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 (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 post-translational 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 world-wide 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.
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 and several of the early pioneers in the field are shown in Figures 1, 2. Thanks to the subsequent advent of molecular biology techniques and the additional pioneering efforts of Joel Habener, Daniel Drucker and others in the 1980s (1, 4, 41), the constituent bioactive peptides glucagon, GLP-1 and GLP-2 are now well recognised yet, as pointed out by Michael Conlon, the possible functional roles of oxyntomodulin, glicentin and GRPP are only just becoming elucidated.
Some of the major milestones in the discovery, secretion and physiology of proglucagon-derived peptides with focus on pre-molecular biology era.
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: These include articles by Conlon, Holst, Drucker, Muller, Marks and their co-authors: 1,2,3,4,5,11,12,13. DPP-4, dipeptidyl peptidase 4; GLI, glucagon-like immunoreactivity; GLP-1, glucagon-like peptide 1; GLP-2, glucagon-like peptide 2; GRPP, glicentin-related pancreatic polypeptide; PC1/3, prohormone convertase 1/3; PC2, prohormone convertase 2.
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.
