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

Apr 3, 2015Physiological reviews

How glucagon and GLP-1 hormones affect the body in health and illness

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Abstract

The preproglucagon gene encodes multiple peptides, including glucagon and GLP-1, which are crucial for glucose metabolism.

GLP-1 is known to enhance insulin release and reduce glucagon secretion, contributing to improved glucose homeostasis.
Glucagon primarily functions as a counterregulatory hormone, increasing during physiological challenges to maintain blood glucose levels.
Recent studies suggest glucagon may also play a role in regulating energy expenditure.
There is evidence of interaction between GLP-1 and glucagon, with GLP-1 inhibiting glucagon secretion.
Dual agonists targeting both glucagon and GLP-1 may lead to greater weight loss compared to single-target therapies.

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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.

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

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