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.

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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.

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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.

Aim To investigate the antidiabetic efficacy of enzymatically stable Peptide YY (PYY) peptides from phylogenetically ancient fish. Materials and methods N‐terminally stabilized, PYY (1–36) sequences from Amia calva (bowfin), Oncorhynchus mykiss (trout), Petromyzon marinus (sea lamprey) and Scaphirhynchus albus (sturgeon), were synthesized, and both biological actions and antidiabetic therapeutic efficacy were assessed. Results All fish PYY (1–36) peptides were resistant to dipeptidyl peptidase‐4 (DPP‐4) degradation and inhibited glucose‐ and alanine‐induced (P < 0.05 to P < 0.001) insulin secretion. In addition, PYY (1–36) peptides imparted significant (P < 0.05 to P < 0.001) β‐cell proliferative and anti‐apoptotic benefits. Proliferative effects were almost entirely absent in β cells with CRISPR‐Cas9‐induced knockout of Npyr1. In contrast to human PYY (1–36), the piscine‐derived peptides lacked appetite‐suppressive actions. Twice‐daily administration of sea lamprey PYY (1–36), the superior bioactive peptide, for 21 days significantly (P < 0.05 to P < 0.001) decreased fluid intake, non‐fasting glucose and glucagon in streptozotocin (STZ)‐induced diabetic mice. In addition, glucose tolerance, insulin sensitivity, pancreatic insulin and glucagon content were significantly improved. Metabolic benefits were linked to positive changes in pancreatic islet morphology as a result of augmented (P < 0.001) proliferation and decreased apoptosis of β cells. Sturgeon PYY (1–36) exerted similar but less impressive effects in STZ mice. Conclusion These observations reveal, for the first time, that PYY (1–36) peptide sequences from phylogenetically ancient fish replicate the pancreatic β‐cell benefits of human PYY (1–36) and have clear potential for the treatment of type 2 diabetes.

Enzymatically stable and specific neuropeptide Y1 receptor (NPYR1) agonists, such as sea lamprey PYY(1-36) (SL-PYY(1-36)), are believed to improve glucose regulation in diabetes by targeting pancreatic islets. In this study, streptozotocin (STZ) diabetic transgenic GluCreERT2;ROSA26-eYFP and Ins1Cre/+;Rosa26-eYFP mouse models have been used to study effects of sustained NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitioning. STZ induced a particularly severe form of diabetes in Ins1Cre/+;Rosa26-eYFP mice, but twice-daily administration (25 nmol/kg) of SL-PYY(1-36) for 11 days consistently improved metabolic status. Blood glucose was decreased (p &lt; 0.05 - p &lt; 0.001) and both fasted plasma and pancreatic insulin significantly increased by SL-PYY(1-36). In both GluCreERT2;ROSA26-eYFP and Ins1Cre/+; Rosa26-eYFP mice, STZ provoked characteristic losses (p &lt; 0.05 - p &lt; 0.001) of islet numbers, beta-cell and pancreatic islet areas together with increases in area and central islet location of alpha-cells. With exception of alpha-cell area, these morphological changes were fully, or partially, returned to non-diabetic control levels by SL-PYY(1-36). Interestingly, STZ apparently triggered decreased (p &lt; 0.001) alpha- to beta-cell transition in GluCreERT2;ROSA26-eYFP mice, together with increased loss of beta-cell identity in Ins1Cre/+;Rosa26-eYFP mice, but both effects were significantly (p &lt; 0.001) reversed by SL-PYY(1-36). SL-PYY(1-36) also apparently reduced (p &lt; 0.05) beta- to alpha-cell conversion in Ins1Cre/+;Rosa26-eYFP mice and glucagon expressing alpha-cells in GluCreERT2;ROSA26-eYFP mice. These data indicate that islet benefits of prolonged NPY1R activation, and especially restoration of beta-cell mass, are observed irrespective of diabetes status, being linked to cell lineage alterations including transdifferentiation of alpha- to beta-cells.

Protein hydrolysates from low-value underutilised fish species are potential sources of high-quality dietary protein and health enhancing peptides. Six blue whiting soluble protein hydrolysates (BW-SPH-A_F), generated at industrial scale using different hydrolysis conditions, were assessed in terms of their protein equivalent content, amino acid profile and score and physicochemical properties in addition to their ability to inhibit dipeptidyl peptidase IV (DPP-IV) and stimulate the secretion of insulin from BRIN-BD11 cells. Furthermore, the effect of simulated gastrointestinal digestion (SGID) on the stability of the BW-SPHs and their associated in vitro antidiabetic activity was investigated. The BW-SPHs contained between 70–74% (w/w) protein and all essential and non-essential amino acids. All BW-SPHs mediated DPP-IV inhibitory (IC50: 2.12–2.90 mg protein/mL) and insulin secretory activity (2.5 mg/mL; 4.7 to 6.4-fold increase compared to the basal control (5.6 mM glucose alone)). All BW-SPHs were further hydrolysed during SGID. While the in vitro DPP-IV inhibitory and insulin secretory activity mediated by some BW-SPHs was reduced following SGID, the activity remained high. In general, the insulin secretory activity of the BW-SPHs were 4.5–5.4-fold higher than the basal control following SGID. The BW-SPHs generated herein provide potential for anti-diabetic related functional ingredients, whilst also enhancing environmental and commercial sustainability.