Luseogliflozin restores GIP responsiveness in diabetic male mice with preserved β-cell function.

Impaired glucose-dependent insulinotropic polypeptide (GIP)-induced insulin secretion is a characteristic feature of type 2 diabetes, whereas glucagon-like peptide-1 (GLP-1) responsiveness is relatively preserved. Our previous study proposed that chronic β-cell depolarization alters G protein signaling and contributes to this differential incretin responsiveness, but whether glucose lowering by sodium-glucose cotransporter 2 inhibition restores incretin responsiveness remains unclear. We investigated the effects of chronic luseogliflozin treatment on incretin responsiveness in two diabetic mouse models, KK-Ay mice with preserved residual β-cell function and streptozotocin/high-fat diet-induced diabetic mice with severe β-cell impairment. Luseogliflozin improved glycemic control in both models without marked changes in body weight or plasma insulin levels. In KK-Ay mice, luseogliflozin restored the glucose-lowering effect of GIP during GIP-preload glucose tolerance test. In contrast, this effect was not observed in streptozotocin/high-fat diet-induced diabetic mice, suggesting that preserved residual β-cell function is required for recovery of GIP responsiveness. Ex vivo analyses using isolated islets further showed that chronic luseogliflozin treatment altered incretin-stimulated insulin secretion, including attenuation of enhanced GLP-1 responsiveness under diabetic conditions. These findings suggest that luseogliflozin may partially normalize aberrant β-cell incretin signaling and restore GIP responsiveness when sufficient β-cell function remains.