Mechanobiology of the diabetic cardiomyocyte: insulin signaling, titin elasticity, and multiscale mechanical dysfunction

Cardiomyocyte function emerges from tightly coupled electromechanical processes that span sarcomeric force generation, titin-based elasticity, excitation-contraction coupling, mitochondrial ATP supply, and mechanotransductive adaptation to load. Insulin signaling integrates these processes across molecular, cellular, and organ scales, thereby contributing to cardiomyocyte mechanical homeostasis. In cardiomyocytes, canonical insulin signaling is initiated by insulin receptor (IR) activation, recruitment of IRS-1/IRS-2, and downstream PI3K-Akt signaling. Through Akt-dependent modulation of mTOR, GSK-3 beta, and FOXO transcription factors, insulin aligns energy availability with mechanical demand while supporting structural integrity of sarcomeres, Z-disc/costameric networks, and intercalated disc architecture. Disruption of insulin signaling and insulin resistance in type 2 diabetes (T2DM) remodel cardiomyocyte mechanics by altering myofilament calcium sensitivity, shifting contractile protein expression, perturbing titin isoform composition and phosphorylation, impairing calcium cycling and beta-adrenergic microdomain signaling, and inducing mitochondrial dysfunction with oxidative stress (Fig. 1). These changes manifest as altered force-pCa relations, reduced contractile reserve, prolonged relaxation, increased passive stiffness, and modified viscoelastic behavior, as measured by quantitative biophysical assays (Fig. 2). Here, we synthesize mechanistic pathways linking insulin signaling to cardiac mechanics; summarize evidence for T2DM-induced cardiomyocyte dysfunction across species and disease stages; describe mechanotransduction failure in diabetes involving costameres, integrins/FAK, and stretch-responsive pathways such as YAP/TAZ; and provide an overview of quantitative tools to measure cardiomyocyte mechanics including AFM, TFM, nanoindentation, optical/magnetic tweezers, skinned-cell mechanics, real-time calcium-contractility platforms, engineered heart tissues, and microphysiological heart-on-chip systems. Finally, we discuss therapeutic perspectives with emphasis on interventions that restore mechanical homeostasis through titin phosphorylation, reduction of AGE-driven stiffening, and normalization of oxidative and inflammatory stress, including SGLT2 inhibitors and GLP-1 agonists.