Regulation of Glucose Handling by the Skeleton: Insights From Mouse and Human Studies.

Abstract

The skeleton is now recognized as an endocrine organ regulating a growing number of physiological processes. Its endocrine function came to light when it was realized that osteoblasts, the bone-forming cells, contribute to the regulation of energy homeostasis by favoring glucose metabolism, insulin sensitivity, and energy expenditure. Accumulating evidence from mouse studies demonstrated that the traditional bone formation marker osteocalcin secreted by osteoblasts, when undercarboxylated through a resorption- and insulin-dependent mechanism, is an active hormone that promotes insulin secretion and improves insulin sensitivity. This metabolic process is counterbalanced by sympathetic nervous system signaling in osteoblasts that under the control of leptin favors carboxylation and therefore inactivation of osteocalcin. These observations in mice triggered extensive studies exploring the cross talk between bone, pancreas, and fat and showed that, in turn, osteoblasts receive signals from endocrine organs during chronic hyperglycemia and insulin resistance that impact their fuel utilization and substrate availability. Clinical studies also have added support to the notion that bone regulates glucose metabolism in humans. This review highlights recent advances in our understanding of the endocrine functions of bone and explores their relationship to clinical observations. A link between the skeleton and glucose handling has long been suggested. Initially this relationship was mainly thought to be the consequence of metabolic dysregulation on bone health. Diabetes is a disease affecting glucose utilization principally, but not only, in muscle and adipose tissue. In reality the hyperglycemia impacts bone as it affects osteoblast differentiation, as well as the quality of the bone matrix. Impaired bone formation is often associated with increased marrow adiposity (1), which is a hallmark of patients both with type 1 and with type 2 diabetes (T1D and T2D). Importantly, in addition to compromised recruitment of osteogenic progenitors, osteoblast differentiation is impaired by chronic hyperglycemia likely contributing to an increased …