Methylsulfonylmethane Attenuates Dexamethasone-Induced Hepatic Insulin Resistance in Rats: Associations with SGK1, p-AMPK/mTOR, Inflammatory and Angiogenic Markers

Background/Objectives: Glucocorticoid therapy remains clinically indispensable, yet its long-term use is profoundly constrained by insulin resistance (IR), hepatic steatosis, and progressive metabolic dysfunction. Methylsulfonylmethane (MSM), a naturally occurring sulfur-containing nutraceutical with established antioxidant and anti-inflammatory activities, has emerged as a promising metabolic modulator; however, its therapeutic relevance in glucocorticoid-induced hepatic IR has not previously been explored. Methods: Male Wistar rats received MSM (200 or 400 mg/kg/day, p.o.) for 14 days, while dexamethasone (DEX) (8 mg/kg/day, i.p.) was administered during the final 7 days to induce severe metabolic dysfunction. Results: DEX provoked profound IR, dyslipidemia, oxidative stress, hepatocellular injury, and steatotic degeneration accompanied by marked ultrastructural abnormalities. Remarkably, MSM conferred dose-dependent metabolic and hepatoprotective effects, significantly restoring glucose homeostasis, insulin responsiveness, lipid metabolism, and hepatic structural integrity. Mechanistically, MSM exerted a pleiotropic regulatory effect through suppression of the glucocorticoid-responsive kinase SGK1, restoration of AMPK/mTOR signaling balance, and normalization of insulin signaling pathways and metabolic transcriptional regulators. Furthermore, MSM effectively attenuated oxidative stress and inflammatory amplification consistent with modulation of the NLRP3/NF-κB/IL-6 axis. Importantly, the current work identifies angiogenic remodeling demonstrated by DEX-induced upregulation of VEGF and CD34, both of which were substantially suppressed by MSM treatment. Conclusions: This study provides novel evidence that MSM mitigates glucocorticoid-induced hepatic IR through coordinated modulation of glucocorticoid-responsive kinases, metabolic signaling networks, redox–inflammatory cascades, and pathological angiogenesis. Consequently, MSM may represent a promising candidate for further preclinical and clinical evaluation regarding its capacity to limit glucocorticoid-associated metabolic burdens.