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Diabetes. 2014 Mar;63(3):1021-31. doi: 10.2337/db13-0887. Epub 2013 Sep 5.

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

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  • 1Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY.


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.

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