SUN-239 SGLT2 Inhibitors Modulate the Immune Cell Metabolic Profile

Abstract B. Safa: None. J. Oakes: None. J. Simmons: None. L. Kirk: None. E. Olson: None. C. Warren: None. E. Wilfong: None. M. Stier: None. S. Bailin: None. C. Gabriel: None. J. Rathmel: None. C. Flynn: None. J. Luther: None. J. Koethe: None. S. Kalams: None. C. Wanjalla: None. M. Mashayekhi: None. Obesity is associated with chronic systemic and adipose inflammation which significantly increases the risk of cardiometabolic diseases. Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce blood glucose and weight by causing glucosuria. Beyond these effects, SGLT2 inhibitors also reduce the risks of heart, kidney, and liver disease through unknown mechanisms. SGLT2 inhibitors reduce inflammation in animals, but their effects on inflammation in humans are less understood. We hypothesize that SGLT2 inhibitors improve inflammation in humans by improving the immune metabolic profile, which is closely linked to immune cell activation and inflammation. In this pilot study, sixteen women with obesity and pre-diabetes were treated with the SGLT2 inhibitor empagliflozin (25 mg/day). Peripheral blood mononuclear cells were collected at baseline and after 12-weeks of treatment. We used the SCENITH protocol (Single Cell ENergetic metabolism by profilIng Translation inHibition) to measure cellular metabolism before and after treatment ex vivo. Within-individual change from baseline was tested using Wilcoxon signed rank. Baseline characteristics include age 55±11.5 years, 68.8% white, 12.5% black, weight 97.2±19.3 kg, and BMI 36.9±5.8 kg/m2. The change in weight was +0.6±2.7 kg at 12 weeks. We tested immune cell dependence on glucose using the glycolysis inhibitor 2-deoxyglucose. Glucose dependence increased in two T cell subsets: naive CD8+ T cells (+7.1±13.3%, p=0.02) and CD4+ central memory cells (+4.6±9.8%, p=0.02). By contrast, glucose dependence decreased in cytotoxic natural killer (NK) cells (-9.6±14.6%, p=0.03). The SGLT2 inhibitor empagliflozin differentially modulates the metabolism of distinct immune cell populations in individuals with obesity and pre-diabetes. Empagliflozin reduces cytotoxic NK cell dependence on glucose as an energy source, which makes these cells more reliant on fatty acid and amino acid oxidation. This immune metabolic profile is associated with a resting/non-activated state and may be anti-inflammatory. Empagliflozin alters glucose dependence in an opposite manner in two T cell subsets, with an increase in glucose reliance and decrease in fatty acid and amino acid oxidation. We propose that SGLT2 inhibitors may promote a less inflammatory metabolic immune phenotype in certain subsets such as cytotoxic NK cells, while facilitating other immune responses (e.g. to vaccines or infections) in naive and memory T cells by increasing glucose dependence. This hypothesis will need to be tested in future studies. Further investigation of immune metabolic effects of SGLT2 inhibition in humans is ongoing in a randomized, controlled trial. Sunday, June 2, 2024