Rabbit Anti-DPP4 monoclonal antibody, clone KN22-53

Aim To elucidate the mechanisms involved in the sequential use of SGLT2 and DPP4 inhibitors (SGLT2i and DPP-4i). Methods Twenty-six type-2 diabetes mellitus patients were recruited into a stepped regimen of 100 mg of canagliflozin daily from day 1, supplemented with 20 mg of teneligliptin daily from day 4. Glucose (Glu), insulin and glucagon were measured at fasting and after ingesting a mixed meal on days 1, 4 and 6. Results Canagliflozin decreased fasting plasma glucose to an extent inversely proportional to the change in the glucagon-to-insulin (G/I) ratio. This correlation at fasting was maintained when adding teneligliptin, while the change in the area under the curve of Glu (GluAUC) correlated closely with that in the G/I ratio at fasting and 60 min with canagliflozin. Moreover, these correlations persisted at 60 and 120 min postprandially, but not at fasting on day 6 when teneligliptin was added. Conclusion The result suggested that the dominant mechanism responsible for the glucose metabolism reflected in the G/I ratio was attributable to SGLT2i and that its active mechanism persisted, despite adding a DPP-4i.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 inhibitors (DPP4I) are used to treat type 2 diabetes (T2DM). DPP4 inhibitors (DPP4) attenuate Nlrp3 inflammasome activation in the kidney. SGLT2 inhibition reduces inflammation and attenuates the progression of diabetic nephropathy (DN). The effects of dapagliflozin (Dapa) on the activation of the Nlrp3 inflammasome and the combined effect of SGLT2 and DPP4 on T2DM-induced inflammasome activation and progression of DN have not been previously studied. We assessed whether Dapa attenuates the inflammasome activation and progression of DN in T2DM mice and whether these effects can be augmented by adding DPP4I saxagliptin (Saxa). Male BTBR ob/ob and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Serum BUN in the WT mice was 16.9 +/- 0.8 mg/dl. It increased to 55.7 +/- 2.8 mg/dl in the BTBR mice. Dapa alone reduced BUN to 31.4 +/- 1.2 mg/dl. A greater effect was seen in the Dapa+Saxa combination (24.8 +/- 0.8 mg/dl). Serum creatinine was 0.16 +/- 0.02 and 1.01 +/- 0.04 mg/dl in the WT and BTBR mice, respectively. Dapa and Dapa+Saxa attenuated the increase of creatinine to 0.65 +/- 0.02 and 0.40 +/- 0.03 mg/dl, respectively. Serum cystatin C was elevated in the BTBR mice (3.9 +/- 0.1 vs. 0.6 +/- 0.2 ng/ml) as compared to WT mice. Dapa (2.4 +/- 0.1) and Dapa+Saxa (1.4 +/- 0.1) attenuated this increase. Kidney weight was higher in the BTBR than that of WT mice. Dapa reduced the kidney/body weight ratio in the BTBR mice. Dapa+Saxa tended to have greater effect, but the difference was not significant. mRNA levels of NALP3, ASC, IL-1 beta, IL-6, caspase-1, TNF-alpha, collagen-1, and collagen-3 significantly increased in the kidneys of the BTBR compared to the WT mice. Dapa alone and to a greater extent, Dapa+Saxa, attenuated the activation of the inflammasome. Yet, the combination did not result in greater attenuation of the collagen-1 and collagen-3 mRNA levels. The P-AMPK/total AMPK ratio was lower in the BTBR mice than in the WT mice. Dapa and Dapa+ Saxa equally increased the ratio. Conclusions: Dapa attenuates T2DM-induced activation of the inflammasome and progression of DN in BTBR ob/ob mice. Adding Saxa to Dapa augmented attenuation of the inflammasome, but had no significant effect on kidney weight or collagen-1 and collagen-3 mRNA levels. Future clinical trials are necessary to study the effect of combined SGLT2 inhibitor and incretin therapy on renal outcomes in patients with T2DM.