Dipeptidyl Peptidase-4 Inhibition Potentiates Stimulated Growth Hormone Secretion and Vasodilation in Women

Abstract

Background: Diminished growth hormone (GH) is associated with impaired endothelial function and fibrinolysis. GH-releasing hormone is the primary stimulus for GH secretion and a substrate of dipeptidyl peptidase-4. We tested the hypothesis that dipeptidyl peptidase-4 inhibition with sitagliptin increases stimulated GH secretion, vasodilation, and tissue plasminogen activator (tPA) activity.

Methods and results: Healthy adults participated in a 2-part double-blind, randomized, placebo-controlled, crossover study. First, 39 patients (29 women) received sitagliptin or placebo on each of 2 days separated by a washout. One hour after study drug, blood was sampled and then arginine (30 g IV) was given to stimulate GH. Vasodilation was assessed by plethysmography and blood sampled for 150 minutes. Following a washout, 19 of the original 29 women received sitagliptin alone versus sitagliptin plus antagonist to delineate GH receptor (GHR)- (n=5), nitric oxide- (n=7), or glucagon-like peptide-1 receptor- (n=7) dependent effects. Sitagliptin enhanced stimulated GH secretion (P<0.01 versus placebo, for 30 minutes) and free insulin-like growth factor-1 (P<0.001 versus placebo, after adjustment for baseline) in women. Vasodilation and tPA increased in all patients, but sitagliptin enhanced vasodilation (P=0.01 versus placebo) and increased tPA (P<0.001) in women only. GHR blockade decreased free insulin-like growth factor-1 (P=0.04 versus sitagliptin alone) and increased stimulated GH (P<0.01), but decreased vascular resistance (P=0.01) such that nadir vascular resistance correlated inversely with GH (rs=-0.90, P<0.001). GHR blockade suppressed tPA. Neither nitric oxide nor glucagon-like peptide-1 receptor blockade affected vasodilation or tPA.

Conclusions: Sitagliptin enhances stimulated GH, vasodilation, and fibrinolysis in women. During sitagliptin, increases in free insulin-like growth factor-1 and tPA occur via the GHR, whereas vasodilation correlates with GH but occurs through a GHR-independent mechanism.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01701973.

Keywords: dipeptidyl peptidase‐4; growth hormone; insulin‐like growth factor‐1; tissue‐type plasminogen activator; vasodilation.

© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1

Dipeptidyl peptidase‐4 (DPP4) inhibition with sitagliptin enhances early stimulated growth hormone (GH) secretion (A) and free insulin–like growth factor‐1 (IGF‐1) levels (B) and shortens the time to peak GH (C) in women (n=29) but not men (n=10). Change in free IGF‐1 levels from baseline to 90 minutes following arginine. (Free IGF‐1 data available in 28 women and 9 men.) Data are presented as mean±SEM. *P≤0.05; †P<0.10 vs placebo at same time point by Wilcoxon signed‐rank test. The effect of treatment on free IGF‐1, in the linear model, was significant in women (P<0.001 vs placebo, after adjustment for baseline free IGF‐1). The effect of treatment on ln(GH), in the linear model, was significant in women for 30 minutes following arginine (P<0.01 vs placebo, after adjustment for baseline GH).

Figure 2

Dipeptidyl peptidase‐4 inhibition with sitagliptin enhances vasodilation during arginine (Arg) stimulated growth hormone secretion in women (n=29) but not men (n=10). The overall effect of treatment, as determined by linear model, was significant in women (P=0.013 effect of treatment on percent change [∆] in forearm blood flow and P=0.003 effect of treatment on percent change in forearm vascular resistance). Data are presented as mean±SEM. *P<0.05 vs placebo at specified time point in the linear model.

Figure 3

Dipeptidyl peptidase‐4 inhibition with 200 mg sitagliptin increases tissue plasminogen activator (tPA) activity levels in women (n=7 women) but decreases tPA activity levels in men relative to baseline (n=7 men) during arginine stimulated growth hormone secretion. The overall effect of treatment on tPA activity, as determined by linear model, was significant after adjustment for baseline tPA activity (P<0.001 effect of treatment in women and P=0.02 effect of treatment in men). There was no effect of 100 mg daily of sitagliptin on tPA activity. Data are presented as mean±SEM. *P<0.05 vs placebo at specified time point in linear model after adjustment for baseline tPA.

Figure 4

The addition of growth hormone (GH) receptor blockade (pegvisomant 80 mg administered SC 72 hours prior) to sitagliptin increases GH levels as a result of reduced negative feedback (n=5 women) (A) and decreases free insulin–like growth factor‐1 (IGF‐1) (B). The addition of GH receptor blockade to sitagliptin further decreases forearm vascular resistance (FVR) during stimulated GH secretion (C). At the nadir in vascular resistance (arrow), a significant correlation between vascular resistance and GH levels was found (D). Pegvisomant decreases tissue plasminogen activator (tPA) activity levels before and throughout arginine (Arg)‐stimulated GH secretion (E). Data are presented as mean±SEM. *P≤0.05 vs placebo at specified time point in the linear model. Linear model–based P values are: P<0.01 effect of treatment on GH, P<0.01 effect of treatment on FVR percent change (∆), and P<0.001 effect of treatment on tPA activity.

Figure 5

l‐N‐monomethylarginine (LNMMA) did not affect the vasodilator response to arginine (Arg)‐stimulated growth hormone (GH) secretion during sitagliptin (A) (n=7 women). Glucagon‐like peptidase‐1 (GLP‐1) receptor blockade (Exendin 9‐39) did not affect the vasodilator response to stimulated GH secretion during sitagliptin (B) (n=7 women). Data are presented as mean±SEM. *P<0.05 vs placebo at specified time point in the linear model. The linear model–based P values for overall effect of treatment were not significant.

Figure 6

The increase in arginine (Arg)‐stimulated growth hormone (GH) secretion during dipeptidyl peptidase‐4 inhibition with sitagliptin is reproducible (n=19 women). Data are presented as mean±SEM unless otherwise noted. There was a significant correlation between stimulated GH secretion following sitagliptin and stimulated GH secretion following sitagliptin plus saline infusion (peak GH response: rs=0.65, P=0.003; GH 30 minutes after arginine: rs=0.51, P=0.02).