Effects of SGLT2 Ablation or Inhibition on Corticosterone Secretion in High-Fat-Fed Mice: Exploring a Nexus with Cytokine Levels

Abstract

Despite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing Type 2 Diabetes (T2D). Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have emerged as effective treatments by promoting urinary glucose excretion. However, the full scope of their mechanisms extends beyond glycaemic control. At present, their immunometabolic effects remain elusive. To investigate the effects of SGLT2 inhibition or deletion, we compared the metabolic and immune phenotype between high fat diet-fed control, chronically dapagliflozin-treated mice and total-body SGLT2/Slc5a2 knockout mice. SGLT2 null mice exhibited superior glucose tolerance and insulin sensitivity compared to control or dapagliflozin-treated mice, independent of glycosuria and body weight. Moreover, SGLT2 null mice demonstrated physiological regulation of corticosterone secretion, with lowered morning levels compared to control mice. Systemic cytokine profiling also unveiled significant alterations in inflammatory mediators, particularly interleukin 6 (IL-6). Furthermore, unbiased proteomic analysis demonstrated downregulation of acute-phase proteins and upregulation of glutathione-related proteins, suggesting a role in the modulation of antioxidant responses. Conversely, IL-6 increased SGLT2 expression in kidney HK2 cells suggesting a role for cytokines in the effects of hyperglycemia. Collectively, our study elucidates a potential interplay between SGLT2 activity, immune modulation, and metabolic homeostasis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/590099v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@140041forg.highwire.dtl.DTLVardef@1ceb1b7org.highwire.dtl.DTLVardef@f575b1org.highwire.dtl.DTLVardef@101d5b4_HPS_FORMAT_FIGEXP M_FIG C_FIG Article HighlightsO_LIThe role of Sodium-glucose co-transporter type 2 (SGLT2) in immunity regulation remains elusive, despite extensive research in SGLT2 inhibitors. C_LIO_LIWe sought to discern the effects of SGLT2 inhibition or deletion on metabolic and immune profiles in high-fat-fed mice, focussing on corticosterone regulation and cytokine alterations. C_LIO_LISGLT2 null mice exhibit enhanced insulin sensitivity, alongside physiologically regulated corticosterone levels and significant alterations in inflammatory cytokines, and we identified changes in protein expression suggestive of antioxidant modulation. C_LIO_LIOur findings emphasize the interplay between immune responses and metabolic regulation mediated by SGLT2 activity. C_LI