Osteocalcin: An Endocrine Link Between Bone and Glucose Metabolism

Bu B Yeap

Expert Rev Endocrinol Metab. 2011;6(2):177-185.

Bone is an Endocrine Organ that Regulates Glucose Metabolism in Mice

Obesity, impaired fasting glucose and impaired glucose tolerance are associated with an increased risk of developing Type 2 diabetes.^[15] Type 2 diabetes arises from insulin resistance in body tissues (e.g., in liver, muscle and fat) and progressive impairment of pancreatic β-cell insulin secretion.^[16] Recent studies in knockout mice have identified a novel mechanism by which cells involved in bone formation (osteoblasts) regulate glucose metabolism, modulating both β-cell insulin secretion and peripheral insulin resistance.^[17] In these studies, enterococcal surface protein (Esp)-knockout mice (Esp^−/−) lacking an osteoblast-expressed receptor-like protein tyrosine phosphatase (OST-PTP) displayed increased β-cell proliferation, hyperinsulinemia, lower glucose levels, and were protected from developing diabetes. Compared with wild-type mice, Esp^−/− mice exhibited increased insulin sensitivity, increased expression of adiponectin in fat tissue and a twofold increase in serum adiponectin (Figure 1A).^[17] In mice, OST-PTP is expressed in bone and testis and not in the pancreas, and mice with osteoblast-specific deletion of OST-PTP possessed the same diabetes-resistant phenotype as Esp^−/− mice, suggesting mediation by an endocrine or humoral factor. In humans, there are >30 tyrosine phosphatases, one of which might possibly mediate this pathway, but the closest human homolog of OST-PTP is a pseudogene and thus not a viable target for new antidiabetic drugs.^[18] However, the diabetes-resistant Esp^−/− phenotype was completely reversed by deletion of a single allele of osteocalcin (Ocn), implicating this distinct osteoblast-secreted circulating protein as a novel bone-derived endocrine regulator of glucose homeostasis (Figure 1B).^[17]

(Enlarge Image)

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.

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Table 1. Studies of total osteocalcin level in relation to insulin resistance, diabetes and metabolic syndrome in humans.
Study (year)	Study (type)	Results	Ref.
Im et al. (2008)	339 postmenopausal women (31 with Type 2 diabetes; X)	Serum TOC was lower in women with Type 2 diabetes vs controls (17.5 vs 22.2 µg/l; p < 0.005), and correlated inversely with HbA1c (r = −0.22, p < 0.001) and IR (r = −16, p = 0.003)	[23]
Zhou et al. (2009)	254 men (128 newly diagnosed Type 2 diabetes) and 180 postmenopausal women (92 with diabetes; X)	Serum TOC was lower in adults with Type 2 diabetes vs controls (15.1 vs 16.8 µg/l; p = 0.003)	[24]
Kindblom et al. (2009)	857 nondiabetic and 153 diabetic men (X)	Diabetic men had lower TOC (21.7 vs 27.8 µg/l; p < 0.001), TOC was inversely related to BMI, fat mass and fasting glucose (p < 0.001)	[25]
Kanazawa et al. (2009)	179 men and 149 postmenopausal women with Type 2 diabetes (X)	TOC correlated negatively with fasting plasma glucose (r = −0.24 for men, p = 0.001; r = −0.19 for women, p = 0.03) and HbA1c (r = −0.16, p = 0.03; r = −0.27, p =0.002). TOC correlated with total adiponectin in women (r = 0.30, p = 0.0003)	[26]
Fernandez-Real et al. (2009)	149 nondiabetic men (X) and 46 nondiabetic men and women (I)	Serum TOC correlated with insulin sensitivity (r = 0.23, p = 0.006) and total adiponectin (r = 0.19, p = 0.02). TOC was increased by dietary weight loss (16.8% of bodyweight) or weight loss (8.7%) and exercise	[27]
Pittas et al. (2009)	380 men and women (X), 198 (L), 5% with diabetes	Serum TOC inversely correlated with fasting glucose (β = −1.16, p = 0.01), insulin (β = −0.32, p = 0.006) and IR (β = −0.12, p = 0.002). Higher TOC was associated with a lower rise in fasting glucose over 3 years (β = −0.89; p = 0.03)	[28]
Saleem et al. (2010)	2493 men and women (X)	Serum TOC inversely correlated with BMI, fasting glucose, IR and leptin, and positively correlated with adiponectin (p < 0.001 for each variable). Higher TOC was associated with reduced odds of metabolic syndrome (highest vs lowest quartile OR: 0.33, 95% CI: 0.23–0.46 in African–Americans; OR: 0.43, 95% CI: 0.31–0.63 in non-Hispanic white individuals)	[29]
Yeap et al. (2010)	2765 older men with metabolic syndrome present in 797 (28.8%; X)	TOC level was inversely associated with waist circumference, glucose, triglyceride levels and IR (all p < 0.001), and was lower in men with metabolic syndrome (20.1 vs 21.4 µg/l; p = 0.002). OR (95% CI) for metabolic syndrome was 2.39 (1.71–3.35) for men with TOC <13.25 µg/l and 1.51 (1.07–2.13) for men with TOC 13.25–16.55 µg/l compared with men with TOC ≥30 µg/l	[30]

CI: Confidence interval; HbA1c: Glycated hemoglobin; I: Interventional study; IR: Insulin resistance; L: Longitudinal study; OR: Odds ratio; TOC: Total osteocalcin; X: Cross-sectional analysis.

Table 2. Studies of undercarboxylated osteocalcin, insulin sensitivity and diabetes control in humans.
Study (year)	Study (type)	Results	Ref.
Hwang et al. (2009)	199 men (X)	Higher ucOC level associated with greater insulin sensitivity (highest vs lowest tertile: HOMA-B 81 vs 65%, p < 0.05)	[31]
Shea et al. (2009)	348 nondiabetic men and women (M = 142, F = 206; X, L)	Lower total and carboxylated osteocalcin levels (not ucOC) associated with IR (p = 0.006 and p = 0.02, respectively), association attenuated by adjustment for adiponectin. Higher carboxylated osteocalcin level at baseline predicted less change in IR at 3 years, lower % ucOC predicted greater increase in IR	[32]
Kanazawa et al. (2009)	50 men and women with poorly controlled Type 2 diabetes (L)	After 1 month of improved glycemic control, TOC level increased (+1.9 µg/l, p < 0.001) and the ratio of ucOC/TOC decreased (-0.15, p < 0.01)	[33]
Kanazawa et al. (2011)	180 men and 109 postmenopausal women with Type 2 diabetes (X)	In adjusted analyses, log (ucOC) was inversely correlated with fasting glucose (β = −0.32, p < 0.001) and HbA1c (β = −0.22, p = 0.17) in men. No corresponding associations of ucOC were seen in postmenopausal women	[34]

B: β-cell function; F: Female; HbA1c: Glycated hemoglobin; HOMA: Homeostasis model assessment; IR: Insulin resistance; L: Longitudinal study; M: Male; ucOC: Undercarboxylated osteocalcin; X: Cross-sectional.

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