Acyl-Ghrelin Influences Pancreatic β-Cell Function by Interference with KATP Channels.

Julia Kaiser, Peter Krippeit-Drews, Gisela Drews

Diabetes 2021 Feb

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The aim for this study was to elucidate how the hypothalamic hunger-inducing hormone acyl-ghrelin (AG), which is also produced in the pancreas, affects β-cell function, with particular attention to the role of ATP-sensitive K+ (KATP) channels and the exact site of action of the hormone. AG hyperpolarized the membrane potential and decreased cytoplasmic calcium concentration [Ca2+]c and glucose-stimulated insulin secretion (GSIS). These effects were abolished in β-cells from SUR1-knockout (KO) mice. AG increased KATP current but only in a configuration with intact metabolism. Unacylated ghrelin counteracted the effects of AG. The influence of AG on membrane potential and GSIS could only be averted in the combined presence of a ghrelin receptor (GHSR1a) antagonist and an inverse agonist. The inhibition of GSIS by AG could be prevented by dibutyryl cyclic-cAMP or 3-isobutyl-1-methylxanthine and the somatostatin (SST) receptor 2-5 antagonist H6056. These data indicate that AG indirectly opens KATP channels probably by interference with the cAMP/cAMP-dependent protein kinase pathway, resulting in a decrease of [Ca2+]c and GSIS. The experiments with SUR1-KO β-cells point to a direct effect of AG on β-cells and not, as earlier suggested, to an exclusive effect by AG-induced SST release from δ-cells. Nevertheless, SST receptors may be involved in the effect of AG, possibly by heteromerization of AG and SST receptors. © 2020 by the American Diabetes Association.

Citation

Julia Kaiser, Peter Krippeit-Drews, Gisela Drews. Acyl-Ghrelin Influences Pancreatic β-Cell Function by Interference with KATP Channels. Diabetes. 2021 Feb;70(2):423-435