Endocrine Abstracts

Sodium-glucose co-transporter 2 (SGLT2) reabsorbs up to 180 g of glucose daily in the kidney. SGLT2 inhibitors have transformed the treatment of type 2 diabetes and cardiovascular disease and are now being explored for non-metabolic indications, including cancer and neurodegeneration. Beyond glycaemic regulation, SGLT2 has emerging roles in immune-metabolic signalling. We previously showed that SGLT2 knockout (KO) mice exhibit reduced IL6 expression and restored adrenal corticosterone secretion, independent of glycosuria or body weight. To investigate underlying mechanisms, we performed data-independent acquisition mass spectrometry on plasma and eight metabolic organs (heart, liver, kidney, spleen, muscle, adrenal glands, white and brown adipose) from obese SGLT2 KO, chronically dapagliflozin-treated, and control mice. Across groups, differentially expressed proteins (DEPs) were enriched for oxidative stress and glutathione-related pathways, with greatest DEP overlap observed between plasma and adrenal glands in SGLT2 KO mice (113 DEPs). Dapagliflozin-treated mice exhibited a similar number of DEPs, predominantly in plasma and muscle. To assess glutathione’s functional relevance in vivo, high-fat diet-fed mice were treated with dapagliflozin ± buthionine sulfoximine (BSO), a glutathione synthesis inhibitor. In male mice, BSO co-treatment significantly improved glucose clearance across intraperitoneal and oral glucose tolerance tests (AUC reduced by ~20%) compared to dapagliflozin alone, despite a 40–50% reduction in total glutathione and no change in body weight. IL6 and TNFα levels were reduced by 30–50% in dapagliflozin and combination groups. In females, BSO caused ~15% weight loss, and glucose tolerance was similar to that of males. Notably, females showed increased glutathione secretion in response to dapagliflozin—an effect not observed in males. These findings reveal a redox-sensitive, sex-specific mechanism whereby glutathione depletion enhances SGLT2 inhibitor efficacy, supporting a novel hormetic interaction. This has important implications for repurposing SGLT2 inhibitors in cardiometabolic and immune-mediated diseases.