Osteocalcin promotes β-cell proliferation during development and adulthood through Gprc6a

摘要

Expanding β-Cell mass through β-Cell proliferation is considered a potential therapeutic approach to treat β-Cell failure in diabetic patients. A necessary step toward achieving this goal is to identify signaling pathways that regulate β-Cell proliferation in vivo. Here we show that osteocalcin, a bone-derived hormone, regulates β-Cell replication in a cyclin D1- dependent manner by signaling through the Gprc6a receptor expressed in these cells. Accordingly, mice lacking Gprc6a in the β-Cell lineage only are glucose intolerant due to an impaired ability to produce insulin. Remarkably, this regulation occurs during both the perinatal peak of β-Cell proliferation and in adulthood. Hence, the loss of osteocalcin/Gprc6a signaling has a profound effect on β-Cell mass accrual during late pancreas morphogenesis. This study extends the endocrine role of osteocalcin to the developmental period and establishes osteocalcin/Gprc6a signaling as a major regulator of β-Cell endowment that can become a potential target for β-Cell proliferative therapies.