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

J Am Heart Assoc. 2018 Feb 25;7(5):e008000. doi: 10.1161/JAHA.117.008000.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Cross-Over Studies
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / administration & dosage*
  • Double-Blind Method
  • Female
  • Fibrinolysis / drug effects
  • Human Growth Hormone / blood*
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Secretory Pathway
  • Sex Factors
  • Sitagliptin Phosphate / administration & dosage*
  • Time Factors
  • Tissue Plasminogen Activator / blood
  • Up-Regulation
  • Vasodilation / drug effects*
  • Young Adult

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • IGF1 protein, human
  • Human Growth Hormone
  • Insulin-Like Growth Factor I
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Tissue Plasminogen Activator
  • Sitagliptin Phosphate

Associated data

  • ClinicalTrials.gov/NCT01701973