Feeding Time-Dependent Changes in the Preventive Effect of Empagliflozin on the Development of Peripheral Neuropathic Pain in Diabetic Model Mice

Abstract

It is known that the daily feeding cycle affects the dosing time-dependent changes in the pharmacodynamics and pharmacokinetics of many drugs. Our previous study demonstrated that administration of empagliflozin (EMPA), sodium-glucose cotransporter 2 (SGLT2) inhibitor, at the beginning of daily feeding cycle (active phase) effectively prevents the development of neuropathic pain in streptozotocin (STZ)-induced diabetic mice. Although the blood glucose levels are closely related to feeding, the relationship between the daily feeding cycle and the optimal dosing time of EMPA remains unclear. In this study, we used STZ-induced diabetic mice and implemented a daily time-restricted feeding (TRF) regimen to investigate whether the dosing time-dependent preventive effect of EMPA on the diabetic neuropathy is modulated by TRF. Animals were housed under a 12-h light/dark cycle, and were assigned to either light-phase TRF (feeding during the light phase) or dark-phase TRF (feeding during the dark phase). The hypoglycemic effect of EMPA was enhanced when the drug was administrated at the beginning of both TRF conditions. A similar influence of the daily feeding cycle on the dosing time-dependent hypoglycemic effect of EMPA was also observed in its preventive effect on the development of diabetic neuropathic pain. Further analysis revealed that dosing time-dependent variations in both the hypoglycemic effect of EMPA and its preventive effect on diabetes-induced pain hypersensitivity were attributable to corresponding changes in urinary glucose excretion. Our results support the notion that the administration of EMPA at the onset of daily feeding cycle effectively suppresses the development of diabetic peripheral neuropathy.