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

Diabetes Obes Metab. 2012 Jun;14(6):518-22. doi: 10.1111/j.1463-1326.2011.01550.x. Epub 2012 Jan 6.


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.

Publication types

  • Comparative Study

MeSH terms

  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Body Mass Index
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl Peptidase 4 / blood
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Fasting / blood
  • Female
  • Glycated Hemoglobin A / drug effects
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hyperglycemia / blood
  • Hyperglycemia / drug therapy*
  • Hypoglycemic Agents / pharmacology*
  • Incretins / blood
  • Male
  • Metformin / pharmacology*
  • Middle Aged


  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Incretins
  • hemoglobin A1c protein, human
  • Metformin
  • Dipeptidyl Peptidase 4