Metformin overcomes high glucose-induced insulin resistance of podocytes by pleiotropic effects on SIRT1 and AMPK

Dorota Rogacka , Irena Audzeyenka , Michał Rychłowski , Patrycja Rachubik , Maria Szrejder , Stefan Angielski , Agnieszka Piwkowska

Abstract

Podocyte insulin sensitivity is critical for glomerular function, and the loss of appropriate insulin signaling leads to alterations and disorders featuring diabetic nephropathy. Energy-sensing pathways, such as AMP-dependent protein kinase (AMPK) and protein deacetylase SIRT1, have been shown to play an important role in insulin resistance. The absence of a stimulating effect of insulin on glucose uptake into podocytes after exposure to hyperglycemic conditions has been demonstrated to be related to a decreased level and activity of SIRT1 protein, leading to reduced AMPK phosphorylation. The present work was undertaken to investigate metformin's ability to restore the insulin responsiveness of podocytes by regulating SIRT1 and AMPK activities. Primary rat podocytes cultured with standard or high glucose concentrations for 5 days were transfected with siRNAs targeting SIRT1, AMPKα1, or AMPKα2. SIRT1 activity was measured by a fluorometric method. Insulin-stimulated changes in glucose uptake were used to detect insulin resistance. Podocyte permeability was measured by a transmembrane albumin flux assay to examine podocytes functioning. Our results demonstrated that metformin activated SIRT1 and AMPK, prevented hyperglycemia-induced reduction of SIRT1 protein levels, ameliorated glucose uptake into podocytes, and decreased glomerular filtration barrier permeability. Furthermore, metformin activated AMPK in a SIRT1-independent manner, as the increase in AMPK phosphorylation after metformin treatment was not affected by SIRT1 downregulation. Therefore, the potentiating effect of metformin on insulin-resistant podocytes seemed to be dependent on AMPK, as well as SIRT1 activity, establishing multilateral effects of metformin action.
Author Dorota Rogacka
Dorota Rogacka,,
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, Irena Audzeyenka
Irena Audzeyenka,,
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, Michał Rychłowski (IFB / IB / LVMB)
Michał Rychłowski,,
- Laboratory of Virus Molecular Biology
, Patrycja Rachubik
Patrycja Rachubik,,
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, Maria Szrejder
Maria Szrejder,,
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, Stefan Angielski
Stefan Angielski,,
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, Agnieszka Piwkowska
Agnieszka Piwkowska,,
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Journal seriesBiochimica et Biophysica Acta-Molecular Basis of Disease, ISSN 0925-4439, (A 40 pkt)
Issue year2018
Vol1864
No1
Pages115-125
Publication size in sheets0.5
Keywords in Englishpodocyte, metformin, hyperglycemia, insulin resistance, SIRT1, AMPK
DOIDOI:10.1016/j.bbadis.2017.10.014
URL https://doi.org/10.1016/j.bbadis.2017.10.014
Languageen angielski
Score (nominal)40
ScoreMinisterial score = 40.0, 09-02-2018, ArticleFromJournal
Ministerial score (2013-2016) = 40.0, 09-02-2018, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 5.476 (2) - 2016=5.725 (5)
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