A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle
Aims/hypothesis Insulin-sensitive tissues (muscle, liver) of individuals with obesity and type 2 diabetes mellitus are in a state of low-grade inflammation, characterised by increased Toll-like receptor (TLR) expression and TLR-driven signalling. However, the cause of this mild inflammatory state is...
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| Veröffentlicht in: | Diabetologia 2014-03, Vol.57 (3), p.582-591 |
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| creator | Hussey, Sophie E. Lum, Helen Alvarez, Andrea Cipriani, Yolanda Garduño-Garcia, Jesús Anaya, Luis Dube, John Musi, Nicolas |
| description | Aims/hypothesis
Insulin-sensitive tissues (muscle, liver) of individuals with obesity and type 2 diabetes mellitus are in a state of low-grade inflammation, characterised by increased Toll-like receptor (TLR) expression and TLR-driven signalling. However, the cause of this mild inflammatory state is unclear. We tested the hypothesis that a prolonged mild increase in plasma NEFA will increase TLR expression and TLR-driven signalling (nuclear factor κB [NFκB] and mitogen-activated kinase [MAPK]) and impair insulin action in muscle of lean healthy individuals.
Methods
Twelve lean, normal-glucose-tolerant participants were randomised to receive a 48 h infusion (30 ml/h) of saline or Intralipid followed by a euglycaemic–hyperinsulinaemic clamp. Vastus lateralis muscle biopsies were performed before and during the clamp.
Results
Lipid infusion impaired insulin-stimulated IRS-1 tyrosine phosphorylation and reduced peripheral insulin sensitivity (
p
|
| doi_str_mv | 10.1007/s00125-013-3111-x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3945433</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1512323314</sourcerecordid><originalsourceid>FETCH-LOGICAL-c599t-7d98dfbc77e44f4c1d012390a4c8490a12b4eeec02b6b6b84ff997ddb16f15c93</originalsourceid><addsrcrecordid>eNqFkdFr1TAUxoMo7m76B_giARH20i2nSdrmRbiMTYXhXib4ZEjT03u7pWlNWp3_vSn3uk1BJA8ncH7ny5fzEfIK2AkwVp5GxiCXGQOecQDI7p6QFQieZ0zk1VOyWtoZVMWXA3IY4w1jjEtRPCcHueC8BClW5OuaxjlOpvPY0M7bgCZiutDRmdgb-un8Yk3nMeBmdmbCSKct0uvBucx1t0gDWhynIVCP048h3C6T27k3nvZztA5fkGetcRFf7usR-Xxxfn32Ibu8ev_xbH2ZWanUlJWNqpq2tmWJQrTCQpOcc8WMsJVIBfJaIKJleV2kU4m2VapsmhqKFqRV_Ii82-mOc91jY9FPwTg9hq434aceTKf_7PhuqzfDd82VkGkZSeB4LxCGbzPGSfddtOic8TjMUYNMhnLO03r_iwqlQJRcQULf_IXeDHPwaRMLVXKhJF8EYUfZMMQYsL33DUwvQetd0DoFrZeg9V2aef34w_cTv5NNwNs9YKI1rg3G2y4-cJVUopBl4vIdF1PLbzA8svjP138BwqLBWQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1497349534</pqid></control><display><type>article</type><title>A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle</title><source>MEDLINE</source><source>SpringerNature Journals</source><creator>Hussey, Sophie E. ; Lum, Helen ; Alvarez, Andrea ; Cipriani, Yolanda ; Garduño-Garcia, Jesús ; Anaya, Luis ; Dube, John ; Musi, Nicolas</creator><creatorcontrib>Hussey, Sophie E. ; Lum, Helen ; Alvarez, Andrea ; Cipriani, Yolanda ; Garduño-Garcia, Jesús ; Anaya, Luis ; Dube, John ; Musi, Nicolas</creatorcontrib><description>Aims/hypothesis
Insulin-sensitive tissues (muscle, liver) of individuals with obesity and type 2 diabetes mellitus are in a state of low-grade inflammation, characterised by increased Toll-like receptor (TLR) expression and TLR-driven signalling. However, the cause of this mild inflammatory state is unclear. We tested the hypothesis that a prolonged mild increase in plasma NEFA will increase TLR expression and TLR-driven signalling (nuclear factor κB [NFκB] and mitogen-activated kinase [MAPK]) and impair insulin action in muscle of lean healthy individuals.
