Signaling defects associated with insulin resistance in nondiabetic and diabetic individuals and modification by sex
Nida Haider, … , Matthias Mann, C. Ronald Kahn
Nida Haider, … , Matthias Mann, C. Ronald Kahn
Published September 10, 2021
Citation Information: J Clin Invest. 2021;131(21):e151818. https://doi.org/10.1172/JCI151818.
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Research Article Metabolism Stem cells

Signaling defects associated with insulin resistance in nondiabetic and diabetic individuals and modification by sex

Abstract

Insulin resistance is present in one-quarter of the general population, predisposing these people to a wide range of diseases. Our aim was to identify cell-intrinsic determinants of insulin resistance in this population using induced pluripotent stem cell–derived (iPSC–derived) myoblasts (iMyos). We found that these cells exhibited a large network of altered protein phosphorylation in vitro. Integrating these data with data from type 2 diabetic iMyos revealed critical sites of conserved altered phosphorylation in IRS-1, AKT, mTOR, and TBC1D1 in addition to changes in protein phosphorylation involved in Rho/Rac signaling, chromatin organization, and RNA processing. There were also striking differences in the phosphoproteome in cells from men versus women. These sex-specific and insulin-resistance defects were linked to functional differences in downstream actions. Thus, there are cell-autonomous signaling alterations associated with insulin resistance within the general population and important differences between men and women, many of which also occur in diabetes, that contribute to differences in physiology and disease.

Authors

Nida Haider, Jasmin Lebastchi, Ashok Kumar Jayavelu, Thiago M. Batista, Hui Pan, Jonathan M. Dreyfuss, Ivan Carcamo-Orive, Joshua W. Knowles, Matthias Mann, C. Ronald Kahn

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Figure 3

I-Res phosphoproteome changes shared with T2D.

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I-Res phosphoproteome changes shared with T2D. (A) Overview of the analy...
(A) Overview of the analysis to compare overlapping phosphoproteome changes in I-Res and T2D patients (FDR < 0.05). Data for Batista et al. can be found in ref. 20. (B) Hierarchical clustering of the insulin/basal ratio of the phosphopeptides showing shared phosphoproteome changes in I-Res and T2D iMyos. Rows represent z scores of the log2-transformed intensity of phosphosites for each sample labeled in the column. (C) Quantification of representative phosphosites from each of the up- and downregulated clusters from B. Data are represented as mean ± SEM of the phosphosites intensity values. *P < 0.05; **P < 0.01, I-Sen vs. I-Res or T2D vs. controls, unpaired t test. (D) Hierarchical clustering of the phosphopeptides showing shared phosphoproteome changes in I-Res and T2D iMyos at the basal state. Rows represent z scores of the log2-transformed intensity of phosphosites for each sample labeled in the column. (E) Quantification of representative phosphosites from each of the up- and downregulated clusters from D. Data for men and women were combined for clearer presentation. Data are represented as mean ± SEM of the phosphosites intensity values. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, basal vs. insulin or I-Sen vs. I-Res or T2D vs. controls, 2-way ANOVA followed by correction for multiple comparison by controlling the FDR.