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Figure 1. Osteoblast-secreted osteocalcin is a novel bone-derived endocrine regulator of glucose homeostasis in mice. (A) Knockout mice (Esp -/- ) lacking an osteoblast-expressed receptor-like protein tyrosine phosphatase are protected from diabetes. (B) This phenotype is neutralized by the deletion of a single allelle of osteocalcin and (C) Ocn -/- mice are glucose intolerant. Esp: Enterococcal surface protein; Ocn: Osteocalcin.
(Figure omitted. See article PDF.)
Figure 2. Both undercarboxylated and g-carboxylated osteocalcin are present in the circulation. (A) Human osteocalcin is a 49 amino acid peptide with glutamate residues at positions 17, 21 and 24, which can be g-carboxylated. (B) Lability at the C-terminus results in a major fragment of 43 amino acids. (C) Carboxylated osteocalcin has greater binding affinity to hydroxyapatite in vivo (to bone) and in vitro (allowing assay of unbound undercarboxylated osteocalcin).
(Figure omitted. See article PDF.)
Figure 3. 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.
(Figure omitted. See article PDF.)
Insulin resistance, diabetes & cardiovascular disease
Type 2 diabetes mellitus is a modern epidemic characterized by underlying insulin resistance and impaired insulin secretion [1]. The states of impaired fasting glucose, impaired glucose tolerance and overt diabetes are associated with progressively increased risks of all-cause and cardiovascular disease (CVD)-related mortality compared with normal glucose tolerance [2-4]. Insulin resistance contributes to disordered glucose metabolism and Type 2 diabetes and may represent a risk factor for CVD independently of diabetes [5,6]. Mechanisms by which insulin resistance and Type 2 diabetes accelerate the development of atherosclerosis (which then manifests with CVD, e.g., heart attack, stroke or arterial disease) include the toxic effects of elevated glucose or glucose metabolites on the vascular endothelium, or deficiency of insulin action contributing to endothelial dysfunction, lipid abnormalities and inflammation (for reviews, see [7,8]). Treating risk factors and having a better control of glucose levels in individuals with Type 2 diabetes can over time partially reduce CVD events and mortality, but substantial residual risk remains [9-11]. Lifestyle...