Editorial: Proglucagon-Derived Peptides

1 School Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom, 2 Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark, 3 Steno Diabetes Center Copenhagen, Gentofte, Denmark, 4 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, 5 Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark


PROGLUCAGON-DERIVED PEPTIDE RESEARCH TOPIC
Identification of the proglucagon gene at the beginning of the 1980s marked a huge breakthrough in research that would lead to discovery of a family of gene products that play a multitude of roles in regulation of feeding, metabolism and gastrointestinal function [ Figure 1A (1-4)]. The peptide family members are also emerging players in pathophysiology and therapy of obesity and diabetes as well as several related metabolic disorders plus short bowel syndrome.
Surprisingly, it was found that glucagon-like immunoreactivity and subsequently the proglucagon protein encoded by the glucagon gene are present not only in the alpha-cells of the pancreatic islets but also in enteroendocrine L-cells of the intestine (5). Thus as shown in Figure 1A, in the pancreas, the precursor is processed by prohormone convertase 2 (PC2) to generate glucagon and glicentin-related pancreatic polypeptide (GRPP), whereas in L-cells, prohormone convertase 1/ 3 (PC1/3) processing results in production of glicentin, oxyntomodulin, glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2). However, recent research challenges this tissue selectivity, demonstrating that under certain circumstances, alpha-cells appear to produce GLP-1, oxyntomodulin and glicentin whereas the intestinal L-cells may be a source of glucagon (4,6).
Less controversial but more remarkably, GLP-1 was found to exert a plethora of physiological actions on intestine, pancreatic islets, brain and other tissues which are exploited in therapeutic approaches to obesity, diabetes, cardiovascular disease and neurodegenerative disorders using stable synthetic analogues or inhibitors of GLP-1 degradation (4). Indeed, GLP-1 mimetics and inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that renders GLP-1 and other proglucagon family members inactive by cleaving off N-terminal amino acids (7), are now well-established therapeutic agents. GLP-2 has also been found to be metabolically active and plays key role in stimulating intestinal growth. This has been exploited by development of N-terminally stabilised GLP-2 analogues for treatment of short bowel syndrome (3). GLP-2 has also been shown recently to inhibit gall bladder emptying in man, thereby promoting replenishment of bile stores following feeding (8).
During the past decade, it has been discovered that far from being inert, oxyntomodulin acts as a dual activator of GLP-1 and glucagon receptors with potential for promoting weight loss and glycaemic control (9). Evidence is emerging that another proglucagon-derived peptide, glicentin, may also have hitherto poorly appreciated physiological roles and utility as biomarker for intestinal or metabolic diseases (10).
As evident from above, we are in a fascinating and highly active era of research on proglucagon-derived peptides that is attracting considerable academic and industry interest geared towards increasing knowledge and the fight against the epidemic of obesity, type 2 diabetes and related disorders.
Under this Research Topic, we have assembled original research articles and reviews on many aspects of the biology, function, pathophysiology and therapeutic potential of posttranslational products of the proglucagon gene, including: In total, we have gathered 24 contributions from 117 leading scientists working in 13 different countries across the globe. The extent of this broad participation is testimony to the rising worldwide interest in research on proglucagon-derived peptides which is evidenced by the number of annual publications returned over time gathered using PubMed when searching for outputs using specific peptides as keywords ( Figures 1B, C). A particularly strong upsurge in research on GLP-1 is evident with annual outputs on this peptide exceeding those published on glucagon since 2008. Interest in GLP-2 is also rising and recent evidence suggests that it has positive actions on bone.
A short appreciation of the papers included in our special collection on proglucagon-derived peptides is given below.

