The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection.

The biguanide, metformin, is the first-choice therapeutic agent for type-2 diabetes, although the mechanisms that underpin metformin clinical efficacy remain the subject of much debate, partly due to the considerable variation in patient response to metformin. Identification of poor responders by ge...

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Autores principales:	Changwei Chen, Jennifer R Gallagher, Jamie Tarlton, Lidy van Aalten, Susan E Bray, Michael L J Ashford, Rory J McCrimmon, Ewan R Pearson, Alison D McNeilly, Calum Sutherland
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9a24a180cc2645e98a6b2242015332ed
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spelling	oai:doaj.org-article:9a24a180cc2645e98a6b2242015332ed2021-12-02T20:09:49ZThe genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection.1932-620310.1371/journal.pone.0253533https://doaj.org/article/9a24a180cc2645e98a6b2242015332ed2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0253533https://doaj.org/toc/1932-6203The biguanide, metformin, is the first-choice therapeutic agent for type-2 diabetes, although the mechanisms that underpin metformin clinical efficacy remain the subject of much debate, partly due to the considerable variation in patient response to metformin. Identification of poor responders by genotype could avoid unnecessary treatment and provide clues to the underlying mechanism of action. GWAS identified SNPs associated with metformin treatment success at a locus containing the NPAT (nuclear protein, ataxia-telangiectasia locus) and ATM (ataxia-telangiectasia mutated) genes. This implies that gene sequence dictates a subsequent biological function to influence metformin action. Hence, we modified expression of NPAT in immortalized cell lines, primary mouse hepatocytes and mouse tissues, and analysed the outcomes on metformin action using confocal microscopy, immunoblotting and immunocytochemistry. In addition, we characterised the metabolic phenotype of npat heterozygous knockout mice and established the metformin response following development of insulin resistance. NPAT protein was localised in the nucleus at discrete loci in several cell types, but over-expression or depletion of NPAT in immortalised cell models did not change cellular responses to biguanides. In contrast, metformin regulation of respiratory exchange ratio (RER) was completely lost in animals lacking one allele of npat. There was also a reduction in metformin correction of impaired glucose tolerance, however no other metabolic abnormalities, or response to metformin, were found in the npat heterozygous mice. In summary, we provide methodological advancements for the detection of NPAT, demonstrate that minor reductions in NPAT mRNA levels (20-40%) influence metformin regulation of RER, and propose that the association between NPAT SNPs and metformin response observed in GWAS, could be due to loss of metformin modification of cellular fuel usage.Changwei ChenJennifer R GallagherJamie TarltonLidy van AaltenSusan E BrayMichael L J AshfordRory J McCrimmonEwan R PearsonAlison D McNeillyCalum SutherlandPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0253533 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Changwei Chen Jennifer R Gallagher Jamie Tarlton Lidy van Aalten Susan E Bray Michael L J Ashford Rory J McCrimmon Ewan R Pearson Alison D McNeilly Calum Sutherland The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection.
description	The biguanide, metformin, is the first-choice therapeutic agent for type-2 diabetes, although the mechanisms that underpin metformin clinical efficacy remain the subject of much debate, partly due to the considerable variation in patient response to metformin. Identification of poor responders by genotype could avoid unnecessary treatment and provide clues to the underlying mechanism of action. GWAS identified SNPs associated with metformin treatment success at a locus containing the NPAT (nuclear protein, ataxia-telangiectasia locus) and ATM (ataxia-telangiectasia mutated) genes. This implies that gene sequence dictates a subsequent biological function to influence metformin action. Hence, we modified expression of NPAT in immortalized cell lines, primary mouse hepatocytes and mouse tissues, and analysed the outcomes on metformin action using confocal microscopy, immunoblotting and immunocytochemistry. In addition, we characterised the metabolic phenotype of npat heterozygous knockout mice and established the metformin response following development of insulin resistance. NPAT protein was localised in the nucleus at discrete loci in several cell types, but over-expression or depletion of NPAT in immortalised cell models did not change cellular responses to biguanides. In contrast, metformin regulation of respiratory exchange ratio (RER) was completely lost in animals lacking one allele of npat. There was also a reduction in metformin correction of impaired glucose tolerance, however no other metabolic abnormalities, or response to metformin, were found in the npat heterozygous mice. In summary, we provide methodological advancements for the detection of NPAT, demonstrate that minor reductions in NPAT mRNA levels (20-40%) influence metformin regulation of RER, and propose that the association between NPAT SNPs and metformin response observed in GWAS, could be due to loss of metformin modification of cellular fuel usage.
format	article
author	Changwei Chen Jennifer R Gallagher Jamie Tarlton Lidy van Aalten Susan E Bray Michael L J Ashford Rory J McCrimmon Ewan R Pearson Alison D McNeilly Calum Sutherland
author_facet	Changwei Chen Jennifer R Gallagher Jamie Tarlton Lidy van Aalten Susan E Bray Michael L J Ashford Rory J McCrimmon Ewan R Pearson Alison D McNeilly Calum Sutherland
author_sort	Changwei Chen
title	The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection.
title_short	The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection.
title_full	The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection.
title_fullStr	The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection.
title_full_unstemmed	The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection.
title_sort	genetic association of the transcription factor npat with glycemic response to metformin involves regulation of fuel selection.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/9a24a180cc2645e98a6b2242015332ed
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The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection.

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