Quantification of the Contribution of GLP-1 to Mediating Insulinotropic Effects of DPP-4 Inhibition With Vildagliptin in Healthy Subjects and Patients With Type 2 Diabetes Using Exendin [9-39] as a GLP-1 Receptor Antagonist

We wanted to quantify the contribution of GLP-1 as a mediator of therapeutic effects of DPP-4 inhibition (vildagliptin), using the GLP-1 receptor antagonist exendin [9-39] in type 2 diabetic patients and in healthy subjects. 32 patients with type 2 diabetes and 29 age- and weight-matched healthy control subjects were treated, in randomized order, with 100 mg q.d. vildagliptin or placebo for 10 days. Meal tests were performed (days 9 and 10), without and with a high dose intravenous infusion of exendin [9-39]. The main endpoint was the ratio of integrated insulin secretion rates (total AUC ISR ) and total AUC glucose over 4 h following the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and GIP and lowered glucose responses without changing AUC ISR /AUC glucose in healthy subjects. Vildagliptin significantly increased this ratio by 10.5 % in type 2-diabetic patients and exendin [9-39] reduced it (both p ISR /AUC glucose ratio achieved with exendin [9-39] was significantly smaller after vildagliptin than after placebo treatment (p = 0.026) and was equivalent to 47 ± 5% of the increments due to vildagliptin. Thus, other mediators appear to contribute significantly to the therapeutic effects of DPP-4 inhibition.