HISTORY AND STRUCTURAL ASPECTS OF PROGLUCAGON-DERIVED PEPTIDES
The collection of papers starts with an historical perspective of studies on the N-terminal domain of proglucagon by Michael Conlon who together with Steve Bloom, Keith Buchanan, Jens Holst, Vincent Marks, Ellis Samols and others, including Roger Unger and Isobel Valverde, pioneered much of the early work in the 1970s on the proglucagon derived peptides (reviewed by Conlon and Marks in 5,11,12). Members of this family were picked up by antibodies raised against glucagon and with glucagon-like immunoreactivity. Some of the major milestones during this period are summarised in Table 1  In the following papers dealing with structural aspects, David Irwin has exploited advances in gene technology to document variations in the evolution and sequences of proglucagon and receptors for its post-translational peptide products. Such comparative data may provide important information regarding unforeseen functional aspects of these peptides. Indeed, the work of Lindquist et al. considers the mutational landscape of proglucagon-derived peptides, highlighting how small structural changes may contribute to the pathophysiology of glucose intolerance and the efficacy of GLP-1-based therapies.

ALPHA-CELL FUNCTION AND SECRETION OF PROGLUCAGON-DERIVED PEPTIDES
Turning to the alpha-cell, Dhanvantari and Asadi consider signalling pathways involved in the regulation of glucagon secretion with focus on direct effects of glucose plus increasingly recognised intra-islet autocrine and paracrine   1 | Some of the major milestones in the discovery, secretion and physiology of proglucagon-derived peptides with focus on pre-molecular biology era.

Year
Author(s) Milestone Reference(s)

Lane Distinguished alpha-and beta-islet cells (11) 1923 Collip
Commented on initial hyperglycaemic effect of pancreatic extracts (12) (46) 1996 Brubaker Role of PC1/3 in differential proglucagon processing gut (47) 1996 Drucker Trophic action of GLP-2 in gutopening way for future therapeutic use of GLP-2 analogues in short bowel syndrome (48) We acknowledge that many investigators have contributed to advances in research on proglucagon-derived peptides and we apologise for any obvious omissions. Interested readers are referred to several excellent reviews for detailed consideration of early work and the advances made after identification of the proglucagon gene

PROGLUCAGON-DERIVED PEPTIDES AS THERAPEUTICS
Although dietary measures may be beneficial in mild cases of type 2 diabetes, most patients likely to benefit therapeutically from activation of proglucagon-derived pathways will require drug intervention. Lafferty et al. address the current status of proglucagon-derived peptides as therapeutics. This includes glucagon, GLP1, GLP-2, oxyntomodulin, glicentin, GRRP as well as unimolecular multi-agonist peptides which activate receptors for GLP-1, glucagon and GIP. The therapeutic application extends to diabetes, obesity, cardiovascular and neurodegenerative diseases, short bowel syndrome, osteoporosis, polycystic ovary syndrome and hypoglycaemia. Hope et al. further consider the strong potential of GLP-1/ glucagon receptor co-agonism as a treatment strategy for obesity. They discuss the importance of relative balance of coagonism, the positive effect of glucagon on energy balance and how its natural hyperglycaemic actions are countered by the insulinotropic action of GLP-1. Tanday et al. demonstrate the value of upregulated unimolecular GLP-1/CCK receptor signalling in rodent obesity-diabetes, indicating the therapeutic potential offered by recapitulation of the interlinked pathways naturally activated by feeding. Exploitation of such an approach requires imagination of peptide chemists to come up with viable peptide analogues. In this vein, it is notable that He et al. describe a simple method for conjugation of two proglucagon peptide analogues via added cysteine residues.

CONCLUDING REMARKS
As evident from the above, research on proglucagon-derived peptides has delivered significant outcomes and had real measurable societal impact. Much has been discovered since elucidation of glucagon, the exploitation of antibody-based technologies by radioimmunoassay and immunocytochemistry and elucidation of the proglucagon gene. The more we dig into the biology of this influential peptide family, the more questions we turn up that need to be answered. We extend our thanks to the authors for their timely contributions, to the reviewers for their efforts in evaluating the manuscripts and to you the readers who we hope will gain knowledge and inspiration from this timely collection of papers.