Osteocalcin induces phosphorylation of FOXO1 in human beta-cells and restores insulin expression under hyperglycemic conditions.

Forkhead box O1 (FOXO1) is a key transcription factor that plays an important role in pancreatic β-cell compensation under physiological and pathological conditions and serves as a key regulator of glucose homeostasis. While FOXO1 expression in osteoblasts contributes to glucose maintenance through regulating osteocalcin, interestingly, osteocalcin acts directly on β-cells by regulating PDX1 and insulin expression. Here, we investigate the effect of osteocalcin on the FOXO1 expression in human pancreatic β-cells. In a human β-cell line and pancreatic islets, the fate of FOXO1 binding to the PDX1 promoter was investigated after osteocalcin treatment, with or without AKT inhibition. Furthermore, we investigated the effect of osteocalcin on PDX1 and insulin gene expression as well as the subcellular localization of FOXO1 and PDX1 in human islets. The data show that osteocalcin treatment increased the amount of phosphorylated FOXO1-S256 via AKT in human islet from high BMI donor. Moreover, human islets from donors with and without diabetes treated with osteocalcin showed a reduced nuclear FOXO1 and an increase in nuclear PDX1. In a human β-cell line and pancreatic islets, osteocalcin increases insulin and PDX1 expression following phosphorylation-dependent ubiquitination and degradation of FOXO1 via the protein kinase B pathway.