Bone as an Endocrine Organ Relevant to Diabetes

Abstract

There are well-established associations between diabetes and fracture risk and yet the mechanism underlying these associations are controversial. Guided by a series of mouse studies, a specific form of the bone protein, osteocalcin, was proposed to be the mechanistic link between these two chronic diseases. Translation to humans initially appeared elusive in part because serum concentrations of osteocalcin are a biomarker of bone turnover and not necessarily specific to the biology of this protein. The suitability of the mouse model for the study of osteocalcin as a therapeutic target also appears ambiguous. With greater discrimination of the different forms of osteocalcin present in circulation and inclusion of multiple measures of bone turnover, evidence currently does not support osteocalcin as a protein critical to the diabetes and fracture association in humans.

Increased trabecular bone and improved biomechanics in an osteocalcin null rat model created by CRISPR/Cas9 technology

“…The role of osteocalcin in humans and in human disease remains undetermined (Booth et al, 2013, 2014; Li et al, 2016). Owing to considerable divergence between mouse and human osteocalcin at both the genomic and protein level, the validity of extrapolating results from the osteocalcin-deficient mouse to human disease has been challenged (Booth et al, 2013, 2014). Similarity and synteny between the rat and human osteocalcin gene locus suggest that the rat might be a more appropriate animal model system to investigate osteocalcin function in humans.…”

“…There are considerable differences between the mouse and human osteocalcin gene loci, complicating interpretation of the results from the osteocalcin-deficient mouse model and raising the possibility that data from the mouse model might not be pertinent to human disease (Booth et al, 2013, 2014). For example, the mouse osteocalcin gene locus underwent a triplication event resulting in two functional copies of osteocalcin expressed in bone ( B glap-1 and B glap-2 ) and an additional copy expressed in other non-osteoid tissues ( B glap-3 ) (Desbois et al, 1994).…”

Biomarkers of Bone Turnover: Potential, Challenges and Pitfalls from the Laboratory Point of view

“…Increasing data underlie the relevance of bone metabolism and turnover biomarker concentration on type 2 diabetes mellitus (T2DM) pathophysiology [25][26][27]. In particular, OC has been significantly related to glucose metabolism, through the increase of insulin release and sensitivity and energy expenditure, and reduction of visceral fat [24][25][26][27][28]29].…”

“…In particular, OC has been significantly related to glucose metabolism, through the increase of insulin release and sensitivity and energy expenditure, and reduction of visceral fat [24][25][26][27][28]29]. In a general population, an inverse relationship was found between OC and fasting plasma glucose, fasting insulin, and homeostasis model assessment-estimated insulin resistance (HOMA-IR) [30].…”

Effect of vitamin K supplementation on insulin sensitivity: a meta-analysis

“…Bone has been well established as an endocrine organ 1,2. Its noncollagenous skeleton hormone named osteocalcin has been positively associated with physical activity3 and insulin sensitivity 4,5.…”