The increased dipeptidyl peptidase-4 activity is not counteracted by optimized glucose control in type 2 diabetes, but is lower in metformin-treated patients

Aim: Dipeptidyl peptidase (DPP)-4 in responsible for incretin degradation and some observations suggest that DPP-4 activity is increased in type 2 diabetes (T2D). We aimed to assess the effect of T2D and glucose control on DPP-4 activity. Methods: In the first set (SET1) of patients, we compared plasma DPP-4 activity between 30 T2D and 20 age-and sex-matched non-diabetic subjects. In the second set (SET2), we measured serum DPP-4 activity in 42 T2D patients before and after a trial of glucose control achieved by add-on basal insulin therapy (NCT00699686). Serum/ plasma DPP-4 activity was determined using chromogenic and fluorigenic substrates, as well as several positive and negative controls. Results: In SET1, plasma DPP-4 activity was significantly higher in T2D vs. controls (32.2 + 1.2 U/ l vs. 21.2 + 1.1 U/ l, p < 10-6). From a meta-analysis of the literature, we found that T2D is associated with a 33% increase in DPP-4 activity compared to controls. In SET2, serum DPP-4 activity was not lowered by intensified glucose control, despite an average haemoglobin A1c (HbA1c) reduction of 1.5%. In both sets of diabetic patients, the use of metformin was associated with a significantly lower DPP-4 activity, independently of age, sex, body mass index and HbA1c. Conclusion: DPP-4 activity is increased in T2D, but is not lowered by glucose control, suggesting that hyperglycaemia is not a direct determinant of DPP-4 activity. However, metformin may indirectly reduce DPP-4 activity.