: 22461615]
[140]
Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22(2): 159-68.
[http://dx.doi.org/10.1016/j.molcel.2006.03.029] [PMID: 16603397]
[141]
Krebs M, Brunmair B, Brehm A, et al. The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man. Diabetes 2007; 56(6): 1600-7.
[http://dx.doi.org/10.2337/db06-1016] [PMID: 17329620]
[142]
Zhou W, Ye S. Rapamycin improves insulin resistance and hepatic steatosis in type 2 diabetes rats through activation of autophagy. Cell Biol Int 2018; 42(10): 1282-91.
[http://dx.doi.org/10.1002/cbin.11015] [PMID: 29908010]
[143]
Reifsnyder PC, Flurkey K, Te A, Harrison DE. Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes. Aging (Albany NY) 2016; 8(11): 3120-30.
[http://dx.doi.org/10.18632/aging.101117] [PMID: 27922820]
[144]
Sakaguchi M, Isono M, Isshiki K, Sugimoto T, Koya D, Kashiwagi A. Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice. Biochem Biophys Res Commun 2006; 340(1): 296-301.
[http://dx.doi.org/10.1016/j.bbrc.2005.12.012] [PMID: 16364254]
[145]
Sataranatarajan K, Mariappan MM, Lee MJ, et al. Regulation of elongation phase of mRNA translation in diabetic nephropathy: amelioration by rapamycin. Am J Pathol 2007; 171(6): 1733-42.
[http://dx.doi.org/10.2353/ajpath.2007.070412] [PMID: 17991718]
[146]
Teutonico A, Schena PF, Di Paolo S. Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol 2005; 16(10): 3128-35.
[http://dx.doi.org/10.1681/ASN.2005050487] [PMID: 16107580]
[147]
Johnston O, Rose CL, Webster AC, Gill JS. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol 2008; 19(7): 1411-8.
[http://dx.doi.org/10.1681/ASN.2007111202] [PMID: 18385422]
[148]
Sivendran S, Agarwal N, Gartrell B, et al. Metabolic complications with the use of mTOR inhibitors for cancer therapy. Cancer Treat Rev 2014; 40(1): 190-6.
[http://dx.doi.org/10.1016/j.ctrv.2013.04.005] [PMID: 23684373]
[149]
Xu KY, Shameem R, Wu S. Risk of hyperglycemia attributable to everolimus in cancer patients: A meta-analysis. Acta Oncol 2016; 55(9-10): 1196-203.
[http://dx.doi.org/10.3109/0284186X.2016.1168939] [PMID: 27142123]
[150]
Dodds SG, Livi CB, Parihar M, et al. Adaptations to chronic rapamycin in mice. Pathobiol Aging Age Relat Dis 2016; 6: 31688.
[http://dx.doi.org/10.3402/pba.v6.31688] [PMID: 27237224]
[151]
Fang Y, Westbrook R, Hill C, et al. Duration of rapamycin treatment has differential effects on metabolism in mice. Cell Metab 2013; 17(3): 456-62.
[http://dx.doi.org/10.1016/j.cmet.2013.02.008] [PMID: 23473038]
[152]
Arif A, Terenzi F, Potdar AA, et al. EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. Nature 2017; 542(7641): 357-61.
[http://dx.doi.org/10.1038/nature21380] [PMID: 28178239]

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