About this Research Topic
Identification of the proglucagon gene at the beginning of the 1980s marked a huge breakthrough in research that would lead to the discovery of a family of gene products that play a multitude of roles in the regulation of feeding, metabolism, and gastrointestinal function. The peptide family members are also emerging players in pathophysiology and therapy of obesity and diabetes as well as several related metabolic disorders.
Surprisingly, it was found that the proglucagon protein encoded by the glucagon gene is present not only in the alpha cells of the pancreatic islets but also in enteroendocrine L cells of the intestine. Thus, in the pancreas, the precursor is processed by PC2 to generate glucagon and glicentin-related pancreatic polypeptide (GRPP), whereas in L cells PC1/3 processing results in the production of glicentin, oxyntomodulin (OXM), GLP-1, and GLP-2.
However, recent research challenges this tissue selectivity, demonstrating that under certain circumstances, alpha cells appear to produce GLP-1, OXM, and glicentin whereas the intestinal L-cells may be a source of glucagon. Less controversial but more remarkably, GLP-1 was found to exert a plethora of physiological actions on the intestine, pancreatic islets, brain, bone, and other tissues which may potentially be exploited in therapeutic approaches to obesity, diabetes, cardiovascular disease, and neurodegenerative disorders using stable synthetic analogs or inhibitors of peptide degradation. Indeed, GLP-1 mimetics and inhibitors of DPP-4, an enzyme that renders GLP-1 and other proglucagon family members inactive, are now well-established therapeutic agents. GLP-2 has also been found to be metabolically active and plays a key role in stimulating intestinal growth. This has been exploited by the development of N-terminally stabilized GLP-2 analogs for the treatment of the short-bowel syndrome.
Recently it has been discovered that far from being inert, oxyntomodulin acts as a dual activator of GLP-1 and glucagon receptors with the potential for promoting weight loss and glycaemic control. Evidence is emerging that another proglucagon-derived peptide, glicentin, may also have hitherto unsuspected physiological roles.
As evident from above, we are in a fascinating 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 aim to assemble original research articles, opinion papers, reviews, and commentaries on any aspect of the biology, function, pathophysiology, and possible therapeutic potential of post-translational products of the proglucagon gene, including:
Ø Glucagon-like peptide 1 (GLP-1)
Ø Oxyntomodulin
Ø Glicentin
Ø Glucagon-like peptide 2 (GLP-2)
Ø Glucagon
Ø Glicentin-related pancreatic polypeptide (GRPP)
Topics that will be covered include, but are not limited to:
Ø Tissue-specific processing by PC1/3 and PC2
Ø Intracellular processing and secretory mechanisms
Ø Degradation by DPP-4 and other enzymes
Ø Receptor interactions, crosstalk, and biological effects
Ø Involvement in feeding, intestinal growth, and metabolic regulation
Ø Islet production of glucagon, other products of the proglucagon gene, and their role in local paracrine cellular actions
Ø Intracellular pathways mediating the signal of proglucagon-derived peptides
Ø Role in obesity, diabetes, irritable bowel syndrome, neurodegeneration, bone, and other disorders
Ø Involvement in diabetes remission induced by gastric surgery or low-calorie diets
Ø Use of stable analogs, small molecule mimetics, or secretion enhancers to convey cardioprotective effects, anti-inflammatory actions, and in the therapy of obesity diabetes and other disorders.
Surprisingly, it was found that the proglucagon protein encoded by the glucagon gene is present not only in the alpha cells of the pancreatic islets but also in enteroendocrine L cells of the intestine. Thus, in the pancreas, the precursor is processed by PC2 to generate glucagon and glicentin-related pancreatic polypeptide (GRPP), whereas in L cells PC1/3 processing results in the production of glicentin, oxyntomodulin (OXM), GLP-1, and GLP-2.
However, recent research challenges this tissue selectivity, demonstrating that under certain circumstances, alpha cells appear to produce GLP-1, OXM, and glicentin whereas the intestinal L-cells may be a source of glucagon. Less controversial but more remarkably, GLP-1 was found to exert a plethora of physiological actions on the intestine, pancreatic islets, brain, bone, and other tissues which may potentially be exploited in therapeutic approaches to obesity, diabetes, cardiovascular disease, and neurodegenerative disorders using stable synthetic analogs or inhibitors of peptide degradation. Indeed, GLP-1 mimetics and inhibitors of DPP-4, an enzyme that renders GLP-1 and other proglucagon family members inactive, are now well-established therapeutic agents. GLP-2 has also been found to be metabolically active and plays a key role in stimulating intestinal growth. This has been exploited by the development of N-terminally stabilized GLP-2 analogs for the treatment of the short-bowel syndrome.
Recently it has been discovered that far from being inert, oxyntomodulin acts as a dual activator of GLP-1 and glucagon receptors with the potential for promoting weight loss and glycaemic control. Evidence is emerging that another proglucagon-derived peptide, glicentin, may also have hitherto unsuspected physiological roles.
As evident from above, we are in a fascinating 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 aim to assemble original research articles, opinion papers, reviews, and commentaries on any aspect of the biology, function, pathophysiology, and possible therapeutic potential of post-translational products of the proglucagon gene, including:
Ø Glucagon-like peptide 1 (GLP-1)
Ø Oxyntomodulin
Ø Glicentin
Ø Glucagon-like peptide 2 (GLP-2)
Ø Glucagon
Ø Glicentin-related pancreatic polypeptide (GRPP)
Topics that will be covered include, but are not limited to:
Ø Tissue-specific processing by PC1/3 and PC2
Ø Intracellular processing and secretory mechanisms
Ø Degradation by DPP-4 and other enzymes
Ø Receptor interactions, crosstalk, and biological effects
Ø Involvement in feeding, intestinal growth, and metabolic regulation
Ø Islet production of glucagon, other products of the proglucagon gene, and their role in local paracrine cellular actions
Ø Intracellular pathways mediating the signal of proglucagon-derived peptides
Ø Role in obesity, diabetes, irritable bowel syndrome, neurodegeneration, bone, and other disorders
Ø Involvement in diabetes remission induced by gastric surgery or low-calorie diets
Ø Use of stable analogs, small molecule mimetics, or secretion enhancers to convey cardioprotective effects, anti-inflammatory actions, and in the therapy of obesity diabetes and other disorders.
Keywords: Proglucagon, Glucagon, GLP-1, GLP-2, Oxyntomodulin, Glicentin, L-cell, Alpha-Cell, Obesity, Diabetes, Intestinal Function, Metabolism
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
