Endocrine Abstracts

Background: Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2), are key products of the L-cell proglucagon-gene with diverse effects on metabolism. Whereas GLP-1 has been extensively studied, much less attention has been devoted to GLP-2. The current study directly compares the impact of GLP-1 and GLP-2 on pancreatic beta-cell function and turnover in vitro, as well as the effects on glucose tolerance and appetite suppression in mice.

Methods: Acute glucose-dependent (1.1, 5.6 and 16.7-mM) insulin secretion studies (10^-12-10^-6 M; 20-min) were performed in BRIN-BD11 beta-cells. The influence of GLP-1 and GLP-2 (10^-8 -10^-6 M) on BRIN-BD11 cell proliferation was assessed by Ki-67 staining, whereas protection against cytokine-induced (IL-1beta, TNF-alpha, IFN-gamma) apoptosis was determined by TUNEL-staining. Acute in vivo gluco-regulatory and satiety actions of the peptides (25 nmol/kg bw) were investigated in overnight-fasted C57BL/6 mice.

Results: As expected, GLP-1 significantly (P < 0.001 - P < 0.0001) enhanced insulin secretion from BRIN-BD11 cells at 1.1, 5.6 and 16.7-mM glucose, whereas GLP-2 lacked beta-cell secretory actions. However, both GLP-1 (36% and 50%) and GLP-2 (42% and 49%) enhanced (P < 0.0001) beta-cell proliferation at 10^-8 and 10^-6 M respectively. In addition, beta-cell protection against cytokine-induced cell stress was significantly (P < 0.0001) reduced by both GLP-1 (39% and 41%) and GLP-2 (36% and 40%). In mice, administration of GLP-1 or GLP-2 significantly suppressed food intake (50% and 40% respectively, P < 0.001 - P < 0.0001) at 30, 60, 120 and 180 mins. When the peptides were administered conjointly with glucose (2g/kg, ip), GLP-1 induced prominent (P < 0.001) reductions in blood glucose levels when compared to glucose control, with GLP-2 also decreasing blood glucose but to a lesser extent (P < 0.01).

Conclusion: Pancreatic beta-cell secretory actions of GLP-1 and GLP-2 are distinct. However, these proglucagon-derived products, secreted from intestinal L-cells in equimolar concentrations, share hitherto unappreciated similarities in terms of their effects on beta-cell turnover and metabolic control.