Somatostatin, cortistatin, ghrelin and glucose metabolism.

At first sight, the title is confusing as it seems to try to merge four unrelated topics into a single presentation. Somatostatin, cortistatin (CST) and ghrelin display broad biological activities, including metabolic effects. However, although apparently unrelated, these peptides entities have more in common than it might be expected and their reciprocal interactions give a new perspective to the hormonal regulation of glucose metabolism. Let's analyze the ghrelin receptor subtype GH secretagogue (GHS)-receptor 1a (R1a). Taking into account the GHS-R1a as receptor of reference, acylated ghrelin is one of its natural ligands. Interestingly, it has been demonstrated that also CST, a neuropeptide, binds with high affinity to the GHS-R1a in human hypothalamus and pituitary tissues. CST is a recently described neuropeptide showing high structural homology with somatostatin that binds to all somatostatin receptor subtypes (SSTRs) with an affinity (1-2 nM). In fact, CST and somatostatin exhibit the same endocrine activities. The existence of specific receptors which selectively bind somatostatin or CST has been hypothesized, based on evidence that CST possesses an action profile different from somatostatin and that CST and somatostatin are often co-expressed in the same neurons but are regulated by different stimuli. Given these findings, the ability of CST to bind the GHS-R1a is of particular relevance because somatostatin and its fragments do not bind the same receptor. Interestingly, the classical synthetic somatostatin analogs, i.e. octreotide, lanreotide and vapreotide bind the GHS-R1a with an affinity lower than that of CST. These findings have generated the hypothesis that CST, because of its ability to bind both SSTRs and GHSRs, would represent the link between ghrelin and "somatostatin/CST" system that had not previously been demonstrated. On the other hand, the GHS-R1a is unlikely to be the only GHS-R. It has been already demonstrated that a GHS-R subtype able to bind non-acylated as well as acylated ghrelin exists and likely mediates biological activities. Another GHS-R subtype likely mediates the influence of unacylated ghrelin on glucose metabolism, since it does not bind nor activates the GHS-R1a. Given this complexity, it is clear that further studies are required to clarify whether ghrelin is the sole ligand or one of a number of ligands activating the GHS-R 1a and whether that receptor used for ghrelin isolation is the sole receptor or one of a group of receptors for such ligands.