Hoofbeats, zebras, and insights into insulin resistance
Robert A. Hegele, Karen Reue
Robert A. Hegele, Karen Reue
Published January 26, 2009
Citation Information: J Clin Invest. 2009;119(2):249-251. https://doi.org/10.1172/JCI38420.
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Commentary

Hoofbeats, zebras, and insights into insulin resistance

Abstract

In this issue of the JCI, Semple and colleagues report phenotypic evaluation of patients with a germline mutation in the gene encoding serine/threonine kinase AKT2 (see the related article beginning on page 315). Their findings support the idea that the postreceptor actions of insulin in the liver — suppression of gluconeogenesis and stimulation of lipogenesis — are mediated through divergent pathways that can be uncoupled. The results appear to refine the arrangement of crucial steps along these pathways and show how comprehensive study of the phenotype, “deep phenotyping,” of patients who carry rare mutations might complement other types of experiments to elucidate complex pathways and mechanisms.

Authors

Robert A. Hegele, Karen Reue

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Figure 1

Proposed model for distinct hepatic insulin resistance (IR) phenotypes resulting from INSR and AKT2 gene mutations.

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Proposed model for distinct hepatic insulin resistance (IR) phenotypes r...
(A) Under normal circumstances, insulin stimulation of the INSR activates apparently independent arms of the signaling pathway: (i) AKT2 activation, phosphorylation of FOXO1, and inhibition of gluconeogenic gene transcription, leading to decreased glucose output, and (ii) activation of SREBP-1c target lipogenic genes, leading to secretion of triglyceride-rich VLDLs (VLDL TG). (B) Mutation in INSR prevents activation of both arms of the pathway, resulting in increased glucose levels without increased TG levels. (C) Mutation in the AKT2 gene impairs inhibition of gluconeogenesis without abolishing the lipogenic effect of insulin, resulting in increased glucose and TG levels. ACC, acetyl-coenzyme A carboxylase; FAS, fatty acid synthase; PEPCK, phosphoenolpyruvate carboxykinase.