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

Abstract

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 beta-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 Czeta, and transactivation of the epidermal growth factor receptor through the c-src kinase. GLP-1 receptor activation also promotes cell survival in beta-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 beta-cell mass and enhanced resistance to beta-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.

Continuous stimulation of human glucagon-like peptide-1 (7–36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes

“…It is generally believed that islet precursor cells exist in the pancreatic ducts [31]. GLP-1 has been shown to induce the production of PDX1 in ducts and the differentiation of duct cells toward insulin-producing cells [32]. In GLP-1-treated NOD mice, we found that the number of newly formed beta cells originating from pancreatic ducts was increased.…”

Islet transplantation outcomes in mice are better with fresh islets and exendin-4 treatment

“…In animals with grafts of 75 islets, the body weights of the exendin-4-treated animals were similar to those of PBS-treated animals, although the exendin-4 mice tended to recover the weight loss after nephrectomy more quickly. It has previously been reported that exendin-4 slows gastric emptying, and therefore animals can lose weight [5]. However, it may be possible that the improvement in glucose homeostasis itself leads to a weight gain despite the effects on gastric emptying.…”

“…Exendin-4 is an agonist of the glucagon like peptide-1 (GLP-1) receptor with a longer half-life than GLP-1 [5]. This peptide has previously been shown to increase beta cell replication and islet neogenesis [6].…”

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

“…Since the normal number of beta cells is maintained in a balance between apoptosis and proliferation, this observation is of considerable interest, and raises the possibility that GLP-1 could be useful in conditions in which beta cell apoptosis is increased. The complicated mechanisms whereby GLP-1 may exert these effects on beta cells were reviewed recently [96].…”