Minireview: Glucagon-Like Peptides Regulate Cell Proliferation and Apoptosis in the Pancreas, Gut, and Central Nervous System

• Published in: Endocrinology (Philadelphia) Vol. 145; no. 6; pp. 2653 - 2659
• Main Authors: Brubaker, P. L., Drucker, D. J.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.06.2004
• Subjects: AKT protein; Animals; Apoptosis; Apoptosis - physiology; Beta cells; Cell activation; Cell culture; Cell Division - physiology; Cell growth; Cell injury; Cell proliferation; Cell survival; Central nervous system; Central Nervous System - physiology; Cyclic AMP; Diabetes; Diabetes mellitus; Digestive system; G protein-coupled receptors; Gastric motility; Gastrointestinal tract; Glucagon; Glucagon - physiology; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Growth factors; Injuries; Intestine; Intestines - cytology; Intestines - physiology; Intracellular signalling; Kinases; Pancreas - cytology; Pancreas - physiology; Peptide Fragments - physiology; Peptides; Peptides - physiology; Protein kinase C; Protein Precursors - physiology; Proteins; Receptor mechanisms; Receptors; Regeneration; Satiety; Src protein; Survival
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2004-0015

Gut peptides exert diverse effects regulating satiety, gastrointestinal motility and acid secretion, epithelial integrity, and both nutrient absorption and disposal. These actions are initiated by activation of specific G protein-coupled receptors and may be mediated by direct or indirect effects on target cells. More recent evidence demonstrates that gut peptides, exemplified by glucagon-like peptides-1 and 2 (GLP-1 and GLP-2), directly regulate signaling pathways coupled to cell proliferation and apoptosis. GLP-1 receptor activation enhances β-cell proliferation and promotes islet neogenesis via activation of pdx-1 expression. The proliferative effects of GLP-1 appear to involve multiple intracellular pathways, including stimulation of Akt, activation of protein kinase Cζ, and transactivation of the epidermal growth factor receptor through the c-src kinase. GLP-1 receptor activation also promotes cell survival in β-cells and neurons via increased levels of cAMP leading to cAMP response element binding protein activation, enhanced insulin receptor substrate-2 activity and, ultimately, activation of Akt. These actions of GLP-1 are reflected by expansion of β-cell mass and enhanced resistance to β-cell injury in experimental models of diabetes in vivo. GLP-2 also promotes intestinal cell proliferation and confers resistance to cellular injury in a variety of cell types. Administration of GLP-2 to animals with experimental intestinal injury promotes regeneration of the gastrointestinal epithelial mucosa and confers resistance to apoptosis in an indirect manner via yet-to-be identified GLP-2 receptor-dependent regulators of mucosal growth and cell survival. These proliferative and antiapoptotic actions of GLP-1 and GLP-2 may contribute to protective and regenerative actions of these peptides in human subjects with diabetes and intestinal disorders, respectively.