Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are related intestinal L-cell derived secretory products. GLP-1 has been extensively studied in terms of its influence on metabolism, but less attention has been devoted to GLP-2 in this regard. The current study compares the effects of these proglucagon-derived peptides on pancreatic beta-cell function, as well as on glucose tolerance and appetite. The insulin secretory effects of GLP-1 and GLP-2 (10−12–10−6 M) were investigated in BRIN-BD11 beta-cells as well as isolated mouse islets, with the impact of test peptides (10 nM) on real-time cytosolic cAMP levels further evaluated in mouse islets. The impact of both peptides (10−8–10−6 M) on beta-cell growth and survival was also studied in BRIN BD11 cells. Acute in vivo (peptides administered at 25 nmol/kg) glucose homeostatic and appetite suppressive actions were then examined in healthy mice. GLP-1, but not GLP-2, concentration dependently augmented insulin secretion from BRIN-BD11 cells, with similar observations made in isolated murine islets. In addition, GLP-1 substantially increased [cAMP]cyt in islet cells and was significantly more prominent than GLP-2 in this regard. Both GLP-1 and GLP-2 promoted beta-cell proliferation and protected against cytokine-induced apoptosis. In overnight fasted healthy mice, as well as mice trained to eat for 3 h per day, the administration of GLP-1 or GLP-2 suppressed appetite. When injected conjointly with glucose, both peptides improved glucose disposal, which was associated with enhanced glucose-stimulated insulin secretion by GLP-1, but not GLP-2. To conclude, the impact of GLP-1 and GLP-2 on insulin secretion is divergent, but the effects of beta-cell signaling and overall health are similar. Moreover, the peripheral administration of either hormone in rodents results in comparable positive effects on blood glucose levels and appetite.

This study aims to compare the effects of GLP-1 and GLP-2 on pancreatic beta-cell function and turnover in vitro, along with their impact on glucose tolerance and appetite suppression in mice.

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.

Background Pancreatic islet β‐cell mass expands during pregnancy, but underlying mechanisms are not fully understood. This study examines the impact of pregnancy and cafeteria diet on islet morphology, associated cellular proliferation/apoptosis rates as well as β‐cell lineage. Methods Non‐pregnant and pregnant Ins 1 Cre/+ ; Rosa26‐eYFP transgenic mice were maintained on either normal or high‐fat cafeteria diet, with pancreatic tissue obtained at 18 days gestation. Immunohistochemical changes in islet morphology, β‐/α‐cell proliferation and apoptosis, as well as islet cell identity, neogenesis and ductal cell transdifferentiation were assessed. Results Pregnant normal diet mice displayed an increase in body weight and glycaemia. Cafeteria feeding attenuated this weight gain while causing overt hyperglycaemia. Pregnant mice maintained on a normal diet exhibited typical expansion in islet and β‐cell area, owing to increased β‐cell proliferation and survival as well as ductal to β‐cell transdifferentiation and β‐cell neogenesis, alongside decreased β‐cell dedifferentiation. Such pregnancy‐induced islet adaptations were severely restricted by cafeteria diet. Accordingly, islets from these mice displayed high levels of β‐cell apoptosis and dedifferentiation, together with diminished β‐cell proliferation and lack of pregnancy‐induced β‐cell neogenesis and transdifferentiation, entirely opposing islet cell modifications observed in pregnant mice maintained on a normal diet. Conclusion Augmentation of β‐cell mass during gestation arises through various mechanisms that include proliferation and survival of existing β‐cells, transdifferentiation of ductal cells as well as β‐cell neogenesis. Remarkably, cafeteria feeding almost entirely annuls pregnancy‐induced islet adaptations, which may contribute to the development of gestational diabetes in the setting of dietary provoked metabolic stress.