Methods
Twelve lean, normal-glucose-tolerant participants were randomised to receive a 48 h infusion (30 ml/h) of saline or Intralipid followed by a euglycaemic–hyperinsulinaemic clamp. Vastus lateralis muscle biopsies were performed before and during the clamp.
Results
Lipid infusion impaired insulin-stimulated IRS-1 tyrosine phosphorylation and reduced peripheral insulin sensitivity (
p
< 0.01). The elevation in circulating NEFA increased expression of
TLR3
,
TLR4
and
TLR5
, and several MAPK (
MAPK8
,
MAP4K4
,
MAP2K3
) and inhibitor of κB kinase-NFκB (
CHUK
[
IKKA
], c-REL [
REL
] and p65 [
RELA
,
NFKB3
,
p65
]) signalling genes (
p
< 0.05). The lipid infusion also increased extracellular signal-regulated kinase (ERK) phosphorylation (
p
< 0.05) and tended to reduce the content of inhibitor of kappa Bα (
p
= 0.09). The muscle content of most diacylglycerol, ceramide and acylcarnitine species was unaffected. In summary, insulin resistance induced by prolonged low-dose lipid infusion occurs together with increased TLR-driven inflammatory signalling and impaired insulin-stimulated IRS-1 tyrosine phosphorylation.
Conclusions/interpretation
A sustained, mild elevation in plasma NEFA is sufficient to increase TLR expression and TLR-driven signalling (NFκB and MAPK) in lean individuals. The activation of this pathway by NEFA may be involved in the pathogenesis of insulin resistance in humans.
Trial registration
ClinicalTrials.gov NCT01740817</description><identifier>ISSN: 0012-186X</identifier><identifier>EISSN: 1432-0428</identifier><identifier>DOI: 10.1007/s00125-013-3111-x</identifier><identifier>PMID: 24337154</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adolescent ; Adult ; Biological and medical sciences ; Blood Glucose - metabolism ; Diabetes ; Diabetes. Impaired glucose tolerance ; Diacylglycerol Kinase - metabolism ; Drug dosages ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Fatty Acids, Nonesterified - metabolism ; Female ; Glucose ; Glucose Clamp Technique ; Human Physiology ; Humans ; Hypotheses ; Immunoblotting ; Insulin - metabolism ; Insulin Resistance ; Insulin Secretion ; Internal Medicine ; Lipids ; Male ; Mass spectrometry ; Medical sciences ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Metabolism ; Metabolites ; Middle Aged ; Muscle, Skeletal - metabolism ; Muscle, Skeletal - physiopathology ; Musculoskeletal system ; NF-kappa B - metabolism ; Obesity ; Pathogenesis ; Phosphorylation ; Plasma ; Protein Serine-Threonine Kinases - metabolism ; Scientific imaging ; Signal Transduction ; Toll-Like Receptors - metabolism ; Transcriptional Activation ; Up-Regulation</subject><ispartof>Diabetologia, 2014-03, Vol.57 (3), p.582-591</ispartof><rights>Springer-Verlag Berlin Heidelberg 2013</rights><rights>2015 INIST-CNRS</rights><rights>Springer-Verlag Berlin Heidelberg 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c599t-7d98dfbc77e44f4c1d012390a4c8490a12b4eeec02b6b6b84ff997ddb16f15c93</citedby><cites>FETCH-LOGICAL-c599t-7d98dfbc77e44f4c1d012390a4c8490a12b4eeec02b6b6b84ff997ddb16f15c93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00125-013-3111-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00125-013-3111-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28594657$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24337154$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hussey, Sophie E.</creatorcontrib><creatorcontrib>Lum, Helen</creatorcontrib><creatorcontrib>Alvarez, Andrea</creatorcontrib><creatorcontrib>Cipriani, Yolanda</creatorcontrib><creatorcontrib>Garduño-Garcia, Jesús</creatorcontrib><creatorcontrib>Anaya, Luis</creatorcontrib><creatorcontrib>Dube, John</creatorcontrib><creatorcontrib>Musi, Nicolas</creatorcontrib><title>A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle</title><title>Diabetologia</title><addtitle>Diabetologia</addtitle><addtitle>Diabetologia</addtitle><description>Aims/hypothesis
Insulin-sensitive tissues (muscle, liver) of individuals with obesity and type 2 diabetes mellitus are in a state of low-grade inflammation, characterised by increased Toll-like receptor (TLR) expression and TLR-driven signalling. However, the cause of this mild inflammatory state is unclear. We tested the hypothesis that a prolonged mild increase in plasma NEFA will increase TLR expression and TLR-driven signalling (nuclear factor κB [NFκB] and mitogen-activated kinase [MAPK]) and impair insulin action in muscle of lean healthy individuals.
