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Metformin Corrects Abnormal Circadian Rhythm and Kir4.1 Channels in Diabetes

PURPOSE: Diabetic retinopathy (DR) is a leading cause of visual impairment. Müller cells in DR are dysfunctional due to downregulation of the inwardly rectifying potassium channel Kir4.1. Metformin, a commonly used oral antidiabetic drug, is known to elicit its action through 5′ adenosine monophosph...

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Autores principales: Alex, Alpha, Luo, Qianyi, Mathew, Deepa, Di, Rong, Bhatwadekar, Ashay D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415324/
https://www.ncbi.nlm.nih.gov/pubmed/32572457
http://dx.doi.org/10.1167/iovs.61.6.46
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author Alex, Alpha
Luo, Qianyi
Mathew, Deepa
Di, Rong
Bhatwadekar, Ashay D.
author_facet Alex, Alpha
Luo, Qianyi
Mathew, Deepa
Di, Rong
Bhatwadekar, Ashay D.
author_sort Alex, Alpha
collection PubMed
description PURPOSE: Diabetic retinopathy (DR) is a leading cause of visual impairment. Müller cells in DR are dysfunctional due to downregulation of the inwardly rectifying potassium channel Kir4.1. Metformin, a commonly used oral antidiabetic drug, is known to elicit its action through 5′ adenosine monophosphate-activated protein kinase (AMPK), a cellular metabolic regulator; however, its effect on Kir4.1 channels is unknown. For this study, we hypothesized that metformin treatment would correct circadian rhythm disruption and Kir4.1 channel dysfunction in db/db mice. METHODS: Metformin was given orally to db/db mice. Wheel-running activity, retinal levels of Kir4.1, and AMPK phosphorylation were determined at study termination. In parallel, rat retinal Müller cell line (rMC-1) cells were treated using metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to assess the effect of AMPK activation on the Kir4.1 channel. RESULTS: The wheel-running activity of the db/db mice was improved following the metformin treatment. The Kir4.1 level in Müller cells was corrected after metformin treatment. Metformin treatment led to an upregulation of clock regulatory genes such as melanopsin (Opn4) and aralkylamine N-acetyltransferase (Aanat). In rMC-1 cells, AMPK activation via AICAR and metformin resulted in increased Kir4.1 and intermediate core clock component Bmal-1 protein expression. The silencing of Prkaa1 (gene for AMPKα1) led to decreased Kir4.1 and Bmal-1 protein expression. CONCLUSIONS: Our findings demonstrate that metformin corrects abnormal circadian rhythm and Kir4.1 channels in db/db mouse a model of type 2 diabetes. Metformin could represent a critical pharmacological agent for preventing Müller cell dysfunction observed in human DR.
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spelling pubmed-74153242020-08-24 Metformin Corrects Abnormal Circadian Rhythm and Kir4.1 Channels in Diabetes Alex, Alpha Luo, Qianyi Mathew, Deepa Di, Rong Bhatwadekar, Ashay D. Invest Ophthalmol Vis Sci Retinal Cell Biology PURPOSE: Diabetic retinopathy (DR) is a leading cause of visual impairment. Müller cells in DR are dysfunctional due to downregulation of the inwardly rectifying potassium channel Kir4.1. Metformin, a commonly used oral antidiabetic drug, is known to elicit its action through 5′ adenosine monophosphate-activated protein kinase (AMPK), a cellular metabolic regulator; however, its effect on Kir4.1 channels is unknown. For this study, we hypothesized that metformin treatment would correct circadian rhythm disruption and Kir4.1 channel dysfunction in db/db mice. METHODS: Metformin was given orally to db/db mice. Wheel-running activity, retinal levels of Kir4.1, and AMPK phosphorylation were determined at study termination. In parallel, rat retinal Müller cell line (rMC-1) cells were treated using metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to assess the effect of AMPK activation on the Kir4.1 channel. RESULTS: The wheel-running activity of the db/db mice was improved following the metformin treatment. The Kir4.1 level in Müller cells was corrected after metformin treatment. Metformin treatment led to an upregulation of clock regulatory genes such as melanopsin (Opn4) and aralkylamine N-acetyltransferase (Aanat). In rMC-1 cells, AMPK activation via AICAR and metformin resulted in increased Kir4.1 and intermediate core clock component Bmal-1 protein expression. The silencing of Prkaa1 (gene for AMPKα1) led to decreased Kir4.1 and Bmal-1 protein expression. CONCLUSIONS: Our findings demonstrate that metformin corrects abnormal circadian rhythm and Kir4.1 channels in db/db mouse a model of type 2 diabetes. Metformin could represent a critical pharmacological agent for preventing Müller cell dysfunction observed in human DR. The Association for Research in Vision and Ophthalmology 2020-06-22 /pmc/articles/PMC7415324/ /pubmed/32572457 http://dx.doi.org/10.1167/iovs.61.6.46 Text en Copyright 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Retinal Cell Biology
Alex, Alpha
Luo, Qianyi
Mathew, Deepa
Di, Rong
Bhatwadekar, Ashay D.
Metformin Corrects Abnormal Circadian Rhythm and Kir4.1 Channels in Diabetes
title Metformin Corrects Abnormal Circadian Rhythm and Kir4.1 Channels in Diabetes
title_full Metformin Corrects Abnormal Circadian Rhythm and Kir4.1 Channels in Diabetes
title_fullStr Metformin Corrects Abnormal Circadian Rhythm and Kir4.1 Channels in Diabetes
title_full_unstemmed Metformin Corrects Abnormal Circadian Rhythm and Kir4.1 Channels in Diabetes
title_short Metformin Corrects Abnormal Circadian Rhythm and Kir4.1 Channels in Diabetes
title_sort metformin corrects abnormal circadian rhythm and kir4.1 channels in diabetes
topic Retinal Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415324/
https://www.ncbi.nlm.nih.gov/pubmed/32572457
http://dx.doi.org/10.1167/iovs.61.6.46
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