SGLT2 inhibitor luseogliflozin restores GIP responsiveness in diabetic male mice with preserved β-cell function

Impaired glucose-dependent insulinotropic polypeptide (GIP) responsiveness is a hallmark of Type 2 Diabetes (T2D), contrasting with relatively preserved glucagon-like peptide-1 (GLP-1) sensitivity. Previous research suggests chronic β-cell depolarization alters G protein signaling, contributing to this differential incretin response. A key therapeutic gap remains whether glucose-lowering interventions, specifically sodium-glucose cotransporter 2 (SGLT2) inhibition, can reverse this impaired incretin responsiveness and normalize β-cell signaling.

Researchers administered chronic luseogliflozin treatment to two distinct male diabetic mouse models: KK-Ay mice, characterized by preserved residual β-cell function, and streptozotocin/high-fat diet (STZ/HFD) mice, exhibiting severe β-cell impairment. The primary endpoints included glycemic control, assessed via GIP-preload glucose tolerance test, and ex vivo analyses of incretin-stimulated insulin secretion using isolated islets. Body weight and plasma insulin levels were also monitored to evaluate systemic effects.

Luseogliflozin treatment improved glycemic control in both KK-Ay and STZ/HFD mouse models, notably without significant changes in body weight or plasma insulin levels. This suggests its primary effect was glucose-lowering rather than systemic weight modulation.

In KK-Ay mice, luseogliflozin successfully restored the glucose-lowering effect of GIP during a GIP-preload glucose tolerance test. This crucial effect was absent in the STZ/HFD diabetic mice, strongly indicating that the recovery of GIP responsiveness is contingent upon preserved residual β-cell function. Further ex vivo analyses of isolated islets revealed that chronic luseogliflozin treatment altered incretin-stimulated insulin secretion. Interestingly, this included an attenuation of the enhanced GLP-1 responsiveness typically observed under diabetic conditions, suggesting a partial normalization of aberrant β-cell incretin signaling.