Intraperitoneal administration of nesfatin‑1 stimulates glucagon‑like peptide‑1 secretion in fasted mice

Abstract

Increasing endogenous secretion of glucagon‑like peptide (GLP)‑1 is considered a promising therapeutic approach for type 2 diabetes because decreased GLP‑1 plasma concentrations have been observed in patients with this condition. Nesfatin‑1, which is a central and peripheral anorexigenic peptide, has been reported to release GLP‑1 from enteroendocrine STC‑1 cells, although whether nesfatin‑1 stimulates GLP‑1 secretion in vivo remains to be elucidated. Previous studies have indicated that nesfatin‑1 has glucose‑lowering and insulinotropic effects in mice and rats; however, the in vivo mechanism remains unclear. The present study aimed to investigate whether peripheral administration of nesfatin‑1 increased blood concentrations of GLP‑1 and insulin in food‑deprived mice. Nesfatin‑1 was administered intraperitoneally to 18‑h fasted mice. Plasma GLP‑1 and insulin concentrations in the mice administered 2.5 µmol/kg nesfatin‑1 were higher than those in saline‑treated mice. Blood glucose concentrations in mice treated with 1.25 and 2.5 µmol/kg nesfatin‑1 were lower than those in saline‑treated mice. The mRNA expression of preproglucagon in mouse ilea after treatment with 1.25 µmol/kg nesfatin‑1 was higher than that in saline‑treated mice. The administration of 1.25 µmol/kg nesfatin‑1 raised GLP‑1 concentrations at 30 and 60 min and insulin concentrations at 30 and 60 min after injection. Furthermore, the higher level of nesfatin‑1‑induced insulin was diminished by pre‑administration of anti‑GLP‑1 antiserum. Intraperitoneally administered nesfatin‑1 increased insulin concentrations by accelerating GLP‑1 secretion. The results are the first in vivo demonstration of promotion of GLP‑1 secretion by nesfatin‑1 in the mouse, suggesting the developmental potential of nesfatin‑1 for GLP‑1 release.

Keywords: glucagon; glucagon‑like peptide 1; glucose; ileum; insulin; nesfatin‑1; pancreas.

Figure 1.

Dose responses to intraperitoneal administration of nesfatin-1. Peripheral blood concentrations of (A) GLP-1, (B) insulin, (C) glucose and (D) glucagon. Blood samples were obtained 30 min following intraperitoneal injection of different doses of synthetic mouse whole nesfatin-1 in overnight food-deprived C57BL/6J mice. Data are presented as the mean ± SEM. The number of mice is shown in parentheses. *P<0.05, **P<0.01 vs. controls using Tukey's multiple comparison test after one-way ANOVA. GLP, glucagon-like peptide.

Figure 2.

The mRNA expression of preproglucagon and insulin following nesfatin-1 injection. The mRNA levels of preproglucagon in the (A) ileum and (B) insulin in the pancreas. Tissue samples were obtained 30 min following intraperitoneal injection of different doses of synthetic mouse whole nesfatin-1 in overnight food-deprived C57BL/6J mice. Data are presented as the mean ± SEM. The number of mice is shown in parentheses. *P<0.05 vs. controls using Tukey's multiple comparison test after one-way ANOVA.

Figure 3.

Changes in GLP-1, insulin, glucose and glucagon concentrations after nesfatin-1 injection. Chronological changes in peripheral blood concentrations of (A) GLP-1, (B) insulin, (C) glucose and (D) glucagon following intraperitoneal administration of 1.25 µmol/kg nesfatin-1 to overnight food-deprived C57BL/6J mice. Data are presented as the mean ± SEM. The number of mice is shown in parentheses. *P<0.05, **P<0.01, ***P<0.01 vs. controls using two-sample t-tests. GLP, glucagon-like peptide.

Figure 4.

Chronological changes in peripheral blood concentrations of nesfatin-1 following nesfatin-1 injection. intraperitoneal injection of 1.25 µmol/kg nesfatin-1 to overnight food-deprived C57BL/6J mice. Plasma concentrations of nesfatin-1 after nesfatin-1 administration were measured using a mouse nesfatin-1 ELISA. Data are presented as the mean ± SEM. n=5 mice/group.

Figure 5.

Blocking GLP-1 or nesfatin-1 with specific antiserum decreases nesfatin-1-induced plasma GLP-1 and insulin concentrations. Plasma concentrations of (A) GLP-1, (B) insulin and (C) glucagon. Anti-GLP-1 or anti-nesfatin-1 serum was intraperitoneally administered 30 min before intraperitoneal administration of 1.25 µmol/kg nesfatin-1 to overnight food-deprived C57BL/6J mice and blood samples were obtained 60 min after nesfatin-1 injection. Data are presented as the mean ± SEM. The number of mice is shown in parentheses. *P<0.05, **P<0.01 vs. controls using Tukey's multiple comparison test after one-way ANOVA. GLP, glucagon-like peptide.