Biotin increases pancreatic glucokinase expression through cGMP and an insulin signaling pathway

Abstract

Besides its role as carboxylase prosthetic group, biotin modifies the expression of critical genes in the regulation of glucose metabolism. In a previous work we demonstrated that biotin increases pancreatic glucokinase mRNA levels. In this study, we explored the mechanisms responsible for biotin-induced pancreatic glucokinase expression. Pancreatic islets in culture increased 2.5-fold glucokinase mRNA content after 2 h incubation with biotin [1 micromolar]. Two-h treatment with cGMP [1 micromolar] produced a similar increase. Islets treated with both compounds showed no further increase, suggesting that cGMP signaling via is involved in this biotin effect. Inhibition of soluble guanylate cyclase activity abolished biotin-induced glucokinase expression whereas cGMP response was not affected. Inhibition of PKG activity suppressed both, biotin and cGMP-induced response. Since cGMP signaling pathway stimulates insulin secretion, we further investigated whether the effect of biotin on glucokinase expression was mediated through an increase in insulin release. Insulin-antibodies in culture media abolished biotin-stimulated glucokinase expression. Furthermore, inhibitors of PI3K/Akt insulin signaling pathway blocked biotin-induced glucokinase expression. Our data indicate that the mechanism responsible for the effect of biotin on glucokinase mRNA abundance involves soluble guanylate cyclase and PKG activation, insulin secretion, and insulin PI3K/Akt signaling. Supported by Conacyt 44266M, Dgapa IN208605.