Endogenous somatostatin is critical in regulating the acute effects of L-arginine on growth hormone and insulin release in mice

Abstract

l-arginine (l-Arg) rapidly stimulates GH and insulin release in vivo. It has been hypothesized that l-Arg stimulates GH release by lowering hypothalamic somatostatin (SST) tone. l-Arg may also act directly at the pituitary to stimulate GH release. Moreover, l-Arg has a direct stimulatory effect on β-cells, which is thought to be blunted by the release of SST from pancreatic δ-cells. To confirm the role of endogenous SST on l-Arg-induced GH and insulin release, wild-type (WT) and SST-knockout (SST-KO) mice were injected with l-Arg (ip; 0.8 g/kg), and pre-/post-injection GH, insulin, and glucose levels were measured. In WT mice, l-Arg evoked a 6-fold increase in circulating GH. However, there was only a modest increase in GH levels in WT pituitary cell cultures treated with l-Arg. In contrast, l-Arg failed to increase GH in SST-KO beyond their already elevated levels. These results further support the hypothesis that the primary mechanism by which l-Arg acutely increases GH in vivo is by lowering hypothalamic SST input to the pituitary and not via direct pituitary effects. Additionally, l-Arg induced a clear first-phase insulin secretion in WT mice, but not in SST-KO. However, SST-KO, but not WT mice, displayed a robust and sustained second-phase insulin release. These results further support a role for endogenous SST in regulating l-Arg-mediated insulin release.

Figure 1.

Acute in Vivo l-Arg-Induced GH Secretion in WT and SST-KO Fed Male and Female Mice and in Vitro l-Arg-Induced GH Secretion in Male and Female WT Pituitary Cells in Vitro A, Plasma GH levels in male (left) and female (right) WT and SST-KO mice in response to l-Arg (ip; 0.8 g/kg). Values are shown as means ± SEM of 5–7 mice per genotype per gender. B, In vitro GH levels in male (left) and female (right) WT primary pituitary cell cultures treated with 100 μM of l-Arg for 1 hour or 24 hours. Values are means ± SEM of 3 independent experiments (3–4 individual wells per treatment per experiment per gender). Asterisks indicate differences between WT and SST-KO (A) or l-Arg treated against vehicle-treated controls (B). *, P < .05; **, P < .01; ***, P < .001.

Figure 2.

Relative Insulin (A and C) and Glucose (B and D) Response to l-Arg (ip; 0.8 g/kg) in Fasted 4 (A and B) and 7 (C and D) Month-Old WT and SST-KO Male Mice Values are shown as means ± SEM of 5–8 mice per genotype. Asterisks indicate differences between WT and SST-KO. *, P < .05; **, P < .01; ***, P < .001. AUC, area under the curve.