Osteocalcin: The extra-skeletal role of a vitamin K-dependent protein in glucose metabolism

摘要

Highlights ? The skeleton not only acts as a structural scaffold but also as an endocrine organ. ? Evidence suggests a complex interplay between the skeleton and glucose metabolism. ? Novel roles include influencing β cell proliferation and enhanced insulin secretion. ? Undercarboxylated and carboxylated osteocalcin are implicated with β-cell dysfunction. ? Further research required to clarify isoformic differences in human glucose regulation. The role of vitamin K in the body has long been associated with blood clotting and coagulation. In more recent times, its role in a range of physiological processes has been described including the regulation of bone and soft tissue calcification, cell growth and proliferation, cognition, inflammation, various oxidative processes and fertility, where osteocalcin is thought to up-regulate the synthesis of the enzymes needed for the biosynthesis of testosterone thereby increasing male fertility. Vitamin K dependent proteins (VKDP) contain γ-carboxyglutamic acid residues which require post-translational, gamma-glutamyl carboxylation by the vitamin K-dependent (VKD) gamma-glutamyl carboxylase enzyme for full functionality. These proteins are present both hepatically and extrahepatically. The role of bone-derived osteocalcin has many physiological roles including, maintenance of bone mass with more recent links to energy metabolism due to the role of the skeleton as an endocrine organ. It has been proposed that insulin binds to bone forming cells (osteoblasts) promoting osteocalcin production which in turn promotes β-cell proliferation, insulin secretion and glucose control. However much of this research has been conducted in animal models with equivocal findings in human studies. This review will discuss the role of osteocalcin in relation to its role in human health, focusing specifically on glucose metabolism.