Regulation of beta cell proliferation by osteocalcin

A fundamental step in developing novel therapies for type 1 diabetes is to identify the mechanisms controlling the proliferation and function of beta-cells. We have recently identified osteocalcin, a factor made by the skeleton and present in the blood of mice and humans, as a new regulator of beta-cell proliferation and insulin production. Indeed, we have shown that mice without osteocalcin diabetes and have a decreased beta-cell mass while mice engineered with an increase of active osteocalcin have increased beta-cell proliferation and increased insulin levels. These studies provided a proof-of-principle that osteocalcin could be an important regulator of beta-cell mass and glucose homeostasis in vivo. That the gene encoding osteocalcin is included in a region of the genome containing a determinant for type 1 diabetes (region Idd17) further suggests that this newly discovered factor might be important for our understanding of this disease. However, our initial studies did not fully characterize the effects of osteocalcin on pancreas biology. In particular, they did not define if osteocalcin is active at any age or life or if its action is restricted in time, or if a long-term exposure to osteocalcin could have detrimental effects such as exhaustion of beta-cell function or development of pancreatic tumors. They did not either define how osteocalcin acts on beta-cells. A large part of the present project is designed to address these questions by studying, from development to death, the pancreas structure, beta-cell content and insulin production in mice displaying an increase of osteocalcin activity. Our project is also designed to begin assessing whether osteocalcin could have a therapeutic potential. To that end we propose to conduct three types of experiments. First, we will treat normal mice with osteocalcin to assess whether beta-cell mass and insulin production can be enhanced by the treatment. Second, we will isolate pancreatic islets and culture them in presence of osteocalcin to determine whether this new factor can increase their content in functional beta-cells. Lastly, we will induce type 1 diabetic in mice with normal or increased levels of osteocalcin and test whether the latter group present less severe or delayed symptoms of this disease. In summary, the proposed studies should define the role and therapeutic potential of a newly identified factor regulating beta-cell proliferation and insulin production.