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

Abstract

BackgroundDiminished 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 ResultsHealthy 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.ConclusionsSitagliptin 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.

Sitagliptin decreases visceral fat and blood glucoses in women with polycystic ovarian syndrome

“…Triglyceride and PAI-1 levels in the women in the current study were one-third of the levels in their study population, thus making it difficult to detect further down-regulation of PAI-1 production. We have previously demonstrated that GH affects tPA activity levels through the GH receptor and downstream IGF-1 secretion,(11) but we did not observe any change in IGF-1 or tPA activity in this study. We also did not see any effect of sitagliptin on inflammation, whereas Makdissi A et al observed an anti-inflammatory effect of 100 mg daily sitagliptin on CRP, IL-6 and free fatty acids after 12 weeks in patients with type 2 diabetes.…”

“…(2) We previously reported that sitagliptin increases forearm vasodilation, measured by strain gauge plethysmography, in healthy women as assessed during stimulated GH secretion with peak levels averaging 11.6 mg/dL. (11) In the present study, we did not observe any effect of sitagliptin on conduit artery vascular function, however. Mean overnight GH levels in this study in patients with PCOS were significantly lower than in our prior study in healthy women.…”

“…Moreover, while vasodilation and tPA activity levels increased in both men and women during stimulated GH secretion, women demonstrated an enhanced vascular response to increased GH. (11) The effect of chronic DPP4 inhibition on pulsatile GH secretion in individuals with low GH levels has not been studied.…”

Effects of adult growth hormone deficiency and replacement therapy on the cardiometabolic risk profile

“…However, at present there are no specific recommendations regarding antidiabetic medications in AGHD. Interestingly, the dipeptidyl peptidase-4 inhibitor sitagliptin has been recently demonstrated to enhance endogenous GH and IGF-1 secretion in women [ 134 ] which may be beneficial in patients with coexisting diabetes and AGHD and is worth being examined in future research.…”

Pharmacology of dipeptidyl peptidase-4 inhibitors and its use in the management of metabolic syndrome: a comprehensive review on drug repositioning

“…In healthy volunteers, antihypertensive effects of sitagliptin has been shown and discussed that this effect is not directly related to GLP-1 or brain natriuretic peptide concentration [106], it could induce vasodilation by increase in growth hormone secretion [107].…”