One of the main pathogenetic features of type 2 diabetes (T2D) is reduction of β cell volume (Vβ). Several antidiabetic oral agents were shown to improve Vβ in experimental studies. While DPP-4 inhibitor (DPi) ameliorated Vβ 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 Vβ. 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 Vβ in GK (p<0.01 vs. W). Vβ 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. Disclosure H. Mizukami: Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd., Mitsubishi Tanabe Pharma Corporation. D. Guo: None. K. Takahashi: None. S. Osonoi: None. S. Ogasawara: None. W. Inaba: None. S. Yagihashi: None.
Pancreatic branch of vagus nerve (pvn) signaling plays a pivotal role in the maintenance of islet β cell volume density (Vβ). In type 2 diabetes (T2D), small fibers in the epidermis is decreased by diabetic insult. It is not still uncovered yet, however, that the reduction of terminal pvn fibers is associated with Vβ in T2DM. Herein, we explored the association between islet pvn fiber density and Vβ. We recruited non-obese spontaneous T2D Goto-Kakizaki (GK) rats and control Wistar rats (W) at 5 weeks of age. GK was divided into DPP-4 inhibitor (DPi)-treated group (GTe) (10mg/kg teneligliptine), SGLT2 inhibitor (SGi)-treated group (GCa) (10mg/kg canagliflozin) and both treated group (GTeCa). During experimental period, 2g/kg oral glucose tolerance test (OGTT) and glucose-stimulated insulin secretion test (GSIS) was performed. At end, pancreata were underwent for the pathological evaluation. OGTT in GK was attenuated (p<0.01 vs. W). Although DPi and SGi in each significantly improved OGTT compared to GK, the effect was the most robust in GTeCa. Low GSIS in GK (p<0.01 vs. W) was significantly improved in GTe and GCaTe (p<0.05 and p<0.01 vs. GK, respectively), although it was comparable between GK and GCa. Pathological evaluation disclosed a significant decrease in Vβ in GK (p<0.01 vs. W). Vβ was the most well-preserved in GCaTe (p<0.05 vs. GTe), followed by GTe (p<0.05 vs. GK), while it was comparable between GK and GCa. The density of pvn fibers labeled by the antibody for vesicular acetylcholine transporter (VachT) were significantly decreased in the islet of GK (p<0.01 vs. W). It was significantly improved in GCa, GTe and GCaTe compared to GK (p<0.05 vs. GCa and GTe; p<0.01 GCaTe, respectively). pvn fiber density in the islets significantly correlated with Vβ (r=0.53, p<0.01). Our results shed light on the association between terminal fiber density of pvn in the islet and Vβ, and the maintenance of the fibers may be beneficial for the prevention from Vβ loss in T2D. Disclosure H. Mizukami: None. D. Guo: None. K. Takahashi: None. S. Osonoi: None. K. Kudo: None. S. Yagihashi: None.
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