Methods
Twelve lean, normal-glucose-tolerant participants were randomised to receive a 48 h infusion (30 ml/h) of saline or Intralipid followed by a euglycaemic–hyperinsulinaemic clamp. Vastus lateralis muscle biopsies were performed before and during the clamp.
Results
Lipid infusion impaired insulin-stimulated IRS-1 tyrosine phosphorylation and reduced peripheral insulin sensitivity (
p
< 0.01). The elevation in circulating NEFA increased expression of
TLR3
,
TLR4
and
TLR5
, and several MAPK (
MAPK8
,
MAP4K4
,
MAP2K3
) and inhibitor of κB kinase-NFκB (
CHUK
[
IKKA
], c-REL [
REL
] and p65 [
RELA
,
NFKB3
,
p65
]) signalling genes (
p
< 0.05). The lipid infusion also increased extracellular signal-regulated kinase (ERK) phosphorylation (
p
< 0.05) and tended to reduce the content of inhibitor of kappa Bα (
p
= 0.09). The muscle content of most diacylglycerol, ceramide and acylcarnitine species was unaffected. In summary, insulin resistance induced by prolonged low-dose lipid infusion occurs together with increased TLR-driven inflammatory signalling and impaired insulin-stimulated IRS-1 tyrosine phosphorylation.
Conclusions/interpretation
A sustained, mild elevation in plasma NEFA is sufficient to increase TLR expression and TLR-driven signalling (NFκB and MAPK) in lean individuals. The activation of this pathway by NEFA may be involved in the pathogenesis of insulin resistance in humans.
Trial registration
ClinicalTrials.gov NCT01740817</description><subject>Adolescent</subject><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Blood Glucose - metabolism</subject><subject>Diabetes</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Diacylglycerol Kinase - metabolism</subject><subject>Drug dosages</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Fatty Acids, Nonesterified - metabolism</subject><subject>Female</subject><subject>Glucose</subject><subject>Glucose Clamp Technique</subject><subject>Human Physiology</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>Immunoblotting</subject><subject>Insulin - metabolism</subject><subject>Insulin Resistance</subject><subject>Insulin Secretion</subject><subject>Internal Medicine</subject><subject>Lipids</subject><subject>Male</subject><subject>Mass spectrometry</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolic Diseases</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Middle Aged</subject><subject>Muscle, Skeletal - metabolism</subject><subject>Muscle, Skeletal - physiopathology</subject><subject>Musculoskeletal system</subject><subject>NF-kappa B - metabolism</subject><subject>Obesity</subject><subject>Pathogenesis</subject><subject>Phosphorylation</subject><subject>Plasma</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Scientific imaging</subject><subject>Signal Transduction</subject><subject>Toll-Like Receptors - metabolism</subject><subject>Transcriptional Activation</subject><subject>Up-Regulation</subject><issn>0012-186X</issn><issn>1432-0428</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqFkdFr1TAUxoMo7m76B_giARH20i2nSdrmRbiMTYXhXib4ZEjT03u7pWlNWp3_vSn3uk1BJA8ncH7ny5fzEfIK2AkwVp5GxiCXGQOecQDI7p6QFQieZ0zk1VOyWtoZVMWXA3IY4w1jjEtRPCcHueC8BClW5OuaxjlOpvPY0M7bgCZiutDRmdgb-un8Yk3nMeBmdmbCSKct0uvBucx1t0gDWhynIVCP048h3C6T27k3nvZztA5fkGetcRFf7usR-Xxxfn32Ibu8ev_xbH2ZWanUlJWNqpq2tmWJQrTCQpOcc8WMsJVIBfJaIKJleV2kU4m2VapsmhqKFqRV_Ii82-mOc91jY9FPwTg9hq434aceTKf_7PhuqzfDd82VkGkZSeB4LxCGbzPGSfddtOic8TjMUYNMhnLO03r_iwqlQJRcQULf_IXeDHPwaRMLVXKhJF8EYUfZMMQYsL33DUwvQetd0DoFrZeg9V2aef34w_cTv5NNwNs9YKI1rg3G2y4-cJVUopBl4vIdF1PLbzA8svjP138BwqLBWQ</recordid><startdate>20140301</startdate><enddate>20140301</enddate><creator>Hussey, Sophie E.