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Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.

Published version
Peer-reviewed

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Authors

Huang-Doran, Isabel  ORCID logo  https://orcid.org/0000-0002-0573-6557
Tomlinson, Patsy 
Payne, Felicity 
Gast, Alexandra 
Sleigh, Alison 

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 p85α/p55α/p50α 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 p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α 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.

Description

Keywords

3T3-L1 Cells, Adipocytes, Adolescent, Animals, Child, Class Ia Phosphatidylinositol 3-Kinase, Dyslipidemias, Fatty Liver, Female, HEK293 Cells, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Male, Mice, Middle Aged, Mutation, Phosphatidylinositol 3-Kinases, Phosphorylation

Journal Title

JCI Insight

Conference Name

Journal ISSN

2379-3708
2379-3708

Volume Title

1

Publisher

American Society for Clinical Investigation
Sponsorship
Wellcome Trust (095515/Z/11/Z)
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (100574/Z/12/Z)
Wellcome Trust (098498/Z/12/Z)
Wellcome Trust (107064/Z/15/Z)
Wellcome Trust (091310/Z/10/Z)
Medical Research Council (MC_PC_12012)
IHD was supported by the Raymond and Beverly Sackler Foundation via the University of Cambridge MB/PhD programme; RKS, IB, DBS, and SO were supported by the Wellcome Trust (grants WT098498, WT098051, WT107064, and WT095515, respectively and Strategic Award 100574/Z/12/Z), the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5), and the United Kingdom National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. The work was also supported by the Innovative Medicines Initiative Joint Undertaking under European Medical Information Framework (EMIF) grant agreement number 115372. UK10K was funded by the Wellcome Trust under award WT091310.