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

Abstract

We quantified the contribution of GLP-1 as a mediator of the therapeutic effects of dipeptidyl peptidase 4 (DPP-4) inhibition (vildagliptin) by using the GLP-1 receptor antagonist exendin in patients with type 2 diabetes and in healthy subjects. Thirty-two patients with type 2 diabetes and 29 age-and weight-matched healthy control subjects were treated in randomized order with 100 mg once daily vildagliptin or placebo for 10 days. Meal tests were performed (days 9 and 10) without and with a high-dose intravenous infusion of exendin . The main end point was the ratio of the areas under the curve (AUCs) of integrated insulin secretion rates (total AUC ISR ) and glucose (total AUC glucose ) over 4 h after the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and glucose-dependent insulinotropic polypeptide and lowered glucose responses without changing AUC ISR /AUC glucose in healthy subjects. Vildagliptin significantly increased this ratio by 10.5% in patients with type 2 diabetes, and exendin [9-39] reduced it (both P < 0.0001). The percentage reduction in the AUC ISR / AUC glucose ratio achieved with exendin [9-39] was significantly smaller after vildagliptin treatment than after placebo treatment (P = 0.026) and was equivalent to 47 6 5% of the increments due to vildagliptin. Thus, other mediators appear to contribute significantly to the therapeutic effects of DPP-4 inhibition.

DPP-4 Inhibition and the Known Unknown

“…The elegant study by Nauck et al (9) reported in this issue of Diabetes provides important insights regarding the mechanisms underlying glucose lowering by DPP-4 inhibition that are consistent with, and complimentary to, outcomes reported by Aulinger et al (10) (Fig.1). In the study by Nauck et al (9), a total of 32 patients with type 2 diabetes managed by diet or metformin and 29 healthy control subjects received vildagliptin 100 mg or placebo for 10 days in a crossover design.…”

“…Hence, the effect of DPP-4 inhibition on gastric emptying is of interest. Although Nauck et al (9) found no effect measured by a breath test (9), there is probably a modest slowing (10,19), albeit much less than that induced by short-acting GLP-1 agonists (16). Gastric emptying is also a determinant of the glycemic response to DPP-4 inhibition (19,20), and strategies that slow gastric emptying and stimulate GLP-1 secretion, such as whey preloads (19), potentiate glucose lowering.…”

“…In the study by Nauck et al (9), a total of 32 patients with type 2 diabetes managed by diet or metformin and 29 healthy control subjects received vildagliptin 100 mg or placebo for 10 days in a crossover design. Meal tests, with concurrent assessment of gastric emptying, were performed on days 9 and 10, with and without intravenous exendin , a GLP-1 receptor antagonist.…”

“…In mice, inhibition of intestinal DPP-4 reduces plasma glucose without affecting plasma DPP-4 activity, GLP-1, or GIP (11). DPP-4 inhibition affects the degradation of other hormones; Nauck et al (9) refer to four possibilities: GIP, oxyntomodulin, pituitary adenylate cyclase-activating peptide, and stromal cell-derived factor-1a. A role for GIP would not be surprising; in mice, DPP-4 inhibition reduces glycemia with targeted deletion of either, but not both, incretin receptors (12).…”

“…In this way, "unknowns" can be resolved to provide therapeutic advances. [10], using sitagliptin) or a mixed meal (Nauck et al [9], using vildagliptin). For the study by Aulinger et al, these proportions have been calculated from mean data for incremental areas under the curve for blood glucose (240 min), insulin-to-glucose ratio (240 min), and glucagon (60 min), using the method proposed by the authors for the glucose-lowering effect.…”