Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions

Abstract

Gauna C, Kiewiet RM, Janssen JA, van de Zande B, Delhanty PJ, Ghigo E, Hofland LJ, Themmen AP, van der Lely AJ. Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions. Am J Physiol Endocrinol Metab 293: E697-E704, 2007. First published June 19, 2007; doi:10.1152/ajpendo.00219.2007.-Acylated and unacylated ghrelin (AG and UAG) are gut hormones that exert pleiotropic actions, including regulation of insulin secretion and glucose metabolism. In this study, we investigated whether AG and UAG differentially regulate portal and systemic insulin levels after a glucose load. We studied the effects of the administration of AG (30 nmol/kg), UAG (3 and 30 nmol/kg), the ghrelin receptor antagonist [D-Lys 3 ]GHRP-6 (1 mol/kg), or various combinations of these compounds on portal and systemic levels of glucose and insulin after an intravenous glucose tolerance test (IVGTT, D-glucose 1 g/kg) in anesthetized fasted Wistar rats. UAG administration potently and dose-dependently enhanced the rise of insulin concentration induced by IVGTT in the portal and, to a lesser extent, the systemic circulation. This UAG-induced effect was completely blocked by the coadministration of exogenous AG at equimolar concentrations. Similarly to UAG, [D-Lys 3 ]GHRP-6, alone or in combination with AG and UAG, strongly enhanced the portal insulin response to IVGTT, whereas exogenous AG alone did not exert any further effect. Our data demonstrate that, in glucose-stimulated conditions, exogenous UAG acts as a potent insulin secretagogue, whereas endogenous AG exerts a maximal tonic inhibition on glucose-induced insulin release. acylated ghrelin; insulin secretion; portal vein; rat GHRELIN IS A GUT HORMONE predominantly produced in the stomach and, to a lesser extent, in other regions of the gastrointestinal tract (9,21,22). Ghrelin circulates in the bloodstream in two different forms: acylated (or n-octanoylated) and unacylated (or des-octanoylated or des-acylated) (21). Acylated ghrelin (AG) has a unique feature: a posttranslational esterification of a fatty (n-octanoic or, to a lesser extent, n-decanoic) acid on serine residue at position 3 (21). This acylation is considered necessary for AG's actions via the growth hormone secretagogue receptor type 1a (GHS-R1a), also called ghrelin receptor (GRLN-R) (7, 21). However, normally AG accounts for less than 10% of the total ghrelin in the circulation. The majority of circulating ghrelin is unacylated (UAG), which binds with high affinity to a receptor, different from GHS-R1a and yet unknown (21,25).Both AG and UAG have pleiotropic activities, including regulation of insulin secretion and glucose metabolism. It has been shown that endogenous AG and UAG are also produced in the endocrine pancreas, which also expresses the GHS-R1a (6,8,13,26,27). It has been found that endogenous AG in the pancreas inhibits the glucose-induced insulin release via the GHS-R1a (8), as demonstrated by the marked increase of insulin response to glucose after blockade of endogenous AG (i.e., v...

Does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing acylated ghrelin levels?

“…For example, Granata et al (34) showed that AG and DAG exert similar beneficial effects on pancreatic b-cells, suggesting that GHS-R1a blockade of AG would have negative effects on pancreatic function. DAG does not antagonize GHS-R1a even in the micromolar range (6). Furthermore, although it activates GHS-R1a at micromolar concentrations, circulating levels of DAG achieved during the infusions only reached the nanomolar range, meaning its effects on AG levels cannot be explained by a GHS-R1a-mediated mechanism.…”

“…However, direct metabolic effects of DAG cannot be excluded in view of the reported GHS-R1a-independent (AG-independent) effects of DAG, which include improved glycemic control through the modulation of glucose and medium-chain fatty acid uptake (2,6,35,36). Another indication of the importance of DAG levels as a potential physiological inhibitor of AG action has been reported already by the above-mentioned studies of transgenic mice overexpressing DAG (32,33,37), which were lighter and shorter compared with controls.…”

“…For example, DAG can inhibit AG-induced glucose output by hepatocytes in vitro (2) and prevents the hyperglycemic effects of AG when co-administered in healthy volunteers (3). This initial observation was followed by several reports on the anti-diabetogenic activity of DAG (2,4,5,6), and recently it has been shown that a continuous infusion of DAG in healthy volunteers improves glucose metabolism (7).…”

Increased plasma ghrelin suppresses insulin release in wethers fed with a high-protein diet

“…Thus, ghrelin indirectly inhibits glucose-induced insulin secretion via the hepatic portal system and the vagus nerve. Furthermore, when unacylated ghrelin (UAG) was injected into rats, the UAG enhanced the increase in insulin concentrations in the portal and peripheral circulation (Gauna et al 2007). This effect was completely blocked by the coadministration of acylated ghrelin.…”

Catalytic antibody degradation of ghrelin increases whole-body metabolic rate and reduces refeeding in fasting mice

“…From a chemical standpoint, ghrelin is the first peptide isolated from natural sources in which the hydroxyl group of a Ser residue (Ser-3) is acylated by n-octanoic acid (3, 39). Octanoylation had not been observed in posttranslational peptide modification, but it is essential for the GH-releasing and potent GHSR1 agonist activity of ghrelin (3,39,40). Hence, degradation of the serine octanoate ester moiety of ghrelin provides an enticing target for obesity research.…”