Endogenous Somatostatin Is Critical in Regulating the Acute Effects of L-Arginine on Growth Hormone and Insulin Release in Mice

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 beta-cells, which is thought to be blunted by the release of SST from pancreatic delta-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. (Endocrinology 154: 2393-2398, 2013)