Circadian Timing of SGLT2 Inhibitor Administration Modulates Therapeutic Effects on Pancreatic Islet Function, Composition, and Gene Expression

Timing of drug administration based on endogenous circadian cycles (i.e., chronotherapy) has been shown to enhance treatment efficacy and improve outcomes in type 2 diabetes (T2DM). Sodium-Glucose Co-transporter 2 inhibitors (SGLT2i) are potent glucose lowering agents which improve cardiovascular health and exert systemic benefits on metabolic organs (e.g., pancreatic islets). Systemic benefits of SGLT2i are attributed to their ability to mimic a fasting state thus raising a question whether chronotherapeutic exposure to SGLT2i timed to the fasting vs. feeding circadian cycle will produce divergent benefits in T2DM. To address this, we generated a diet-induced T2DM mouse model by exposing male C57BL/6 mice to 14 weeks of high fat/high sucrose (HFHS) diet. Following induction of diabetes, mice were assigned into 3 groups for 4 weeks: 1) DAPAFAST: mice with daily Dapagliflozin (DAPA) oral gavage (1 mg/kg) given at the onset of the fasting (FAST) circadian cycle; 2) DAPAFED: daily DAPA oral gavage at the onset of the feeding (FED) cycle; 3) DAPAVEH: daily vehicle (VEH) gavage. DAPAFAST and DAPAFED groups demonstrated comparable lowering of basal and OGTT glucose versus DAPAVEH (~30%, p<0.05). In contrast, whereas improved glucose tolerance in DAPAFAST was associated with enhanced insulin secretion (p<0.05 vs. DAPAVEH), no changes in β-cell function was noted in DAPAFED mice. Consistently, RNAseq analysis of DAPAFAST isolated islets revealed attenuated expression of genes enriched for key pathways regulating β-cell failure such as p53, FOXO, and TGFβ signaling (all p<0.05). We also noted divergent effects on islet morphology with DAPAFAST group uniquely characterized by increased α-cell mass compared to DAPAFED and DAPAVEH (~70% increase, p<0.05). These data demonstrate divergent metabolic and islet effects of SGLT2i therapy highlighting the importance of chronotherapeutic approaches for optimal treatment of T2DM. Disclosure M.Dhanasekaran: None. K.Rakshit: None. T.K.Her: None. A.Matveyenko: None.