Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
PI3-kinase mutation linked to insulin and growth factor resistance in vivo
Jonathon N. Winnay, … , C. Ronald Kahn, Pål R. Njølstad
Jonathon N. Winnay, … , C. Ronald Kahn, Pål R. Njølstad
Published March 14, 2016
Citation Information: J Clin Invest. 2016;126(4):1401-1412. https://doi.org/10.1172/JCI84005.
View: Text | PDF
Research Article Metabolism

PI3-kinase mutation linked to insulin and growth factor resistance in vivo

  • Text
  • PDF
Abstract

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors. Heterozygous mutations in the gene encoding the p85α regulatory subunit of PI3K (PIK3R1) have been identified in patients with SHORT syndrome — a disorder characterized by short stature, partial lipodystrophy, and insulin resistance. Here, we evaluated whether SHORT syndrome–associated PIK3R1 mutations account for the pathophysiology that underlies the abnormalities by generating knockin mice that are heterozygous for the Pik3r1Arg649Trp mutation, which is homologous to the mutation found in the majority of affected individuals. Similar to the patients, mutant mice exhibited a reduction in body weight and length, partial lipodystrophy, and systemic insulin resistance. These derangements were associated with a reduced capacity of insulin and other growth factors to activate PI3K in liver, muscle, and fat; marked insulin resistance in liver and fat of mutation-harboring animals; and insulin resistance in vitro in cells derived from these mice. In addition, mutant mice displayed defective insulin secretion and GLP-1 action on islets in vivo and in vitro. These data demonstrate the ability of this heterozygous mutation to alter PI3K activity in vivo and the central role of PI3K in insulin/growth factor action, adipocyte function, and glucose metabolism.

Authors

Jonathon N. Winnay, Marie H. Solheim, Ercument Dirice, Masaji Sakaguchi, Hye-Lim Noh, Hee Joon Kang, Hirokazu Takahashi, Kishan K. Chudasama, Jason K. Kim, Anders Molven, C. Ronald Kahn, Pål R. Njølstad

×

Figure 5

p85WT/R649W mice display impaired insulin signaling in vivo.

Options: View larger image (or click on image) Download as PowerPoint
p85WT/R649W mice display impaired insulin signaling in vivo.
(A) Analysi...
(A) Analysis of insulin signaling in adipose tissue, liver, and skeletal muscle of p85WT/WT and p85WT/R649W mice administered insulin (5 U) or vehicle. Immunoblot analysis was performed with the indicated antibodies. (B) Quantification of p-AKT (S473) performed using ImageJ. Results are presented as mean ± SEM (n = 5–6 animals). (C) AKT activity was assessed in skeletal muscle and liver (n = 4–5 animals). (D) Immunofluorescence performed on liver sections using anti-PIP3 antibody (original magnification, ×40). (E) Immunoblot analysis of insulin signaling in primary hepatocytes isolated from p85WT/WT and p85WT/R649W mice in the absence or presence of insulin (10 nM) for the indicated times (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001; #P < 0.0005, unpaired Student’s t test.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts