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Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity
Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signalin...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642855/ https://www.ncbi.nlm.nih.gov/pubmed/26378251 http://dx.doi.org/10.1091/mbc.E15-08-0553 |
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author | Ma, Gary S. Lopez-Sanchez, Inmaculada Aznar, Nicolas Kalogriopoulos, Nicholas Pedram, Shabnam Midde, Krishna Ciaraldi, Theodore P. Henry, Robert R. Ghosh, Pradipta |
author_facet | Ma, Gary S. Lopez-Sanchez, Inmaculada Aznar, Nicolas Kalogriopoulos, Nicholas Pedram, Shabnam Midde, Krishna Ciaraldi, Theodore P. Henry, Robert R. Ghosh, Pradipta |
author_sort | Ma, Gary S. |
collection | PubMed |
description | Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles. |
format | Online Article Text |
id | pubmed-4642855 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-46428552016-01-30 Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity Ma, Gary S. Lopez-Sanchez, Inmaculada Aznar, Nicolas Kalogriopoulos, Nicholas Pedram, Shabnam Midde, Krishna Ciaraldi, Theodore P. Henry, Robert R. Ghosh, Pradipta Mol Biol Cell Articles Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles. The American Society for Cell Biology 2015-11-15 /pmc/articles/PMC4642855/ /pubmed/26378251 http://dx.doi.org/10.1091/mbc.E15-08-0553 Text en © 2015 Ma et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | Articles Ma, Gary S. Lopez-Sanchez, Inmaculada Aznar, Nicolas Kalogriopoulos, Nicholas Pedram, Shabnam Midde, Krishna Ciaraldi, Theodore P. Henry, Robert R. Ghosh, Pradipta Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity |
title | Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity |
title_full | Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity |
title_fullStr | Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity |
title_full_unstemmed | Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity |
title_short | Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity |
title_sort | activation of g proteins by giv-gef is a pivot point for insulin resistance and sensitivity |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642855/ https://www.ncbi.nlm.nih.gov/pubmed/26378251 http://dx.doi.org/10.1091/mbc.E15-08-0553 |
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