Synergistic Effects of Long-Term Combination Therapy of DPP-4 Inhibitor and SGLT2 Inhibitor on the Preservation of Beta-Cell Volume in Rats with Type 2 Diabetes

One of the main pathogenetic features of type 2 diabetes (T2D) is reduction of β cell volume (V_β). Several antidiabetic oral agents were shown to improve V_β in experimental studies. While DPP-4 inhibitor (DPi) ameliorated V_β possibly via the action of GLP-1, recent studies reported that SGLT2 inhibitor (SGi) may facilitate GLP-1 secretion from L cells. These findings raised a hypothesis that the combination therapy (CT) of DPi and SGi may potentiate the effects of DPi on V_β. To explore this possibility, we recruited non-obese spontaneous T2D Goto-Kakizaki (GK) rats and control Wistar rats (W) at 5 weeks of age. GK was divided into DPi treated group (GTe) (10mg/kg teneligliptine), SGi-treated group (GCa) (10mg/kg canagliflozin) and CT group (GTeCa). During experimental period, diabetic state was evaluated by glycated Hb (gHb), 2g/kg oral glucose tolerance test (OGTT), glucose-stimulated insulin secretion test (GSIS) and serum active GLP-1. At end, pancreata were underwent for the pathological evaluation of each endocrine cell volume by tetra-immnohistochemistry. Over 24 weeks of treatment, GK showed higher gHb and deteriorated OGTT (p<0.01 vs. W). Although DPi and SGi in each significantly improved gHb and OGTT compared to GK, the effect was the most marked in GTeCa. Of note, active GLP-1 was the highest in GCaTe among all groups (p<0.vs. GTe), while the level in GTe was higher than in W, GK, and GCa (p<0.01). GK showed attenuated GSIS (p<0.01 vs. W). It was significantly improved in GTe and GCaTe compared to GK (p<0.vs. GTe, p<0.01 vs. GCaTe), although it was comparable between GK and GCa. Pathological evaluation disclosed a significant decrease in V_β in GK (p<0.01 vs. W). V_β was the most well-preserved in GCaTe (p<0.vs. GTe), followed by GTe (p<0.vs. GK), while it was comparable between GK and GCa. Our findings suggest that CT of DPi and SGi is more effective for β cell function and pathology in T2D than the monotherapy of DPi or SGi.