Osteocalcin: An Endocrine Link Between Bone and Glucose Metabolism

Bu B Yeap

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

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 or pharmacological interventions can reduce insulin resistance and risk of progression to Type 2 diabetes, but limited resources and drug safety concerns are barriers to providing the required intensive therapy to large numbers of people over long periods of time.^[12,13] Together, diabetes and CVD represent an ever-increasing burden of morbidity and premature mortality consuming substantial healthcare resources.^[14,15] Improved understanding of the pathophysiology of insulin resistance and its relationship with CVD would help to identify those at the highest risk of poorer health outcomes and provide a foundation for developing novel preventative or therapeutic approaches to preserving health.

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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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