Redox Homeostasis in Metabolic Syndrome and Type II Diabetes: Role of Skeletal Muscle and Impact of Gold-Standard Treatments

Abstract

Metabolic syndrome and type II diabetes pose a significant international health burden, with the latter characterized by insulin resistance. Patients must rely on therapies that maintain glucose homeostasis when endogenous systems become dysfunctional. Skeletal muscle, as the largest insulin-sensitive tissue in the body, plays a critical role in maintaining glucose homeostasis. During disease progression, chronic nutrient overload shifts redox balance to a pro-oxidant state, further exacerbating metabolic dysfunction. First-line treatments, such as metformin and insulin, along with newly adopted incretin-based therapies, modulate the redox state of skeletal muscle. This review explores how the redox state of healthy skeletal muscle is altered throughout metabolic disease progression and how these changes contribute to a worsening phenotype. We also highlight how each class of regularly prescribed medications targets redox-sensitive systems in skeletal muscle, identifying literature gaps and areas for future investigation.

Keywords: diabetes pharmacotherapy; metabolic disease; redox homeostasis; skeletal muscle; type II diabetes.

Figure 1

Insulin signaling pathway in skeletal muscle and role of ROS and redox sensitive systems. Insulin binds its receptor leading to activation of IRS and production of O₂^•− via NOX enzymes, which is dismutated by SOD to form H₂O₂ that can enter the cell via aquaporins. Mitochondria also produce H₂O₂ that participate in the insulin signaling cascade. PTP1B is a negative regulator of insulin, acting through inhibition of IRS phosphorylation. Physiological levels of H₂O₂ inhibit PTP1B, thereby augmenting insulin’s downstream actions on PI3K and MAPK. MAPK activation leads to cell proliferation and growth. IRS also activates PI3K which mediates many of insulin’s action on cellular metabolism. PI3K mediates the conversion of PIP₂ to PIP₃, which activates PDK and mTORC2 to activate Akt. H₂O₂ can also augment activation of Akt at physiological levels. Akt activates mTOR leading to increased protein synthesis and inhibits AS160 and GSK3 which lead to GLUT4 translocation and activation of glycogen synthase (GS) to promote glycogen synthesis. AS160 mediates GLUT4 translocation through its action on Rab8a and Rab13, which is complemented by Rac1 activation by PI3K. GSK3 is also involved in regulation of transcription factors like activation of NF-κB and Nrf2 which are involved in positive regulation of inflammatory signaling and anabolic metabolism, respectively. Akt activation also inhibits FOXO transcription factors, thereby inhibiting catabolic metabolic processes like gluconeogenesis. As shown, physiologic level of ROS are crucial for modulating both negative regulators of the insulin signaling cascade, as well as augmenting activation of key players like Akt and IR phosphorylation. Solid black arrows represent activation or phosphorylation; dashed arrows indicate conversion of molecules or processes involving translocation across the cell; orange arrows denote ROS/redox signaling; blue nodes represent key stages in insulin-dependent signaling; purple, pink, and teal nodes show transcription factors and respective boxes reflect the broad outcomes of this transcriptional regulation; dark red nodes represent negative regulators of insulin signaling.

Figure 2

Interconnected cycle of nutrient overload, redox imbalance, and insulin resistance in the pathogenesis of metabolic disease and type 2 diabetes mellitus. Lifestyle choices and genetic factors lead to persistent nutrient overload, overwhelming metabolic processes and leading to mitochondrial dysfunction and excessive ROS production. Supraphysiologic ROS levels activate inflammatory pathways through myokine/cytokine release and activation of transcription factors. This inflammatory response and damaging ROS molecules lead to an increase in misfolded proteins causing endoplasmic reticulum stress and further shifts in redox balance compounding oxidative distress. This activates stress pathways like JNK and inhibits impairs insulin signaling, reducing the ability of skeletal muscle to maintain nutrient homeostasis, further driving nutrient overload. Solid arrows depict the self-reinforcing cycle, while the dashed arrow indicated external factors that contribute to its initiation and amplification.

Figure 3

Systemic sites of action of type II diabetes therapies and their redox implications. Antidiabetic drug classes act across multiple tissues to regulate glucose homeostasis whilst influencing redox balance and ROS generation. Biguanides (metformin, dark red) act primarily on the liver and muscle to modulate Complex I activity, AMPK signaling, and antioxidant defenses. Insulin (blue) lowers glucose-induced oxidative distress and enhances NO-dependent vascular signaling. SGLT2 inhibitors (gold) act on the kidney but secondarily improve lipid handling, mitochondrial remodeling, and antioxidant capacity in skeletal muscle. Insulin secretagogues (sulfonylureas, meglitinides, pink) increase insulin secretion, indirectly affecting redox balance. Incretin-based therapies (GLP-1 receptor agonists, dual GLP-1/GIP agonists, and DPP-4 inhibitors, teal and lavender) exert multisystem effects, including improved mitochondrial biogenesis, reduced ROS production, and enhanced vascular perfusion. Arrows denote the primary organ(s) targeted by each therapy. Each class of drug’s mechanism of action on target organ(s) is/are discussed in depth in the main body text.