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

Metabolism. 2020 Jun;107:154232. doi: 10.1016/j.metabol.2020.154232. Epub 2020 Apr 14.


Aims: Parasympathetic nerve (PN) signaling plays a crucial role in the maintenance of pancreatic β-cell volume density (Vβ). PN may be pathologically affected in diabetic polyneuropathy (DPN). However, the association between the reduction of PNs in islets and Vβ 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: Vβ in GK was significantly decreased (p < 0.01 vs. W), whereas Vβ 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 Vβ (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 Vβ (cutoff value, 16.39).

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

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

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Canagliflozin / therapeutic use*
  • Cell Count
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetic Neuropathies / drug therapy*
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Drug Therapy, Combination
  • Glycated Hemoglobin / analysis
  • Hypoglycemic Agents / therapeutic use*
  • Insulin-Secreting Cells / pathology*
  • Islets of Langerhans / pathology
  • Male
  • Pancreas / pathology
  • Parasympathetic Nervous System / pathology
  • Pyrazoles / therapeutic use*
  • Rats
  • Rats, Wistar
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*
  • Thiazolidines / therapeutic use*


  • 3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine
  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Pyrazoles
  • Sodium-Glucose Transporter 2 Inhibitors
  • Thiazolidines
  • Canagliflozin