Huang-Doran, Isabel ORCID: 0000-0002-0573-6557, Tomlinson, Patsy, Payne, Felicity ORCID: 0000-0003-4228-581X, Gast, Alexandra, Sleigh, Alison ORCID: 0000-0002-3859-8701, Bottomley, William, Harris, Julie, Daly, Allan, Rocha, Nuno, Rudge, Simon, Clark, Jonathan, Kwok, Albert, Romeo, Stefano, McCann, Emma, Mueksch, Barbara, Dattani, Mehul, Zucchini, Stefano, Wakelam, Michael ORCID: 0000-0003-4059-9276, Foukas, Lazaros C., Savage, David B., Murphy, Rinki, O'Rahilly, Stephen, Barroso, Ines ORCID: 0000-0001-5800-4520 and Semple, Robert K. (2016). Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations. JCI Insight, 1 (17). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 2379-3708

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Abstract

Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85 alpha/p55 alpha/p50 alpha subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85 alpha with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85 alpha overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Huang-Doran, IsabelUNSPECIFIEDorcid.org/0000-0002-0573-6557UNSPECIFIED
Tomlinson, PatsyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Payne, FelicityUNSPECIFIEDorcid.org/0000-0003-4228-581XUNSPECIFIED
Gast, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sleigh, AlisonUNSPECIFIEDorcid.org/0000-0002-3859-8701UNSPECIFIED
Bottomley, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harris, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daly, AllanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rocha, NunoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudge, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clark, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kwok, AlbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Romeo, StefanoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McCann, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueksch, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dattani, MehulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zucchini, StefanoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wakelam, MichaelUNSPECIFIEDorcid.org/0000-0003-4059-9276UNSPECIFIED
Foukas, Lazaros C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Savage, David B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Murphy, RinkiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Rahilly, StephenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barroso, InesUNSPECIFIEDorcid.org/0000-0001-5800-4520UNSPECIFIED
Semple, Robert K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-258276
DOI: 10.1172/jci.insight.88766
Journal or Publication Title: JCI Insight
Volume: 1
Number: 17
Date: 2016
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 2379-3708
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MOLECULAR-WEIGHT ADIPONECTIN; PHOSPHOINOSITIDE 3-KINASE; REGULATORY SUBUNIT; P85-ALPHA SUBUNIT; MICE LACKING; HUMAN IMMUNODEFICIENCY; EMBRYONIC LETHALITY; PLASMA ADIPONECTIN; HEPATIC STEATOSIS; CELL-GROWTHMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25827

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