Insulin Receptors, Osteoblasts & Osteocalcin
Recently, independent reports from the Karsenty laboratory and from the research group of Clemens indicate that insulin signaling in osteoblasts regulates glucose metabolism via the ucOC pathway. Mice with osteoblast-specific deletion of the insulin receptor (InsRosb −/−) are hyperglycemic with reduced insulin secretion and decreased ucOC. Additional experimental data from that study indicated that insulin signaling in osteoblasts favored bone resorption by osteoclasts, with decarboxylation of osteocalcin occurring in resorption lacunae, resulting in increased circulating ucOC and a positive feedback loop on insulin secretion (Figure 3). These findings were supported by an independent report demonstrating that disruption of insulin receptor expression in osteoblasts reduced TOC and ucOC levels, resulting in glucose intolerance and reduced insulin levels in mice. Therefore, in these mouse models, there is a positive feedback loop by which insulin action via the insulin receptor on osteoblasts increases decarboxylation of osteocalcin, thereby increasing circulating ucOC, whole body insulin sensitivity and insulin secretion. These findings illuminate novel mechanisms involved in insulin signaling and regulation of glucose metabolism and re-emphasize the need to consider bone turnover in conjunction with ucOC. The putative feed-forward loop would need to be carefully regulated in vivo. Other factors impacting on this pathway await identification and the importance of these mechanisms to skeletal and glucose metabolism in humans requires further clarification. In particular, there are treatments for osteoporosis that increase bone mineral density and reduce fracture risk by inhibiting osteoclast function.[53–55] However, the impact of such antiresorptive therapy for osteoporosis on glucose metabolism remains unclear and this information will be important when evaluating the applicability of the mechanisms described in cells and mice to humans.
Insulin action in osteoblasts regulates undercarboxylated osteocalcin availability. (A) Activation of the insulin receptor decreases OPG expression in osteoblasts, which favors resorptive activity in osteoclasts. (B) cOC is secreted by osteoblasts and undergoes decarboxylation in resorption lacunae, thus increasing ucOC levels. (C) Circulating ucOC enhances insulin sensitivity and insulin secretion. cOC: Carboxylated osteocalcin; OPG: Osteoprotegerin; ucOC: Undercarboxylated osteocalcin.
Expert Rev Endocrinol Metab. 2011;6(2):177-185. © 2011 Expert Reviews Ltd.
Cite this: Osteocalcin: An Endocrine Link Between Bone and Glucose Metabolism - Medscape - Mar 01, 2011.