Acute Administration of Unacylated Ghrelin Has No Effect on Basal or Stimulated Insulin Secretion in Healthy Humans

Abstract

Unacylated ghrelin (UAG) is the predominant ghrelin isoform in the circulation. Despite its inability to activate the classical ghrelin receptor, preclinical studies suggest that UAG may promote β-cell function. We hypothesized that UAG would oppose the effects of acylated ghrelin (AG) on insulin secretion and glucose tolerance. AG (1 µg/kg/h), UAG (4 µg/kg/h), combined AG+UAG, or saline were infused to 17 healthy subjects (9 men and 8 women) on four occasions in randomized order. Ghrelin was infused for 30 min to achieve steady-state levels and continued through a 3-h intravenous glucose tolerance test. The acute insulin response to glucose (AIRg), insulin sensitivity index (SI), disposition index (DI), and intravenous glucose tolerance (kg) were compared for each subject during the four infusions. AG infusion raised fasting glucose levels but had no effect on fasting plasma insulin. Compared with the saline control, AG and AG+UAG both decreased AIRg, but UAG alone had no effect. SI did not differ among the treatments. AG, but not UAG, reduced DI and kg and increased plasma growth hormone. UAG did not alter growth hormone, cortisol, glucagon, or free fatty acid levels. UAG selectively decreased glucose and fructose consumption compared with the other treatments. In contrast to previous reports, acute administration of UAG does not have independent effects on glucose tolerance or β-cell function and neither augments nor antagonizes the effects of AG.

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

“…We have recently shown that a 210-min continuous infusion of AG or co-infusion of AG and dAG to healthy subjects yielded a decreased acute insulin response to glucose and i.v. glucose tolerance, whereas dAG infusion alone did not alter these parameters (70). However, the lack of effect of dAG on glucose metabolism is not universally observed.…”

Ghrelin and Insulin Secretion in Humans: Not a Tale of Two Hormones?

“…In the current issue, Tong et al (19) investigated the effects of bolus followed by continuous, 210-min intravenous infusions of pharmacologic AG and UAG doses (1 and 4 mg/kg/h, respectively) on circulating insulin in healthy volunteers under fasting and intravenous glucosestimulated conditions. The key findings of the study are negative, as the inhibitory effect of AG on plasma insulin following intravenous glucose was unaffected by concomitant UAG infusion.…”

“…Moreover, AG-UAG interactions should be systematically investigated in clinical conditions characterized by insulin resistance, when a decline in circulating UAG and higher AG-UAG ratios have been reported (3,4,8). Under these conditions, potential differential modulation by AG and UAG of additional regulators of insulin secretion should be also considered, including autonomic nervous signaling (13), circulating hormones such as growth hormone and cortisol (1,6,19), and dietary carbohydrate intake as shown by Tong et al (19). Finally, the well-demonstrated positive impact of both AG and UAG on b-cell survival and proliferation, leading to enhanced b-cell mass and higher circulating insulin in streptozotocin-induced type 1 diabetes models (10,20), poses important questions; longer-term interactions between altered insulin release and beneficial changes in b-cell mass should be directly investigated during longterm modification of ghrelin profile.…”

“…In summary, Tong et al (19) provide a model for the challenging investigation of AG-UAG interactions in vivo in humans, and they show no independent effect of UAG Figure 1-Relevant experimental or clinical conditions with well-defined or poorly defined effects of exogenous AG, UAG, or their interactions on insulin secretion in humans. A: Inhibitory effects of high-dose AG on intravenous (Iv) glucose-induced insulin secretion, unaffected by high-dose UAG; no independent effects of high-dose UAG on insulin secretion (14,19).…”

“…A: Inhibitory effects of high-dose AG on intravenous (Iv) glucose-induced insulin secretion, unaffected by high-dose UAG; no independent effects of high-dose UAG on insulin secretion (14,19). B: Inhibitory effects of physiologic AG dose on intravenous glucose-induced insulin secretion (15); no information on potential physiologic UAG interactions.…”