Osteocalcin promotes ß-cell proliferation during development and adulthood through Gprc6a.

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