Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease

• Published in: Physiological reviews Vol. 95; no. 2; pp. 513 - 548
• Main Authors: Sandoval, Darleen A, D'Alessio, David A
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.04.2015
• Subjects: Animals; Blood Glucose - metabolism; Cells; Diabetes Mellitus - metabolism; Diabetes Mellitus - physiopathology; Energy Metabolism; Enteroendocrine Cells - metabolism; Gene expression; Gene Expression Regulation; Glucagon - genetics; Glucagon - metabolism; Glucagon-Like Peptide 1 - genetics; Glucagon-Like Peptide 1 - metabolism; Glucagon-Secreting Cells - metabolism; Glucose; Homeostasis; Humans; Metabolism; Peptides; Signal Transduction
• ISSN: 0031-9333; 1522-1210
• DOI: 10.1152/physrev.00013.2014

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.