</creator><creator>Lum, Helen</creator><creator>Alvarez, Andrea</creator><creator>Cipriani, Yolanda</creator><creator>Garduño-Garcia, Jesús</creator><creator>Anaya, Luis</creator><creator>Dube, John</creator><creator>Musi, Nicolas</creator><general>Springer Berlin Heidelberg</general><general>Springer</general><general>Springer Nature B.V</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140301</creationdate><title>A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle</title><author>Hussey, Sophie E. ; Lum, Helen ; Alvarez, Andrea ; Cipriani, Yolanda ; Garduño-Garcia, Jesús ; Anaya, Luis ; Dube, John ; Musi, Nicolas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c599t-7d98dfbc77e44f4c1d012390a4c8490a12b4eeec02b6b6b84ff997ddb16f15c93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Biological and medical sciences</topic><topic>Blood Glucose - metabolism</topic><topic>Diabetes</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Diacylglycerol Kinase - metabolism</topic><topic>Drug dosages</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Fatty Acids, Nonesterified - metabolism</topic><topic>Female</topic><topic>Glucose</topic><topic>Glucose Clamp Technique</topic><topic>Human Physiology</topic><topic>Humans</topic><topic>Hypotheses</topic><topic>Immunoblotting</topic><topic>Insulin - metabolism</topic><topic>Insulin Resistance</topic><topic>Insulin Secretion</topic><topic>Internal Medicine</topic><topic>Lipids</topic><topic>Male</topic><topic>Mass spectrometry</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolic Diseases</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Middle Aged</topic><topic>Muscle, Skeletal - metabolism</topic><topic>Muscle, Skeletal - physiopathology</topic><topic>Musculoskeletal system</topic><topic>NF-kappa B - metabolism</topic><topic>Obesity</topic><topic>Pathogenesis</topic><topic>Phosphorylation</topic><topic>Plasma</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Scientific imaging</topic><topic>Signal Transduction</topic><topic>Toll-Like Receptors - metabolism</topic><topic>Transcriptional Activation</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hussey, Sophie E.</creatorcontrib><creatorcontrib>Lum, Helen</creatorcontrib><creatorcontrib>Alvarez, Andrea</creatorcontrib><creatorcontrib>Cipriani, Yolanda</creatorcontrib><creatorcontrib>Garduño-Garcia, Jesús</creatorcontrib><creatorcontrib>Anaya, Luis</creatorcontrib><creatorcontrib>Dube, John</creatorcontrib><creatorcontrib>Musi, Nicolas</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetologia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hussey, Sophie E.</au><au>Lum, Helen</au><au>Alvarez, Andrea</au><au>Cipriani, Yolanda</au><au>Garduño-Garcia, Jesús</au><au>Anaya, Luis</au><au>Dube, John</au><au>Musi, Nicolas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle</atitle><jtitle>Diabetologia</jtitle><stitle>Diabetologia</stitle><addtitle>Diabetologia</addtitle><date>2014-03-01</date><risdate>2014</risdate><volume>57</volume><issue>3</issue><spage>582</spage><epage>591</epage><pages>582-591</pages><issn>0012-186X</issn><eissn>1432-0428</eissn><abstract>Aims/hypothesis
Insulin-sensitive tissues (muscle, liver) of individuals with obesity and type 2 diabetes mellitus are in a state of low-grade inflammation, characterised by increased Toll-like receptor (TLR) expression and TLR-driven signalling. However, the cause of this mild inflammatory state is unclear. We tested the hypothesis that a prolonged mild increase in plasma NEFA will increase TLR expression and TLR-driven signalling (nuclear factor κB [NFκB] and mitogen-activated kinase [MAPK]) and impair insulin action in muscle of lean healthy individuals.
