Ghrelin influences β-cell function by interference with KATP channels

Objective:

Ghrelin is well known as a hunger-inducing hormone which is mainly secreted from stomach cells. Meanwhile it has become evident, that ghrelin is produced in the pancreas as well and influences β-cell function. For many years it was well accepted, that ghrelin decreases glucose stimulated insulin secretion (GSIS) through the growth hormone secretagogue receptor 1a (GHS-R1a) coupled to Gαi/cAMP/TRPM2. This assumption was recently challenged by the discovery that the GHS-R1a is expressed in δ-cells. Accordingly, ghrelin may induce the secretion of somatostatin, which, in turn, acts in a paracrine manner on β-cells and inhibits GSIS.

Aims:

The aim of this study was to further elucidate how ghrelin interferes with β-cell function. Methods Patch-clamp and fluorescence techniques and RIA were used to determine [Ca2+]c, GSIS, and electrophysiological parameters in β-cells or islets of WT and SUR1-KO mice.

Results:

Ghrelin significantly hyperpolarized membrane potential (n = 9) and decreased [Ca2+]c (n = 20) and GSIS at stimulating glucose concentration. These effects were abolished in β-cells and islets from SUR1-KO mice. Ghrelin had no influence on KATP single channel current in excised patches (n = 8), but increased KATP current in a whole-cell configuration with intact metabolism (n = 8). Furthermore, the inhibition of GSIS could be prevented in the presence of db-cAMP (n = 8) or IBMX (n = 5) and with the somatostatin receptor 2 – 5 (SST-R2 – 5) antagonist H6056 (n = 6).

Conclusion:

These data indicate that ghrelin indirectly opens KATP channels probably by interference with the cAMP/PKA pathway resulting in a decrease of [Ca2+]c and GSIS. There is evidence for the involvement of SST-R2 – 5.