Apelin administration improves insulin sensitivity in overweight men during hyperinsulinaemic‐euglycaemic clamp

• Published in: Diabetes, obesity & metabolism Vol. 20; no. 1; pp. 157 - 164
• Main Authors: Gourdy, Pierre, Cazals, Laurent, Thalamas, Claire, Sommet, Agnès, Calvas, Fabienne, Galitzky, Monique, Vinel, Claire, Dray, Cédric, Hanaire, Hélène, Castan‐Laurell, Isabelle, Valet, Philippe
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2018; Wiley Subscription Services, Inc
• Subjects: adipokine; Adolescent; Adult; Animal models; Anti-Obesity Agents - administration & dosage; Anti-Obesity Agents - adverse effects; Anti-Obesity Agents - therapeutic use; Apelin - adverse effects; Apelin - analogs & derivatives; Apelin - blood; Apelin - therapeutic use; Apelin Receptors - agonists; Apelin Receptors - metabolism; apelin/APJ system; Body Mass Index; Body weight; Cross-Over Studies; Diabetes; Diabetes mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Glucose; Glucose Clamp Technique; Glucose tolerance; Humans; hyperinsulinaemic‐euglycaemic clamp; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - therapeutic use; Infusions, Intravenous; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins - administration & dosage; Intercellular Signaling Peptides and Proteins - adverse effects; Intercellular Signaling Peptides and Proteins - pharmacokinetics; Intercellular Signaling Peptides and Proteins - therapeutic use; Intravenous administration; Male; Mens health; Overweight; Overweight - blood; Overweight - drug therapy; Overweight - metabolism; Peptide Fragments - administration & dosage; Peptide Fragments - adverse effects; Peptide Fragments - pharmacokinetics; Peptide Fragments - therapeutic use; Proof of Concept Study; Rodents; type 2 diabetes; Young Adult; apelin/APJ system; hyperinsulinaemic-euglycaemic clamp; type 2 diabetes; adipokine; insulin resistance
• ISSN: 1462-8902; 1463-1326; 1463-1326
• DOI: 10.1111/dom.13055

Aims Apelin is a recently identified adipokine known to improve glucose tolerance and insulin sensitivity in murine models. This study was dedicated to the proof of concept that apelin administration also enhances insulin sensitivity in humans. Materials and Methods Healthy overweight men were enrolled in this randomized, double‐blind, placebo‐controlled, cross‐over study that successively considered the efficacy and the tolerance of 2 doses of (pyr1)‐Apelin‐13. A first group of subjects received 9 nmol/kg (n = 8) of (pyr1)‐Apelin‐13 and, after examination of safety data, a second group received 30 nmol/kg (n = 8). Each volunteer underwent 2 hyperinsulinaemic‐euglycaemic clamps where the basal level of glucose infusion rate (GIR) was measured from the 90th to the 120th minute (level 1). Continuous intravenous administration of apelin or placebo was ongoing for 2 hours and GIR was finally evaluated from the 210th to the 240th minute (level 2). Primary evaluation endpoint was the difference in GIR between level 2 and level 1 (ΔGIR). Results A slight increase in ΔGIR was observed with the low apelin dose (0.65 ± 0.71 mg/kg/min, P = .055) whereas the highest dose significantly improved insulin sensitivity (0.82 ± 0.71 mg/kg/min, P = .033). Cardiovascular monitoring and safety reports did not reveal any side effect of apelin administration. Conclusion As the first demonstration of the insulin‐sensitizing action of apelin in humans, alongside numerous studies in rodents, this trial confirms that the apelin/APJ pathway should be considered as a new target to design alternative therapeutic strategies to control insulin resistance in type 2 diabetic patients.