The pharmacokinetics of acyl, des-acyl, and total ghrelin in healthy human subjects

Abstract

Background Ghrelin stimulates growth hormone (GH) secretion and regulates energy and glucose metabolism. The two circulating isoforms, acyl (AG) and desacyl (DAG) ghrelin, have distinct metabolic effects and are under active investigation for their therapeutic potentials. However, there is only limited data on the pharmacokinetics of AG and DAG. Objectives To evaluate key pharmacokinetic parameters of AG, DAG, and total ghrelin in healthy men and women. Methods In study 1 AG (1, 3 and 5 μg/kg/h) was infused over 65 min in 12 healthy (8F/4M) subjects in randomized order in. In study 2 AG (1 μg/kg/h), DAG (4 μg/kg/h), or both were infused over 210 min in 10 healthy individuals (5 F/5 M). Plasma AG and DAG were measured using specific two-site ELISAs (study1 and 2), and total ghrelin with a commercial RIA (study 1). Pharmacokinetic parameters were estimated by non-compartmental analysis. Results After the 1, 3 and 5 μg/kg/h doses of AG there was a dose-dependent increase in the maximum concentration (Cmax) and area under the curve [AUC(0-last)] of AG and total ghrelin. Among the different AG doses there was no difference in the elimination half-life, systemic clearance (CL), and volume of distribution. DAG had decreased CL relative to AG. The plasma DAG:AG ratio approximates 2:1 during steady state infusion of AG. Infusion of AG caused an increase of DAG, but DAG administration did not change plasma AG. Ghrelin administration did not affect plasma acylase activity. Conclusions The pharmacokinetics of AG and total ghrelin appear to be linear and proportional in the dose range tested. AG and DAG have very distinct metabolic fates in the circulation. There is deacylation of AG in the plasma but no evidence of acylation.

Circulating acylghrelin levels are suppressed by insulin and increase in response to hypoglycemia in healthy adult volunteers

“…It is unlikely that the rebound increase in AG following hyperinsulinemia and hypoglycemia is caused by increased concentrations of GH or FFA, because previous reports showed that total ghrelin was not correlated with GH (20) and that increased concentrations of FFA reduce total concentrations of ghrelin (21). In our study, we report AG-to-UAG ratios close to 150%, which is significantly higher than previous estimates ranging from 4% (1) to 50% (22). We believe that our data yield a better estimate due to improved sample handling and assay technique.…”

“…The protocol was registered at Clinicaltrials.gov (ID NCT01919788). Nine healthy men averagely aged 22.5 (18)(19)(20)(21)(22)(23)(24)(25)(26)(27) years with an average BMI of 23.4 (21.7-26.0) kg/m 2 were recruited in this study. All had a normal physical examination.…”

MECHANISMS IN ENDOCRINOLOGY: Regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions

“…infusion in humans, AG is deacylated to dAG and therefore it is important to understand the possible actions of dAG. It is also important to note that dAG has a slower rate of clearance when compared with AG (68). An acute i.v.…”

Response to inquiry by Gaylinn et al. on ‘Administration of UAG improves glycemic control in obese subjects with diabetes’

“…They comment that, while we clearly demonstrated the anti-diabetogenic potential of UAG, our observation that AG levels are suppressed may be an assay artefact. They refer to a similar UAG infusion study by Tong et al (3) in which a decline in AG was not observed. Gaylinn et al attribute this to technical differences in the antibody used to capture AG in the sandwich assay.…”