Osteocalcin as a hormone regulating glucose metabolism

Abstract

The number of patients with osteoporosis and diabetes is rapidly increasing all over the world. Bone is recently recognized as an endocrine organ. Accumulating evidence has shown that osteocalcin, which is specifically expressed in osteoblasts and secreted into the circulation, regulates glucose homeostasis by stimulating insulin expression in pancreas and adiponectin expression in adipocytes, resulting in improving glucose intolerance. On the other hand, insulin and adiponectin stimulate osteocalcin expression in osteoblasts, suggesting that positive feedforward loops exist among bone, pancreas, and adipose tissue. In addition, recent studies have shown that osteocalcin enhances insulin sensitivity and the differentiation in muscle, while secreted factors from muscle, myokines, regulate bone metabolism. These findings suggest that bone metabolism and glucose metabolism are associated with each other through the action of osteocalcin. In this review, I describe the role of osteocalcin in the interaction among bone, pancreas, brain, adipose tissue, and muscle.

Keywords: Adiponectin; Diabetes mellitus; Glucagon-like peptide-1; Glucose; Insulin; Osteocalcin; Undercarboxylated osteocalcin.

Figure 1

The effects of osteocalcin on pancreas and adipose tissue. Undercarboxylated osteocalcin (ucOC) is an active form regulating glucose metabolism. Esp inactivate osteocalcin by carboxylating ucOC. ucOC increases insulin expression in pancreas and adiponectin expression in adipose tissue.

Figure 2

Schematic representation of the endocrine loops between bone and pancreas. Insulin signaling stimulates the expression of osteocalcin and osteoblastic differentiation via inhibiting Twist2, an inhibitor of Runx2, as well as FoxO1, resulting in accumulation of carboxylated osteocalcin in bone matrix. Conversely, insulin activates osteoclasts and accelerate bone turnover via increasing the ratio of osteoprotegerin/receptor activator of nuclear factor kappa-B ligand. Activated osteoclasts decarboxylate bone matrix-embedded osteocalcin, and then undercarboxylated osteocalcin (ucOC) is released into the circulation. UcOC stimulates the expression of insulin in pancreas and of adiponectin in adipose tissue. OST-PTP: Osteotesticular protein tyrosine phosphatase; AMPK: AMP-activated protein kinase; OPG/RANKL: Osteoprotegerin/receptor activator of nuclear factor kappa-B ligand; IR: Insulin receptor.

Figure 3

Schematic representation of the regulation of insulin secretion by leptin. Leptin directly inhibits insulin expression in pancreas. Leptin activates SNS by decreasing serotonin and cAMP response element binding protein in hypothalamus, and then enhanced SNS suppresses osteoblast differentiation and osteocalcin expression through the Adrβ2 in osteoblasts. Thus, leptin indirectly inhibits insulin expression via central nervous system and bone. SNS: Sympathetic nervous system.

Figure 4

Schematic representation of the endocrine loops between bone and pancreas, and adipose tissue. Insulin signaling stimulates the expression of osteocalcin and osteoblastic differentiation via inhibiting Twist2, an inhibitor of Runx2, as well as FoxO1, resulting in accumulation of carboxylated osteocalcin in bone matrix. Adiponectin also stimulates osteocalcin expression and the differentiation of osteoblasts via AMP-activated protein kinase (AMPK) signaling pathway. Both insulin and adiponectin activate osteoclasts and accelerate bone turnover via increasing the ratio of RANKL/OPG. Activated osteoclasts decarboxylate bone matrix-embedded osteocalcin, and then undercarboxylated osteocalcin (ucOC) is released into the circulation. UcOC stimulates the expression of insulin in pancreas and of adiponectin in adipose tissue. OST-PTP: Osteotesticular protein tyrosine phosphatase; IR: Insulin receptor.

Figure 5

Schematic representation of the mechanisms regulating glucose metabolism by bone. Undercarboxylated osteocalcin (ucOC) secreted from bone directly stimulates insulin secretion from pancreas and indirectly through increasing the secretion of glucagon-like peptide-1 (GLP-1) from small intestine. UcOC stimulates the expression of adiponectin in adipose tissue, resulting in increasing insulin sensitivity. UcOC also enhances insulin signaling in muscle. G-protein coupled receptor family C group 6 member A (GPRC6A) is a receptor for ucOC and expressed in pancreas β-cells, epithelial cells of small intestine, adipocytes, and myotubes.