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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: Chen, Changwei, Gallagher, Jennifer R., Tarlton, Jamie, van Aalten, Lidy, Bray, Susan E., Ashford, Michael L. J., McCrimmon, Rory J., Pearson, Ewan R., McNeilly, Alison D., Sutherland, Calum
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248654/
https://www.ncbi.nlm.nih.gov/pubmed/34197485
http://dx.doi.org/10.1371/journal.pone.0253533
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author Chen, Changwei
Gallagher, Jennifer R.
Tarlton, Jamie
van Aalten, Lidy
Bray, Susan E.
Ashford, Michael L. J.
McCrimmon, Rory J.
Pearson, Ewan R.
McNeilly, Alison D.
Sutherland, Calum
author_facet Chen, Changwei
Gallagher, Jennifer R.
Tarlton, Jamie
van Aalten, Lidy
Bray, Susan E.
Ashford, Michael L. J.
McCrimmon, Rory J.
Pearson, Ewan R.
McNeilly, Alison D.
Sutherland, Calum
author_sort Chen, Changwei
collection PubMed
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.
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spelling pubmed-82486542021-07-09 The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection Chen, Changwei Gallagher, Jennifer R. Tarlton, Jamie van Aalten, Lidy Bray, Susan E. Ashford, Michael L. J. McCrimmon, Rory J. Pearson, Ewan R. McNeilly, Alison D. Sutherland, Calum PLoS One Research Article 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. Public Library of Science 2021-07-01 /pmc/articles/PMC8248654/ /pubmed/34197485 http://dx.doi.org/10.1371/journal.pone.0253533 Text en © 2021 Chen et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Chen, Changwei
Gallagher, Jennifer R.
Tarlton, Jamie
van Aalten, Lidy
Bray, Susan E.
Ashford, Michael L. J.
McCrimmon, Rory J.
Pearson, Ewan R.
McNeilly, Alison D.
Sutherland, Calum
The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection
title 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_short 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248654/
https://www.ncbi.nlm.nih.gov/pubmed/34197485
http://dx.doi.org/10.1371/journal.pone.0253533
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