Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/105234 https://doi.org/10.3390/metabo11090574 |
Resumo: | Inhibition of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase is associated with an increased risk of new-onset type 2 diabetes. We studied the association of genetic or pharmacological HMG-CoA reductase inhibition with plasma and adipose tissue (AT) metabolome and AT metabolic pathways. We also investigated the effects of statin-mediated pharmacological inhibition of HMG-CoA reductase on systemic insulin sensitivity by measuring the HOMA-IR index in subjects with or without statin therapy. The direct effects of simvastatin (20-250 nM) or its active metabolite simvastatin hydroxy acid (SA) (8-30 nM) were investigated on human adipocyte glucose uptake, lipolysis, and differentiation and pancreatic insulin secretion. We observed that the LDL-lowering HMGCR rs12916-T allele was negatively associated with plasma phosphatidylcholines and sphingomyelins, and HMGCR expression in AT was correlated with various metabolic and mitochondrial pathways. Clinical data showed that statin treatment was associated with HOMA-IR index after adjustment for age, sex, BMI, HbA1c, LDL-c levels, and diabetes status in the subjects. Supra-therapeutic concentrations of simvastatin reduced glucose uptake in adipocytes and normalized fatty acid-induced insulin hypersecretion from β-cells. Our data suggest that inhibition of HMG-CoA reductase is associated with insulin resistance. However, statins have a very mild direct effect on AT and pancreas, hence, other tissues as the liver or muscle appear to be of greater importance. |
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Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolomestatinsadipose tissue-cellinsulin resistanceglucose uptaketype 2 diabetesInhibition of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase is associated with an increased risk of new-onset type 2 diabetes. We studied the association of genetic or pharmacological HMG-CoA reductase inhibition with plasma and adipose tissue (AT) metabolome and AT metabolic pathways. We also investigated the effects of statin-mediated pharmacological inhibition of HMG-CoA reductase on systemic insulin sensitivity by measuring the HOMA-IR index in subjects with or without statin therapy. The direct effects of simvastatin (20-250 nM) or its active metabolite simvastatin hydroxy acid (SA) (8-30 nM) were investigated on human adipocyte glucose uptake, lipolysis, and differentiation and pancreatic insulin secretion. We observed that the LDL-lowering HMGCR rs12916-T allele was negatively associated with plasma phosphatidylcholines and sphingomyelins, and HMGCR expression in AT was correlated with various metabolic and mitochondrial pathways. Clinical data showed that statin treatment was associated with HOMA-IR index after adjustment for age, sex, BMI, HbA1c, LDL-c levels, and diabetes status in the subjects. Supra-therapeutic concentrations of simvastatin reduced glucose uptake in adipocytes and normalized fatty acid-induced insulin hypersecretion from β-cells. Our data suggest that inhibition of HMG-CoA reductase is associated with insulin resistance. However, statins have a very mild direct effect on AT and pancreas, hence, other tissues as the liver or muscle appear to be of greater importance.This research was funded by research grants from the Excellence of Diabetes Research in Sweden (EXODIAB), European Commision via the Marie Sklodowska Curie Innovative Training Network TREATMENT (H2020-MSCA-ITN-721236), the Uppsala University Hospital ALF grants, Svenska Sällskapet för Medicinsk Forskning (Swedish Society for Medical Research), the Diabetes Foundation (Swedish Diabetes Association), the Ernfors Foundation, and the P.O Zetterling Foundation.MDPI2021-08-25info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/105234http://hdl.handle.net/10316/105234https://doi.org/10.3390/metabo11090574eng2218-1989Sarsenbayeva, AsselJui, Bipasha NandiFanni, GiovanniBarbosa, PedroAhmed, FoziaKristófi, RobinCen, JingChowdhury, AzazulSkrtic, StankoBergsten, PeterFall, ToveEriksson, Jan W.Pereira, Maria J.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-04-06T10:20:20Zoai:estudogeral.uc.pt:10316/105234Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:21:50.108495Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome |
title |
Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome |
spellingShingle |
Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome Sarsenbayeva, Assel statins adipose tissue -cell insulin resistance glucose uptake type 2 diabetes |
title_short |
Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome |
title_full |
Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome |
title_fullStr |
Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome |
title_full_unstemmed |
Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome |
title_sort |
Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome |
author |
Sarsenbayeva, Assel |
author_facet |
Sarsenbayeva, Assel Jui, Bipasha Nandi Fanni, Giovanni Barbosa, Pedro Ahmed, Fozia Kristófi, Robin Cen, Jing Chowdhury, Azazul Skrtic, Stanko Bergsten, Peter Fall, Tove Eriksson, Jan W. Pereira, Maria J. |
author_role |
author |
author2 |
Jui, Bipasha Nandi Fanni, Giovanni Barbosa, Pedro Ahmed, Fozia Kristófi, Robin Cen, Jing Chowdhury, Azazul Skrtic, Stanko Bergsten, Peter Fall, Tove Eriksson, Jan W. Pereira, Maria J. |
author2_role |
author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Sarsenbayeva, Assel Jui, Bipasha Nandi Fanni, Giovanni Barbosa, Pedro Ahmed, Fozia Kristófi, Robin Cen, Jing Chowdhury, Azazul Skrtic, Stanko Bergsten, Peter Fall, Tove Eriksson, Jan W. Pereira, Maria J. |
dc.subject.por.fl_str_mv |
statins adipose tissue -cell insulin resistance glucose uptake type 2 diabetes |
topic |
statins adipose tissue -cell insulin resistance glucose uptake type 2 diabetes |
description |
Inhibition of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase is associated with an increased risk of new-onset type 2 diabetes. We studied the association of genetic or pharmacological HMG-CoA reductase inhibition with plasma and adipose tissue (AT) metabolome and AT metabolic pathways. We also investigated the effects of statin-mediated pharmacological inhibition of HMG-CoA reductase on systemic insulin sensitivity by measuring the HOMA-IR index in subjects with or without statin therapy. The direct effects of simvastatin (20-250 nM) or its active metabolite simvastatin hydroxy acid (SA) (8-30 nM) were investigated on human adipocyte glucose uptake, lipolysis, and differentiation and pancreatic insulin secretion. We observed that the LDL-lowering HMGCR rs12916-T allele was negatively associated with plasma phosphatidylcholines and sphingomyelins, and HMGCR expression in AT was correlated with various metabolic and mitochondrial pathways. Clinical data showed that statin treatment was associated with HOMA-IR index after adjustment for age, sex, BMI, HbA1c, LDL-c levels, and diabetes status in the subjects. Supra-therapeutic concentrations of simvastatin reduced glucose uptake in adipocytes and normalized fatty acid-induced insulin hypersecretion from β-cells. Our data suggest that inhibition of HMG-CoA reductase is associated with insulin resistance. However, statins have a very mild direct effect on AT and pancreas, hence, other tissues as the liver or muscle appear to be of greater importance. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-08-25 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/105234 http://hdl.handle.net/10316/105234 https://doi.org/10.3390/metabo11090574 |
url |
http://hdl.handle.net/10316/105234 https://doi.org/10.3390/metabo11090574 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
2218-1989 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
MDPI |
publisher.none.fl_str_mv |
MDPI |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799134108815720448 |