Methods
Twelve lean, normal-glucose-tolerant participants were randomised to receive a 48 h infusion (30 ml/h) of saline or Intralipid followed by a euglycaemic–hyperinsulinaemic clamp. Vastus lateralis muscle biopsies were performed before and during the clamp.
Results
Lipid infusion impaired insulin-stimulated IRS-1 tyrosine phosphorylation and reduced peripheral insulin sensitivity (
p
< 0.01). The elevation in circulating NEFA increased expression of
TLR3
,
TLR4
and
TLR5
, and several MAPK (
MAPK8
,
MAP4K4
,
MAP2K3
) and inhibitor of κB kinase-NFκB (
CHUK
[
IKKA
], c-REL [
REL
] and p65 [
RELA
,
NFKB3
,
p65
]) signalling genes (
p
< 0.05). The lipid infusion also increased extracellular signal-regulated kinase (ERK) phosphorylation (
p
< 0.05) and tended to reduce the content of inhibitor of kappa Bα (
p
= 0.09). The muscle content of most diacylglycerol, ceramide and acylcarnitine species was unaffected. In summary, insulin resistance induced by prolonged low-dose lipid infusion occurs together with increased TLR-driven inflammatory signalling and impaired insulin-stimulated IRS-1 tyrosine phosphorylation.
Conclusions/interpretation
A sustained, mild elevation in plasma NEFA is sufficient to increase TLR expression and TLR-driven signalling (NFκB and MAPK) in lean individuals. The activation of this pathway by NEFA may be involved in the pathogenesis of insulin resistance in humans.
Trial registration
ClinicalTrials.gov NCT01740817</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>24337154</pmid><doi>10.1007/s00125-013-3111-x</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Diabetologia, 2014-03, Vol.57 (3), p.582-591 |
| issn | 0012-186X 1432-0428 |
| language | eng |
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| source | MEDLINE; SpringerNature Journals |
| subjects | Adolescent Adult Biological and medical sciences Blood Glucose - metabolism Diabetes Diabetes. Impaired glucose tolerance Diacylglycerol Kinase - metabolism Drug dosages Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Extracellular Signal-Regulated MAP Kinases - metabolism Fatty Acids, Nonesterified - metabolism Female Glucose Glucose Clamp Technique Human Physiology Humans Hypotheses Immunoblotting Insulin - metabolism Insulin Resistance Insulin Secretion Internal Medicine Lipids Male Mass spectrometry Medical sciences Medicine Medicine & Public Health Metabolic Diseases Metabolism Metabolites Middle Aged Muscle, Skeletal - metabolism Muscle, Skeletal - physiopathology Musculoskeletal system NF-kappa B - metabolism Obesity Pathogenesis Phosphorylation Plasma Protein Serine-Threonine Kinases - metabolism Scientific imaging Signal Transduction Toll-Like Receptors - metabolism Transcriptional Activation Up-Regulation |
| title | A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle |
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