TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists

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Abstract

This article is addressed to endocrinologists treating patients with diabetic complications as well as to basic scientists studying an elusive link between diseases and aging. It answers some challenging questions. What is the link between insulin resistance (IR), cellular aging and diseases? Why complications such as retinopathy may paradoxically precede the onset of type II diabetes. Why intensive insulin therapy may initially worsen retinopathy. How nutrient- and insulin-sensing mammalian target of rapamycin (mTOR) pathway can drive insulin resistance and diabetic complications. And how rapamycin, at rational doses and schedules, may prevent IR, retinopathy, nephropathy and beta-cell failure, without causing side effects.

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Most cited references 142

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Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling.

Yonghao Yu, Sang-Oh Yoon, George Poulogiannis … (2011)

The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor-bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen-activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down-regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1.

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Record: found
Abstract: found
Article: not found

Rapamycin slows aging in mice.

John E Wilkinson, Lisa Burmeister, Susan V Brooks … (2012)

Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age-dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in spontaneous activity, occur more slowly in rapamycin-treated mice, suggesting strongly that rapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease. We also note, however, that mice treated with rapamycin starting at 9 months of age have significantly higher incidence of testicular degeneration and cataracts; harmful effects of this kind will guide further studies on timing, dosage, and tissue-specific actions of rapamycin relevant to the development of clinically useful inhibitors of TOR action. © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

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Record: found
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Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis.

M Harris, R. Klein, T A Welborn … (1992)

To investigate duration of the period between diabetes onset and its clinical diagnosis. Two population-based groups of white patients with non-insulin-dependent diabetes (NIDDM) in the United States and Australia were studied. Prevalence of retinopathy and duration of diabetes subsequent to clinical diagnosis were determined for all subjects. Weighted linear regression was used to examine the relationship between diabetes duration and prevalence of retinopathy. Prevalence of retinopathy at clinical diagnosis of diabetes was estimated to be 20.8% in the U.S. and 9.9% in Australia and increased linearly with longer duration of diabetes. By extrapolating this linear relationship to the time when retinopathy prevalence was estimated to be zero, onset of detectable retinopathy was calculated to have occurred approximately 4-7 yr before diagnosis of NIDDM. Because other data indicate that diabetes may be present for 5 yr before retinopathy becomes evident, onset of NIDDM may occur 9-12 yr before its clinical diagnosis. These findings suggest that undiagnosed NIDDM is not a benign condition. Clinically significant morbidity is present at diagnosis and for years before diagnosis. During this preclinical period, treatment is not being offered for diabetes or its specific complications, despite the fact that reduction in hyperglycemia, hypertension, and cardiovascular risk factors is believed to benefit patients. Imprecise dating of diabetes onset also obscures investigations of the etiology of NIDDM and studies of the nature and importance of risk factors for diabetes complications.

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Author and article information

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group

ISSN (Electronic): 2041-4889

Publication date (Print): December 2013

Publication date (Electronic): 12 December 2013

Publication date PMC-release: 1 December 2013

Volume: 4

Issue: 12

Page: e964

Affiliations

[1 ]Department of Cell Stress Biology, Roswell Park Cancer Institute, BLSC , L3-312, Elm and Carlton Streets, Buffalo, NY, USA

Author notes

[* ]Department of Cell Stress Biology, Roswell Park Cancer Institute, BLSC , Elm and Carlton Streets, Buffalo, NY 14263, USA. Tel: +1 716 8458086; Fax: +1 716 8453944; E-mail: Mikhail.blagosklonny@ 123456roswellpark.org or blagosklonny@ 123456oncotarget.com

Article

Publisher Item ID: cddis2013506

DOI: 10.1038/cddis.2013.506

PMC ID: 3877573

PubMed ID: 24336084

SO-VID: 6fa3dd99-f793-4529-9c5f-1a7a8dd8139d

License:

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

History

Date received : 23 October 2013

Date revision received : 11 November 2013

Date accepted : 13 November 2013

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