Background: Mechanistic target of rapamycin (mTOR) regulates lipid and glucose metabolism thus playing a key role in metabolic diseases like type 2 diabetes mellitus (T2DM). Recently, we demonstrated a functional interaction of microRNA-496 (miR-496) with mTOR and its impact on the regulation of human ageing. Objectives: As T2DM is most prevalent in older adults, we hypothesized that miR-496 may also have an impact on mTOR regulation in T2DM. Methods: Based on real-time PCR and enzyme-linked immunosorbent assay, mTOR gene and protein expression as well as miR-496 expression were monitored in peripheral blood mononuclear cells (PBMC) from T2DM patients (median age: 71) and healthy age- and BMI matched controls (median age: 69). -Results: We demonstrated significant upregulation of phospho-mTOR and P70S6 Kinase (P70S6K) levels and significant downregulation of miR-496 in PBMC from elderly T2DM patients in comparison to a BMI and age-matched control cohort. Moreover, significant upregulation of phospho-mTOR protein and significant downregulation of miR-496 were observed in advanced stages of obesity. Conclusions: BMI-dependent upregulation of mTOR and the inverse expression profile of miR-496 observed in elderly T2DM patients suggest a correlation with T2DM. Hence, our results indicate a potential association of miR-496 with mTOR expression in elderly T2DM patients and obesity. Since phosphorylation of P70S6K was also elevated in T2DM patients, we conclude that mTOR signaling through TORC1 may be affected in the regulation of T2DM.

1.
Laplante M, Sabatini DM. mTOR signaling in growth control and disease.
Cell
. 2012 Apr; 149(2): 274–93.
2.
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 Jul; 78(1): 35–43.
3.
Lamming DW, Sabatini DM. A Central role for mTOR in lipid homeostasis.
Cell Metab
. 2013 Oct; 18(4): 465–9.
4.
Munson MJ, Ganley IG. MTOR, PIK3C3, and autophagy: signaling the beginning from the end.
Autophagy
. 2015; 11(12): 2375–6.
5.
Schmidt KM, Hellerbrand C, Ruemmele P, Michalski CW, Kong B, Kroemer A, et al. Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models.
Oncotarget
. 2017 Apr; 8(15): 24491–505.
6.
Parkhitko AA, Favorova OO, Khabibullin DI, Anisimov VN, Henske EP. Kinase mTOR: regulation and role in maintenance of cellular homeostasis, tumor development, and aging.
Biochemistry (Mosc)
. 2014 Feb; 79(2): 88–101.
7.
Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during progression to diabetes.
Diabetes
. 2004 Dec; 53 Suppl 3:S16–21.
8.
Chakrabarti P, Kandror KV. The role of mTOR in lipid homeostasis and diabetes progression.
Curr Opin Endocrinol Diabetes Obes
. 2015 Oct; 22(5): 340–6.
9.
Esau C, Kang X, Peralta E, Hanson E, Marcusson EG, Ravichandran LV, et al. MicroRNA-143 regulates adipocyte differentiation.
J Biol Chem
. 2004 Dec; 279(50): 52361–5.
10.
Xie H, Lim B, Lodish HF. MicroRNAs -induced during adipogenesis that accelerate fat cell development are downregulated in obesity.
Diabetes
. 2009 May; 58(5): 1050–7.
11.
Dehwah MA, Xu A, Huang Q. MicroRNAs and type 2 diabetes/obesity.
J Genet Genomics
. 2012 Jan; 39(1): 11–8.
12.
Kadamkode V, Banerjee G. Micro RNA: an epigenetic regulator of type 2 diabetes.
MicroRNA
. 2014; 3(2): 86–97.
13.
Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes.
Circ Res
. 2010 Sep; 107(6): 810–7.
14.
Rubie C, Kölsch K, Halajda B, Eichler H, Wagenpfeil S, Roemer K, et al. microRNA-496 - A new, potentially aging-relevant regulator of mTOR.
Cell Cycle
. 2016; 15(8): 1108–16.
15.
WHO. Obesity - preventing and managing the global epidemic. WHO Technical Report Series 894 (Genf); 2000.
16.
Chey S, Claus C, Liebert UG. Improved method for simultaneous isolation of proteins and nucleic acids.
Anal Biochem
. 2011 Apr; 411(1): 164–6.
17.
Lee PL, Jung SM, Guertin DA. The Complex Roles of Mechanistic Target of Rapamycin in Adipocytes and Beyond.
Trends Endocrinol Metab
. 2017 May; 28(5): 319–39.
18.
Brandão BB, Guerra BA, Mori MA. Shortcuts to a functional adipose tissue: the role of small non-coding RNAs.
Redox Biol
. 2017 Aug; 12: 82–102.
19.
Wu X, Schneider N, Platen A, Mitra I, Blazek M, Zengerle R, et al. In situ characterization of the mTORC1 during adipogenesis of human adult stem cells on chip.
Proc Natl Acad Sci USA
. 2016; 113(29):E4143–50.
20.
Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance.
Physiol Rev
. 2007 Apr; 87(2): 507–20.
21.
Boden G. Obesity, insulin resistance and free fatty acids.
Curr Opin Endocrinol Diabetes Obes
. 2011 Apr; 18(2): 139–43.
22.
Chakrabarti P, English T, Shi J, Smas CM, Kandror KV. Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage.
Diabetes
. 2010 Apr; 59(4): 775–81.
23.
Ost A, Svensson K, Ruishalme I, Brännmark C, Franck N, Krook H, et al. Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes.
Mol Med
. 2010 Jul-Aug; 16(7-8): 235–46.
24.
Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes.
Nat Rev Mol Cell Biol
. 2008 May; 9(5): 367–77.
25.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function.
Cell
. 2004 Jan; 116(2): 281–97.
26.
Tavintharan S, Chi LS, Fang SC, Arunmozhiarasi A, Jeyaseelan K. Riboregulators and metabolic disorders: getting closer towards understanding the pathogenesis of diabetes mellitus?
Curr Mol Med
. 2009 Apr; 9(3): 281–6.
27.
Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, et al. A pancreatic islet-specific microRNA regulates insulin secretion.
Nature
. 2004 Nov; 432(7014): 226–30.
28.
Ortega FJ, Moreno-Navarrete JM, Pardo G, Sabater M, Hummel M, Ferrer A, et al. MiRNA expression profile of human subcutaneous adipose and during adipocyte differentiation.
PLoS One
. 2010 Feb; 5(2):e9022.
29.
Ortega FJ, Mercader JM, Catalán V, Moreno-Navarrete JM, Pueyo N, Sabater M, et al. Targeting the circulating microRNA signature of obesity.
Clin Chem
. 2013 May; 59(5): 781–92.
30.
Pek SL, Sum CF, Lin MX, Cheng AK, Wong MT, Lim SC, et al. Circulating and visceral adipose miR-100 is down-regulated in patients with obesity and Type 2 diabetes.
Mol Cell Endocrinol
. 2016 May; 427: 112–23.
31.
Zhang ZW, Guo RW, Lv JL, Wang XM, Ye JS, Lu NH, et al. MicroRNA-99a inhibits insulin-induced proliferation, migration, dedifferentiation, and rapamycin resistance of vascular smooth muscle cells by inhibiting insulin-like growth factor-1 receptor and mammalian target of rapamycin.
Biochem Biophys Res Commun
. 2017 Apr; 486(2): 414–22.
32.
Wang Y, Liu J, Liu C, Naji A, Stoffers DA. MicroRNA-7 regulates the mTOR pathway and proliferation in adult pancreatic β-cells.
Diabetes
. 2013 Mar; 62(3): 887–95.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.