Physiology of Proglucagon Peptides: Role of Glucagon and GLP-1 in Health and Disease

Abstract

The preproglucagon gene (Gcg) is expressed by specific enteroendocrine cells (L-cells) of the intestinal mucosa, pancreatic islet α-cells, and a discrete set of neurons within the nucleus of the solitary tract. Gcg encodes multiple peptides including glucagon, glucagon-like peptide-1, glucagon-like peptide-2, oxyntomodulin, and glicentin. Of these, glucagon and GLP-1 have received the most attention because of important roles in glucose metabolism, involvement in diabetes and other disorders, and application to therapeutics. The generally accepted model is that GLP-1 improves glucose homeostasis indirectly via stimulation of nutrient-induced insulin release and by reducing glucagon secretion. Yet the body of literature surrounding GLP-1 physiology reveals an incompletely understood and complex system that includes peripheral and central GLP-1 actions to regulate energy and glucose homeostasis. On the other hand, glucagon is established principally as a counterregulatory hormone, increasing in response to physiological challenges that threaten adequate blood glucose levels and driving glucose production to restore euglycemia. However, there also exists a potential role for glucagon in regulating energy expenditure that has recently been suggested in pharmacological studies. It is also becoming apparent that there is cross-talk between the proglucagon derived-peptides, e.g., GLP-1 inhibits glucagon secretion, and some additive or synergistic pharmacological interaction between GLP-1 and glucagon, e.g., dual glucagon/GLP-1 agonists cause more weight loss than single agonists. In this review, we discuss the physiological functions of both glucagon and GLP-1 by comparing and contrasting how these peptides function, variably in concert and opposition, to regulate glucose and energy homeostasis.

Evidence of Extrapancreatic Glucagon Secretion in Man

“…Although the exact origin cannot be determined in this study, the fact that oral glucose stimulation resulted in significant hyperglucagonemic responses, whereas intravenous glucose infusion suppressed circulating glucagon levels, directs the attention to the gastrointestinal tract. Glucagon is a product of the preproglucagon gene (GCG), which is expressed by both pancreatic a-cells and specific enteroendocrine cells (L cells) of the intestinal mucosa and neurons within the nucleus of the solitary tract (38,39). GCG encodes the precursor hormone proglucagon, which after posttranslational processing yields different and multiple biologically active proglucagonderived peptides depending on the presence and relative activity of the processing enzymes PC1/3 and PC2 (40).…”

Naturally-occurring TGR5 agonists modulating glucagon-like peptide-1 biosynthesis and secretion

“…Firstly, the compounds appeared to stimulate cAMP in STC-1 pGIP neo cells (data not shown). GLP-1 secretion both in vitro and in vivo has been linked to Gs-coupled GPCRs which increase cAMP and activate PKA [30]. TGR5 is one such GPCR which was first discovered in 2002 and apparently acts physiologically as the primary mediator of bile-acid induced GLP-1 release [19,21].…”

Can Avicenna Help Manage the Diabetes Epidemic in Central Asia?

“…Accelerating lipid oxidation provides energy for glucose anabolism. It is well-established that in states of poorly controlled diabetes with severe insulin deficiency or ketoacidosis, plasma glucagon concentrations are extremely high and that failure to suppress fasting levels of glucagon after eating contributes to hyperglycemia [45,46]. With clinical studies underway, it has become apparent that suppression of glucagon secretion or antagonization of the glucagon receptor constitutes potentially effective treatment strategies for patients with T2DM [43,47].…”