Nonclassical Islet Peptides: Pancreatic and Extrapancreatic Actions

The pancreas has physiologically important endocrine and exocrine functions; secreting enzymes into the small intestine to aid digestion and releasing multiple peptide hormones via the islets of Langerhans to regulate glucose metabolism, respectively. Insulin and glucagon, in combination with ghrelin, pancreatic polypeptide and somatostatin, are the main classical islet peptides critical for the maintenance of blood glucose. However, pancreatic islets also synthesis numerous 'nonclassical' peptides that have recently been demonstrated to exert fundamental effects on overall islet function and metabolism. As such, insights into the physiological relevance of these nonclassical peptides have shown impact on glucose metabolism, insulin action, cell survival, weight loss, and energy expenditure. This review will focus on the role of individual nonclassical islet peptides to stimulate pancreatic islet secretions as well as regulate metabolism. In addition, the more recognised actions of these peptides on satiety and energy regulation will also be considered. Furthermore, recent advances in the field of peptide therapeutics and obesity-diabetes have focused on the benefits of simultaneously targeting several hormone receptor signalling cascades. The potential for nonclassical islet hormones within such combinational approaches will also be discussed.</p

NPYR modulation: Potential for the next major advance in obesity and type 2 diabetes management?

The approval of the glucagon-like peptide 1 (GLP-1) mimetics semaglutide and liraglutide for management of obesity, independent of type 2 diabetes (T2DM), has initiated a resurgence of interest in gut-hormone derived peptide therapies for the management of metabolic diseases, but side-effect profile is a concern for these medicines. However, the recent approval of tirzepatide for obesity and T2DM, a glucose-dependent insulinotropic polypeptide (GIP), GLP-1 receptor co-agonist peptide therapy, may provide a somewhat more tolerable option. Despite this, an increasing number of non-incretin alternative peptides are in development for obesity, and it stands to reason that other hormones will take to the limelight in the coming years, such as peptides from the neuropeptide Y family. This narrative review outlines the therapeutic promise of the neuropeptide Y family of peptides, comprising of the 36 amino acid polypeptides neuropeptide Y (NPY), peptide tyrosine-tyrosine (PYY) and pancreatic polypeptide (PP), as well as their derivatives. This family of peptides exerts a number of metabolically relevant effects such as appetite regulation and can influence pancreatic beta-cell survival. Although some of these actions still require full translation to the human setting, potential therapeutic application in obesity and type 2 diabetes is conceivable. However, like GLP-1 and GIP, the endogenous NPY, PYY and PP peptide forms are subject to rapid in vivo degradation and inactivation by the serine peptidase, dipeptidyl-peptidase 4 (DPP-4), and hence require structural modification to prolong circulating half-life. Numerous protective modification strategies are discussed in this regard herein, alongside related impact on biological activity profile and therapeutic promise.</p

Xenin and Related Peptides: Potential Therapeutic Role in Diabetes and Related Metabolic Disorders

Xenin bioactivity and its role in normal physiology has been investigated by several research groups since its discovery in 1992. The 25 amino acid peptide hormone is secreted from the same enteroendocrine K-cells as the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), with early studies highlighting the biological significance of xenin in the gastrointestinal tract, along with effects on satiety. Recently there has been more focus directed towards the role of xenin in insulin secretion and potential for diabetes therapies, especially through its ability to potentiate the insulinotropic actions of GIP as well as utilisation in dual/triple acting gut hormone therapeutic approaches. Currently, there is a lack of clinically approved therapies aimed at restoring GIP bioactivity in type 2 diabetes mellitus, thus xenin could hold real promise as a diabetes therapy. The biological actions of xenin, including its ability to augment insulin secretion, induce satiety effects, as well as restoring GIP sensitivity, earmark this peptide as an attractive antidiabetic candidate. This minireview will focus on the multiple biological actions of xenin, together with its proposed mechanism of action and potential benefits for the treatment of metabolic diseases such as diabetes