Beneficial effects of combination therapy of canagliflozin and teneligliptin on diabetic polyneuropathy and β-cell volume density in spontaneously type 2 diabetic Goto-Kakizaki rats

Aims: Parasympathetic nerve (PN) signaling plays a crucial role in the maintenance of pancreatic β-cell volume density (V_β). PN may be pathologically affected in diabetic polyneuropathy (DPN). However, the association between the reduction of PNs in islets and V_β and the therapeutic effects of a DPP4 inhibitor (DPP4i) and an SGLT2 Inhibitor (SGLT2i) in nonobese type 2 diabetes mellitus (T2DM) Goto-Kakizaki rats (GK) have not been investigated.

Materials and methods: We divided 5-week old male GK and Wistar rats (W) into a DPP4i-treated group (GKTe), SGLT2i-treated group (GKCa), and combination-treated group (GKCaTe). After 25 weeks, the pancreata was pathologically evaluated.

Results: V_β in GK was significantly decreased (p < 0.01 vs. W), whereas V_β was the most well preserved in GKCaTe (p < 0.05 vs. GKTe), followed by GKTe (p < 0.05 vs. GK). The decreased amount of PNs in the islets and intraepidermal nerve fiber density (IENFD) in GK was significantly improved in the treated groups compared with GK (p < 0.05 vs. GKCa and GKTe and p < 0.01 vs. GKCaTe). PN density and IENFD were significantly correlated with V_β (r = 0.55, p < 0.01 and r = 0.54, p < 0.01, respectively). IENFD was identified as a surrogate marker for the prediction of V_β (cutoff value, 16.39).

Conclusions: The combination therapy of DPP4i and SGLT2i improved V_β accompanied by PNs density and IENFD. IENFD was proportionally correlated with V_β. Therefore, the prevention of DPN development may be concurrently beneficial for the preservation of V_β in nonobese T2DM.

Combination therapy; DPP4 inhibitor; Parasympathetic innervation; SGLT2 inhibitor; Type 2 diabetes; β-Cell.