Constant intravenous ghrelin infusion in healthy young men: clinical pharmacokinetics and metabolic effects

Abstract

Ghrelin levels fluctuate rapidly and dynamically with surges before meal times and postprandial troughs, and ghrelin increases appetite and food intake. Circulating ghrelin correlates negatively with body mass index (BMI), but obese individuals have a reduced postprandial decrease in ghrelin levels. Whether this reflects changes in secretion or clearance of ghrelin is uncertain. We therefore studied the pharmacokinetics of ghrelin in relation to anthropometric and biochemical measures. We also studied the effects of ghrelin on hormones and metabolites. In fasting humans, we used a constant infusion rate of ghrelin lasting 180 min at 5 pmol.kg body wt(-1).min(-1) in a randomized, double-blind, placebo-controlled crossover study. Serum ghrelin (s-ghrelin; total levels) was distributed and eliminated according to a two-compartment model. s-Ghrelin initial half-life was 24 +/- 2 min and terminal half-life 146 +/- 36 min, respectively. Mean residence time (MRT) of ghrelin was 93 +/- 16 min. MRT correlated positively with both BMI (r = 0.51, P < 0.001) and high-density cholesterol (HDL) levels (r = 0.75, P < 0.001). Serum insulin levels remained constant during ghrelin infusion, whereas plasma glucose increased 0.3 +/- 0.1 mmol/l (P < 0.01) and free fatty acid levels more than doubled (to 1.03 +/- 0.08 mmol/l, P < 0.001), translating into a significant reduction of insulin sensitivity (P < 0.001). In conclusion, 1) we describe novel pharmacokinetics of ghrelin that are useful when tailoring ghrelin infusion rates in clinical experiments, 2) BMI and HDL correlate positively with MRT of infused ghrelin, and 3) supraphysiological ghrelin levels impair insulin sensitivity.

Plasma Ghrelin Levels Are Associated with Coronary Microvascular and Endothelial Dysfunction in Peritoneal Dialysis Patients

“…In the present study, multiple linear regression analysis revealed a clear trend for an inverse correlation only between ghrelin and LDL cholesterol levels, which may indicate that ghrelin may have a critical impact on serum cholesterol levels. [29] Although Lee et al [30] reported the association of serum HDL cholesterol with plasma ghrelin levels, in the present study, no association of HDL cholesterol and plasma ghrelin levels was found. An experimental study reported that low plasma ghrelin levels raise blood pressure levels in rats [5] ; however, our study was also unable to show such a relationship in PD patients.…”

Neuroendocrine Control of Hepatic Gluconeogenesis

“…Exogenous ghrelin suppresses glucose-stimulated insulin secretion but demonstrates no efect on basal levels of serum insulin. These observations suggest that ghrelin impairs insulin sensitivity [34,35]. Evidence from rodent models also consistently demonstrates that exogenous ghrelin administration induces hyperglycaemia and worsens glycaemic control under a high-fat diet condition [36,37].…”

“…Circulating GLP-1 has two forms, GLP and GLP [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] amide. About 80% of circulating GLP1 in human is GLP [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] amide [18]. Plasma levels of GLP-1 in the basal level range between 5-10 pM and its level could increase to 50 pM after a meal.…”

Therapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis

“…Although the potential for ghrelin as a prokinetic agent in the treatment of GI motility disorders such as gastroparesis is promising, it is limited by its short half-life [76] and plasma instability. Consequently, several synthetic ghrelin agonists have been developed and investigated for clinical use.…”