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 ( r s =−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: NCT 01701973.