SAT671 SGLT2 Inhibition Decreases Adipose Tissue And Global Inflammaging Profile Of Older Obese Adults With Pre-Diabetes

• Published in: Journal of the Endocrine Society 2023-10, Vol.7 (Supplement_1)
• Main Authors: Nie, Jia, Semwal, Manpreet K, Acosta, Francisca M, Stepanenko, Allison R, Brown, Marissa, Moody, Alexander J, Sanchez, Noah, Cortes, Tiffany M, Qin, Yuejuan, Triplitt, Curtis, Clarke, Geoffrey, Espinoza, Sara E, Musi, Nicolas, Solis-Herrera, Carolina
• Format: Article
• Language: English
• Subjects: Adipose Tissue, Appetite, & Obesity
• ISSN: 2472-1972; 2472-1972
• DOI: 10.1210/jendso/bvad114.119

Disclosure: J. Nie: None. M.K. Semwal: None. F.M. Acosta: None. A.R. Stepanenko: None. M. Brown: None. A.J. Moody: None. N. Sanchez: None. T.M. Cortes: None. Y. Qin: None. C. Triplitt: None. G. Clarke: None. S.E. Espinoza: None. N. Musi: None. C. Solis-Herrera: None. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are drugs for treating T2D. Through their glucosuric effect, you see a reduced HbA1c, weight loss, and improved insulin sensitivity/ β-cell function. Beyond their glycemic properties, SGLT2i provide substantial cardio-renal benefits. Given their multiple therapeutic advantages and established safety profile, there is the presupposition that SGLT2i may have various beneficial possibilities in medical practice. An area of interest for SGLT2i is their use as agents for late-aging and longevity. SGLT2i are known to promote a calorie restriction (CR) state by promoting glucosuria and fatty acid-oxidation/ketogenesis and reducing insulin levels. CR activates a myriad of anti-aging-related pathways, including senescence-associated “inflammaging,” which can be triggered by obesity and states of overnutrition. However, clinical research in this area remains largely unexplored. A single-center, open-label, randomized-controlled clinical trial was designed to determine the effect of SGLT2i on the aging-related processes of global and adipose tissue inflammation and senescence. Twenty older, obese, pre-diabetic subjects (Age=70±1.5, BMI=33.7±0.6, A1c=5.9±0.03) were randomized dapagliflozin 10mg/day (SGLT2i) vs. nutritional counseling for weight loss (control) in a 1:1 fashion for 12 weeks. Healthspan and clinical evaluation were performed at baseline and weeks 10-12 of the study. The SGLT2i group showed a significant decrease (-5.4±1.7, p=0.01) in weight loss, downward trend in HbA1c (-0.02±0.06 vs. +0.06±0.04), and significant loss in %Fat vs. control (-1%, p=0.05 vs. -0.5%, p=0.1). Given adiposity changes observed with SGLT2i, in a subset of subjects (n=10), subcutaneous fat biopsies were performed, and single nuclei (sn)RNA-seq done to map changes in adipose cellular populations (mature adipocytes, immune, endothelial, and adipogenic progenitor cells) and molecular profiling. Notably, with SGLT2i, the mature adipocyte, immune, and adipogenic progenitor cells, saw a significant (p≤0.05) decrease in senescent score. Globally, plasma-measured inflammaging-associated factors in the IL8 and TNFα families, also saw a significant decrease (p≤0.05) with SGLT2