Twenty-four-hour profiles of acylated and total ghrelin: relationship with glucose levels and impact of time of day and sleep

Abstract

Context: The acylation of ghrelin is essential for its stimulatory effects on GH release and appetite. Most of the physiology of ghrelin has been defined based on the assay of total ghrelin (TG), which mainly reflects levels of unacylated ghrelin. Whether levels of acylated ghrelin (AG) are influenced by circadian time and sleep and impact glucose regulation under physiologic conditions is not known.

Methods: Blood was sampled at 10- to 30-min intervals for 24 h in 14 healthy young lean men under controlled conditions of activity, light-dark cycle, and sleep-wake schedule. The subjects ingested three identical carbohydrate-rich meals at 5-h intervals. Sleep was polygraphically monitored. Levels of TG and AG were measured by RIA. The 24-h profiles of glucose and insulin levels were assessed simultaneously.

Results: Postprandial glucose concentrations were positively correlated with mean levels of AG but not TG, independently of insulin. Postprandial suppression and rebound of AG and TG occurred in parallel and were not impacted by time of day. The nocturnal elevation of AG and TG reflects the postdinner rebound curbed by an inhibitory effect of sleep. The ratio of AG to TG was lower during sleep than during wake, consistent with a reduction of orexigenic signal.

Conclusions: Individual differences in AG levels may be an important predictor of overall glucose control under physiological conditions. Sleep, but not time of day, impacts postprandial TG and AG responses. The inhibitory effect of sleep on ghrelin release and acylation is consistent with the association between sleeping and fasting.

Fig. 1.

Twenty-four-hour mean (±se) profiles of total ghrelin, acylated ghrelin, glucose, and insulin obtained in healthy young men who were allowed to sleep from 2300 to 0700 h. The meal included identical carbohydrate-rich meals presented at 5-h intervals (0900, 1400, and 1900 h). The dotted line represents the occurrence of a hypothetical fourth identical meal 5 h after the dinner meal, i.e. at midnight. The black bars represent the sleep period.

Fig. 2.

A, Association between 24-h glucose levels and 24-h acylated ghrelin levels. B, Association between 24-h glucose levels and 24-h total ghrelin levels. C, Twenty-four-hour mean (±se) profiles of glucose for subjects with high and low 24-h acylated ghrelin levels. The arrows represent identical carbohydrate-rich meals presented at 5-h intervals.

Fig. 3.

A, Early meal responses of total ghrelin, acylated ghrelin, and incremental AUC of glucose from 0 to 1.5 h postmeal and incremental AUC of insulin from 0 to 1.5 h after the meal (top to bottom), B, Association between the magnitudes of the degree of postmeal inhibition of total ghrelin (upper panel) and acylated ghrelin (lower panel) with the rebounds.

Fig. 4.

Mean (±se) levels of total ghrelin (upper panel) and acylated ghrelin (lower panel) at mean peak levels for daytime (0900, 1400, and 1900 h) meals and at hypothetical peak time of a nocturnal (2400 h) meal.