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Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes
AIMS/HYPOTHESIS: We aimed to identify microRNAs (miRNAs) associated with type 2 diabetes and risk of developing the disease in skeletal muscle biopsies from phenotypically well-characterised twins. METHODS: We measured muscle miRNA levels in monozygotic (MZ) twins discordant for type 2 diabetes usin...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287682/ https://www.ncbi.nlm.nih.gov/pubmed/25403480 http://dx.doi.org/10.1007/s00125-014-3434-2 |
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author | Bork-Jensen, Jette Scheele, Camilla Christophersen, Daniel V. Nilsson, Emma Friedrichsen, Martin Fernandez-Twinn, Denise S. Grunnet, Louise G. Litman, Thomas Holmstrøm, Kim Vind, Birgitte Højlund, Kurt Beck-Nielsen, Henning Wojtaszewski, Jørgen Ozanne, Susan E. Pedersen, Bente K. Poulsen, Pernille Vaag, Allan |
author_facet | Bork-Jensen, Jette Scheele, Camilla Christophersen, Daniel V. Nilsson, Emma Friedrichsen, Martin Fernandez-Twinn, Denise S. Grunnet, Louise G. Litman, Thomas Holmstrøm, Kim Vind, Birgitte Højlund, Kurt Beck-Nielsen, Henning Wojtaszewski, Jørgen Ozanne, Susan E. Pedersen, Bente K. Poulsen, Pernille Vaag, Allan |
author_sort | Bork-Jensen, Jette |
collection | PubMed |
description | AIMS/HYPOTHESIS: We aimed to identify microRNAs (miRNAs) associated with type 2 diabetes and risk of developing the disease in skeletal muscle biopsies from phenotypically well-characterised twins. METHODS: We measured muscle miRNA levels in monozygotic (MZ) twins discordant for type 2 diabetes using arrays. Further investigations of selected miRNAs included target prediction, pathway analysis, silencing in cells and association analyses in a separate cohort of 164 non-diabetic MZ and dizygotic twins. The effects of elevated glucose and insulin levels on miRNA expression were examined, and the effect of low birthweight (LBW) was studied in rats. RESULTS: We identified 20 miRNAs that were downregulated in MZ twins with diabetes compared with their non-diabetic co-twins. Differences for members of the miR-15 family (miR-15b and miR-16) were the most statistically significant, and these miRNAs were predicted to influence insulin signalling. Indeed, miR-15b and miR-16 levels were associated with levels of key insulin signalling proteins, miR-15b was associated with the insulin receptor in non-diabetic twins and knockdown of miR-15b/miR-16 in myocytes changed the levels of insulin signalling proteins. LBW in twins and undernutrition during pregnancy in rats were, in contrast to overt type 2 diabetes, associated with increased expression of miR-15b and/or miR-16. Elevated glucose and insulin suppressed miR-16 expression in vitro. CONCLUSIONS: Type 2 diabetes is associated with non-genetic downregulation of several miRNAs in skeletal muscle including miR-15b and miR-16, potentially targeting insulin signalling. The paradoxical findings in twins with overt diabetes and twins at increased risk of the disease underscore the complexity of the regulation of muscle insulin signalling in glucose homeostasis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-014-3434-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users. |
format | Online Article Text |
id | pubmed-4287682 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-42876822015-01-15 Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes Bork-Jensen, Jette Scheele, Camilla Christophersen, Daniel V. Nilsson, Emma Friedrichsen, Martin Fernandez-Twinn, Denise S. Grunnet, Louise G. Litman, Thomas Holmstrøm, Kim Vind, Birgitte Højlund, Kurt Beck-Nielsen, Henning Wojtaszewski, Jørgen Ozanne, Susan E. Pedersen, Bente K. Poulsen, Pernille Vaag, Allan Diabetologia Article AIMS/HYPOTHESIS: We aimed to identify microRNAs (miRNAs) associated with type 2 diabetes and risk of developing the disease in skeletal muscle biopsies from phenotypically well-characterised twins. METHODS: We measured muscle miRNA levels in monozygotic (MZ) twins discordant for type 2 diabetes using arrays. Further investigations of selected miRNAs included target prediction, pathway analysis, silencing in cells and association analyses in a separate cohort of 164 non-diabetic MZ and dizygotic twins. The effects of elevated glucose and insulin levels on miRNA expression were examined, and the effect of low birthweight (LBW) was studied in rats. RESULTS: We identified 20 miRNAs that were downregulated in MZ twins with diabetes compared with their non-diabetic co-twins. Differences for members of the miR-15 family (miR-15b and miR-16) were the most statistically significant, and these miRNAs were predicted to influence insulin signalling. Indeed, miR-15b and miR-16 levels were associated with levels of key insulin signalling proteins, miR-15b was associated with the insulin receptor in non-diabetic twins and knockdown of miR-15b/miR-16 in myocytes changed the levels of insulin signalling proteins. LBW in twins and undernutrition during pregnancy in rats were, in contrast to overt type 2 diabetes, associated with increased expression of miR-15b and/or miR-16. Elevated glucose and insulin suppressed miR-16 expression in vitro. CONCLUSIONS: Type 2 diabetes is associated with non-genetic downregulation of several miRNAs in skeletal muscle including miR-15b and miR-16, potentially targeting insulin signalling. The paradoxical findings in twins with overt diabetes and twins at increased risk of the disease underscore the complexity of the regulation of muscle insulin signalling in glucose homeostasis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-014-3434-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Springer Berlin Heidelberg 2014-11-19 2015 /pmc/articles/PMC4287682/ /pubmed/25403480 http://dx.doi.org/10.1007/s00125-014-3434-2 Text en © Springer-Verlag Berlin Heidelberg 2014 |
spellingShingle | Article Bork-Jensen, Jette Scheele, Camilla Christophersen, Daniel V. Nilsson, Emma Friedrichsen, Martin Fernandez-Twinn, Denise S. Grunnet, Louise G. Litman, Thomas Holmstrøm, Kim Vind, Birgitte Højlund, Kurt Beck-Nielsen, Henning Wojtaszewski, Jørgen Ozanne, Susan E. Pedersen, Bente K. Poulsen, Pernille Vaag, Allan Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes |
title | Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes |
title_full | Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes |
title_fullStr | Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes |
title_full_unstemmed | Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes |
title_short | Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes |
title_sort | glucose tolerance is associated with differential expression of micrornas in skeletal muscle: results from studies of twins with and without type 2 diabetes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287682/ https://www.ncbi.nlm.nih.gov/pubmed/25403480 http://dx.doi.org/10.1007/s00125-014-3434-2 |
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