Preproglucagon derived peptides and thyrotropin (TSH) secretion in the rat: robust and sustained lowering of blood TSH levels in exendin-4 injected animals.

We have investigated the acute effects of preproglucagon derived peptides (PGDP) - glucagon, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), and exendin-4 (EX4), a GLP-1 receptor agonist, on thyrotropin (TSH) secretion in the rat. Within 120 min after subcutaneous injection, neither glucagon nor GLP-1 or GLP-2 had an effect on blood rTSH concentration in adult female rat. On the contrary, EX4 injection significantly lowered the plasma thyrotropin level. A potent inhibitory effect of EX4 administration on blood rTSH level was seen even 12 h after bolus peptide administration, whereas EX4-induced elevation in blood glucose concentration returned to normal values after 6 h of experiment. EX4 administration in doses from 0.05 to 1.00 nmol/100 g body weight resulted in very similar drop in blood rTSH levels. To check whether EX4-induced lowering in blood rTSH concentrations may be prevented by exendin-(9-39) [EX(9-39)], rats were treated with EX4 and/or EX(9-39). Both the bolus administration and the 3-day treatment with EX(9-39) notably lowered blood rTSH concentration of studied rats. Administration of EX(9-39) did not change blood rTSH response to EX4. Results of our in vivo studies are rather unexpected and raise serious questions on the specificity of EX4 and EX(9-39) action in vivo. Since both the native EX4 molecule as well as its truncated form [EX(9-39)] exerts a similar inhibitory effect on TSH secretion in the rat, it seems legitimate to suggest that this action depends only on 9-39 amino acid sequence of EX4. Moreover, obtained results suggest that both EX4 and EX(9-39)-evoked inhibition of TSH secretion in the rat is not dependent on their interaction with GLP-1 receptor only. Detailed mechanism of such action remains to be elucidated.