Cell-intrinsic insulin signaling defects in human iPS cell-derived hepatocytes in type 2 diabetes.

Summary

Using iPSC-derived human hepatocytes and phosphoproteomics, the authors map widespread losses of canonical insulin signaling and the emergence of new phosphorylation programs in T2D, implicating ROCK1/2, MST4, and BCKDK. ROCK1/2 inhibition partially restores insulin action, nominating actionable kinase targets for hepatic insulin resistance.

Key Findings

• Over 300 phosphosites showed impaired insulin signaling in T2D hepatocytes, including losses in PI3K/AKT cascade targets.
• More than 500 emergent phosphorylation sites appeared in T2D on pathways such as Rho-GTPase, RNA metabolism, vesicle trafficking, and chromatin.
• Kinome inference implicated increased ROCK1/2 and MST4/BCKDK activity with reduced AKT2/3 signaling; ROCK1/2 inhibition partially rescued insulin action.

Clinical Implications

Suggests ROCK1/2 (and possibly MST4/BCKDK) as drug targets to restore hepatic insulin action; supports biomarker development based on phosphosite signatures for patient stratification.

Limitations

• Preclinical in vitro model without in vivo human validation
• Sample size and donor heterogeneity details are not fully delineated

Future Directions

Test ROCK1/2 and related kinase inhibitors in translational models and early-phase trials; develop phosphosite-based biomarkers to stratify hepatic insulin resistance phenotypes.