Ghrelin and insulin metabolism

Ghrelin is a novel gut-brain peptide that has somatotropic, food-intake increasing (orexigenic) and adipogenic effects [1]. Several studies have provided evidence that ghrelin may be involved also in glucose and insulin metabolism. It is not surprising considering the observed adipogenic effect of ghrelin in rodents [2] and the correlation between body fatness and plasma ghrelin levels in humans [3]. Adipose tissue and free fatty acids are key regulators of insulin sensitivity, and increasing adiposity is associated with insulin resistance [4]. Therefore, the effect of ghrelin on insulin metabolism may occur through its effect on energy metabolism. Indeed, fasting plasma ghrelin levels are negatively correlated with per cent body fat and fasting levels of insulin and leptin [3]. It is not an unexpected finding that obese patients with type 2 diabetes mellitus have lower fasting plasma ghrelin concentrations than normalweight patients without diabetes [5]. Central mechanisms controlling energy homeostasis may be involved in the interplay between hunger (ghrelin) and satiety (leptin, insulin) signals. The orexigenic potency of ghrelin has been suggested to be caused by the activation of hypothalamic neuropeptide Y (NPY) neurones in the arcuate nucleus [6] which are inhibited by insulin and leptin [7]. It has been also suggested that the most important hypothalamic target of ghrelin might be agouti-related peptide (AGRP) [8]. In relation to meals, a secretion pattern of ghrelin reciprocal to that of insulin has been observed [9]. Food intake and glucose load have been shown to decrease plasma ghrelin levels [5] while insulin infusion decreased ghrelin levels in a recent study by Saad et al . [10]. These findings are in accordance with the theory that insulin may be an important regulator of plasma ghrelin levels in different states of nutrition. However, the suppressive effect of parenteral administration of insulin on plasma ghrelin levels was not demonstrated in another study [11], and, on the contrary, Toshinai et al . [12] reported recently that the ghrelin mRNA level in the stomach actually increases after administration of insulin and leptin in mouse. Importantly, in the study by Tschöp et al . [3] insulin was a significant independent determinant of fasting ghrelin, explaining 36·5% of the variance. Therefore, some additional mechanisms in addition to those related to adiposity, which could explain the interaction between ghrelin and insulin, must be considered. Ghrelin and its receptor are expressed widely [13], including pancreatic beta-cells [14], supporting the notion that it could have direct effects on insulin secretion. However, studies about the effect of ghrelin on insulin secretion have been inconsistent in animal and human models, and both stimulatory [15–17] and inhibitory [18,19] effects have been reported while others have not shown any effect [20]. Recently, ghrelin was reported to affect the insulin signalling system, implicating peripheral actions of ghrelin in glucose homeostasis [21]. In hepatoma cells, ghrelin had an anti-insulin action and up-regulated gluconeogenesis. Metabolic properties of skeletal muscle may play a role in the aetiology of obesity and related comorbidities, like insulin resistance. Unfortunately, there is not yet data on how ghrelin affects skeletal muscle metabolism. The fact that ghrelin is one of the most potent stimulants of growth hormone (GH) secretion [1] should not be overlooked when explaining its effects on insulin metabolism. Growth hormone is known to counteract insulin action on glucose metabolism [22]. Interestingly, low ghrelin levels observed in acromegalic patients have been attributed, at least in part, to insulin resistance [23]. However, based on the current knowledge it is difficult to speculate what role the somatotropic effect plays in the influence of ghrelin on insulin metabolism. Proposed interaction between ghrelin and insulin is shown in Figure 1. Ghrelin, secreted mainly by the stomach, circulates in the bloodstream and stimulates pituitary GH secretion. Minimal amounts of ghrelin are secreted also by the hypothalamus where it may activate AGRP or NPY, causing increase of food intake. In rodents, ghrelin induces adiposity. Ghrelin and its receptor are expressed also in pancreatic beta-cells, supporting the notion that it could have an effect on insulin secretion. Recently, ghrelin was reported to affect the insulin signalling system, suggesting peripheral effects of ghrelin on insulin metabolism. In conclusion, ghrelin may influence glucose and insulin metabolism through its effects on adiposity, or through paracrine effects on insulin secretion or insulin signalling pathways. In addition, the effects on insulin metabolism Department of Internal Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland (O. Ukkola).