Deprogram and reprogram to solve the riddle of insulin resistance
Victoria L. Tokarz, … , Paul Delgado-Olguín, Amira Klip
Victoria L. Tokarz, … , Paul Delgado-Olguín, Amira Klip
Published November 1, 2021
Citation Information: J Clin Invest. 2021;131(21):e154699. https://doi.org/10.1172/JCI154699.
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Commentary

Deprogram and reprogram to solve the riddle of insulin resistance

Abstract

Skeletal muscle preeminently determines whole-body glycemia. However, the molecular basis and inheritable influence that drive the progression of insulin resistance to type 2 diabetes remain debated. In this issue of the JCI, Haider and Lebastchi report on their use of induced pluripotent stem cell–derived (iPSC–derived) myoblasts (iMyos) to uncover multiple phosphoproteomic changes that carried over from the human to the cell-culture system. In this system devoid of in vivo influences, the researchers annotated changes between the sexes and between the most and least insulin-sensitive quintiles of a healthy population (defined by steady-state blood glucose levels). Many phosphoproteomic differences were detected in the absence of insulin, revealing that changes in the basal landscape of cells determine the efficiency of insulin action. Basal and insulin-dependent deficiencies of iPSCs and iMyos likely involve genetic and epigenetic determinants that modulate insulin sensitivity.

Authors

Victoria L. Tokarz, Paul Delgado-Olguín, Amira Klip

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Figure 1

Diabetes-in-a-dish approach to exploring the molecular origins of skeletal muscle insulin resistance.

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Diabetes-in-a-dish approach to exploring the molecular origins of skelet...
Blood cells from I-Sen or I-Res donors (men and women) were deprogrammed with Sendai virus to generate iPSCs, then redifferentiated in vitro into iMyos. The unique phosphoproteomic signature of these iMyos (before or after insulin stimulation) was compared with that of iMyos from T2D donors to reveal overlapping dysregulated phosphorylation networks in I-Res and T2D iMyos and a sex-specific phosphoproteomic fingerprint. I-Res and T2D iMyos exhibited dysregulated phosphorylation and signaling networks in I-Res and T2D iMyos, including Rho/Rac GTPase signaling, chromatin organization, and RNA splicing and processing. These phosphoproteomic changes were reflected in functional differences in the DNA damage response and actin cytoskeleton remodeling. Notably, I-Sen and I-Res iMyos displayed a sex-specific phosphoproteomic fingerprint. The dysregulated phosphoproteome in I-Sen and I-Res iMyos under basal conditions implies a cell-autonomous defect in insulin handling. Genetic and epigenetic mechanisms of inheritability that could lead to an altered phosphoproteome and downstream functional outcomes warrant further investigation. Overall, the work of Haider and Lebastchi et al. (7) represents a major leap in our understanding of insulin resistance. LC MS/MS, liquid chromatography–tandem mass spectrometry.