Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced via tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.

No abstract

Purpose of review The antiobesity effects of activation of hypothalamic neuropeptide Y2 receptors (NPYR2) by the gut-derived hormone, peptide YY (PYY), are established. However, more recent insight into the biology of PYY has demonstrated remarkable benefits of sustained activation of pancreatic beta-cell NPYR1, that promises to open a new therapeutic avenue in diabetes. Recent findings The therapeutic applicability of NPYR2 agonists for obesity has been considered for many years. An alternative pathway for the clinical realisation of PYY-based drugs could be related to the development of NPYR1 agonists for treatment of diabetes. Thus, although stimulation of NPYR1 on pancreatic beta-cells has immediate insulinostatic effects, prolonged activation of these receptors leads to well defined beta-cell protective effects, with obvious positive implications for the treatment of diabetes. In this regard, NPYR1-specific, long-acting enzyme resistant PYY analogues, have been recently developed with encouraging preclinical effects observed on pancreatic islet architecture in diabetes. In agreement, the benefits of certain types of bariatric surgeries on beta-cell function and responsiveness have also been linked to elevated PYY secretion and NPY1 receptor activation. Summary Enzymatically stable forms of PYY, that selectively activate NPYR1, may have significant potential for preservation of beta-cell mass and the treatment of diabetes.

No abstract

Recent studies have identified a beneficial role for peptide tyrosine tyrosine (PYY) on pancreatic beta-cell function and survival. These effects are linked to the activation of neuropeptide Y1 receptors (NPYR1s) by PYY(1-36). However, PYY(1-36) is subject to rapid degradation by dipeptidyl peptidase-4 (DPP-4), resulting is the loss of NPYR1 activity. Therefore, the aim of this study was to develop 2 enzymatically stable PYY(1-36) analogues, namely, (P 3 L 31 P 34 )PYY(1-36) and PYY(1-36)(Lys 12 PAL), with further structural modifications to enhance NPYR1 specificity. As expected, (P 3 L 31 P 34 )PYY(1-36) was fully resistant to DPP-4-mediated degradation in vitro, whereas PYY(1-36) and PYY(1-36)(Lys 12 PAL) were both liable to DPP-4 breakdown. PYY(1-36) and (P 3 L 31 P 34 )PYY(1-36) induced significant reductions in glucose-stimulated insulin secretion (GSIS) from BRIN BD11 cells, but only PYY(1-36) diminished alanine-stimulated insulin secretion. In contrast, PYY(1-36)(Lys 12 PAL) had no impact on GSIS or alanine-induced insulin release. All 3 PYY peptides significantly enhanced proliferation in BRIN BD11 and 1.1B4 beta-cell lines, albeit only at the highest concentration examined, 10 -6 M, for (P 3 L 31 P 34 )PYY(1-36) and PYY(1-36)(Lys 12 PAL) in BRIN BD11 cells. Regarding the protection of beta-cells against cytokine-induced apoptosis, PYY(1-36) induced clear protective effects. Both (P 3 L 31 P 34 )PYY(1-36) and PYY(1-36)(Lys 12 PAL) offered some protection against apoptosis in BRIN BD11 cells, but were significantly less efficacious than PYY(1-36). Similarly, in 1.1B4 cells, both PYY analogues (10 -6 M) protected against cytokine-induced apoptosis, but (P 3 L 31 P 34 )PYY(1-36) was significantly less effective than PYY(1-36). All 3 PYY peptides had no impact on refeeding in overnight fasted mice. These data underline the beta-cell benefits of PYY(1-36) and highlight the challenges of synthesising stable, bioactive, NPYR1-specific, PYY(1-36) analogues.