Nateglinide, but not repaglinide, stimulates growth hormone release in rat pituitary cells by inhibition of K+ channels and stimulation of cyclic AMP-dependent exocytosis
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Objective: GH causes insulin resistance, impairs glycemic control and increases the risk of vascular diabetic complications. Sulphonylureas stimulate GH secretion and this study was undertaken to investigate the possible stimulatory effect of repaglinide and nateglinide, two novel oral glucose regulators, on critical steps of the stimulus-secretion coupling in single rat somatotrophs. Methods: Patch-clamp techniques were used to record whole-cell ATP-sensitive K+ (K-ATP) and delayed outward K+ currents, membrane potential and Ca2+-dependent exocytosis. GH release was measured from perifused rat somatotrophs. Results: Both nateglinide and repaglinide dose-dependently suppressed K-ATP channel activity with half-maximal inhibition being observed at 413 nM and 13 nM respectively. Both compounds induced action potential firing in the somatotrophs irrespective of whether GH-releasing hormone was present or not. The stimulation of electrical activity by nateglinide, but not repaglinide, was associated with an increased mean duration of the action potentials. The latter effect correlated with a reduction of the delayed outward K+ current, which accounts for action potential repolarization. The latter effect had a K-d of 19 muM but was limited to 38% inhibition. When applied at concentrations similar to those required to block K-ATP channels, nateglinide in addition potentiated Ca2+-evoked exocytosis 3.3-fold (K-d = 3 muM) and stimulated GH release 4.5-fold. The latter effect was not shared by repaglinide. The stimulation of exocytosis by nateglinide was mimicked by cAMP and antagonized by the protein kinase A inhibitor Rp-cAMPS. Conclusion: Nateglinide stimulates GH release by inhibition of plasma membrane K+ channels, elevation of cytoplasmic cAMP levels and stimulation of Ca2+-dependent exocytosis. By contrast, the effect of repaglinide was confined to inhibition of the K-ATP channels.
Ämnesklassifikation (UKÄ) – OBLIGATORISK
|Tidskrift||European Journal of Endocrinology|
|Status||Published - 2002|
|Peer review utförd||Ja|