Table 1: Human Epidemiological studies linking osteocalcin with energy metabolism, fertility and vascular calcification
Endpoint:
Diabetic parameters (insulin
sensitivity, -cell function,
insulin secretion, blood
glucose levels (BLG))
Study
Chen et al 1
Wang et al2
Levinger et al3
Levinger et al4
Kanazawa et al5
Kanazawa et al6
Kindblom et al7
Lu et al8
Gower et al9
Pollock et al10
Yeap et al11
Iki et al12
Hwang et al13
Furusyo et al14
Thrailkill et al15
Poomthavorn16 et al
Correlation with osteocalcin (total: tOCN and undercarboxylated: ucOCN)
Fasting and 30 min post oGTT BGL negatively correlated with tOCN
30 min post oGTT BGL negatively correlated with ucOCN
Insulin sensitivity (HOMA-IR) negatively correlated with tOCN
Insulin sensitivity (HOMA-IR) not correlated with osteocalcin
Fasting BGL negatively correlated with tOCN in males
Fasting BGL negatively correlated with ucOCN in all patients
BGL post exercise negatively correlated with ucOCN
Insulin sensitivity is positively associated with ucOCN
Insulin sensitivity (HOMA-IR) negatively correlated with tOCN in T2DM patients
-cell function positively correlated with tOCN in T2DM patients
Fasting BGL negatively correlated with ucOCN in male T2DM patients
BGL negatively correlated with tOCN
Serum insulin moderately associated (positively) with tOCN
Non-diabetic patients had significantly higher serum tOCN than diabetic patients
BGL not associated with tOCN or ucOCN across three generations of non-diabetic women
Skeletal muscle insulin sensitivity positively associated with tOCN
Heptic insulin sensitivity not associated with tOCN
-cell function positively associated with ucOCN in patients with impaired glucose function
-cell function positively associated with ucOCN in overweight children with prediabetes
Fasting BGL inversely associated with tOCN
Insulin sensitivity (HOMA2-IR) inversely associated with tOCN
Overall risk of metabolic syndrome negatively correlated with tOCN
Fasting BGL inversely associated with ucOCN in elderly Japanese men
Insulin sensitivity (HOMA-IR) negatively correlated with ucOCN in elderly Japanese men
Fasting BGL inversely associated with ucOCN in middle-aged male subjects
Glucose tolerance inversely associated with ucOCN in middle-aged male subjects
-cell function positively associated with ucOCN in middle-aged male subjects
Fasting BGL inversely associated with ucOCN
Insulin secretion positively correlated with ucOCN in Type 1 diabetic patients
No association between glucose metabolism and tOCN or ucOCN in obese children
Pepene CE
17
Schwetz et al18
Garanty-Bogacka et al19
Bulló et al20
Mori et al21
Shea et al22
Diaz-Lopez et al23
Lucey et al24
Prats-Puig et al25
Pittas et al26
Glycated hemoglobin
(HbA1c)
Polgreen et al27
Wang et al2
Kanazawa et al5
Kanazawa et al6
Kanazawa et al28
Iki et al12
Furusyo et al14
Thrailkill et al15
Garanty-Bogacka et al19
Insulin secretion positively correlated with tOCN and ucOCN in prediabetic and diabetic children
Serum insulin not associated with tOCN in lean or overweight women with PCOS
Serum insulin positively associated with ucOCN in lean but not overweight PCOS patients
Insulin resistant PCOS patients have lower tOCN and ucOCN than non insulin resistant PCOS
patients
Insulin resistance(HOMA-IR) inversely correlated with tOCN in obese children and adolescents
Increased -cell function was positively associated with increases in tOCN in elderly males
Improved insulin sensitivity (HOMA-IR) was positively associated with increased ucOCN in elderly
males
Higher fasting insulin levels were positively associated with baseline tOCN in elderly men
Insulin resistance not associated with ucOCN in T2DM patients
Insulin resistance(HOMA-IR) not associated with ucOCN in elderly patients
Insulin resistance(HOMA-IR) inversely associated with tOCN in elderly patients
Insulin resistance(HOMA-IR) not associated with ucOCN in patients at risk for cardiovascular
disease
Insulin resistance(HOMA-IR) inversely associated with tOCN in patients at risk for cardiovascular
disease
Fasting BGL inversely associated with tOCN in young overweight women with low baseline OCN
Insulin sensitivity (HOMA-IR) inversely associated with tOCN in young overweight women with
low baseline OCN
Insulin secretion positively associated with higher ucOCN/cOCN ratio in healthy lean children
Fasting BGL inversely associated with tOCN in adults 65 years and older
Fasting insulin inversely associated with tOCN in adults 65 years and older
Insulin resistance(HOMA-IR) inversely associated with tOCN in adults 65 years and older
No association between insulin resistance and ucOCN or tOCN
HbA1c inversely correlated with tOCN
HbA1c inversely correlated with tOCN in T2DM patients
HbA1c inversely correlated with ucOCN in male T2DM patients
HbA1c inversely correlated with tOCN in T2DM patients
HbA1c inversely correlated with ucOCN in elderly Japanese men
HbA1c inversely correlated with ucOCN
HbA1c inversely correlated with ucOCN in Type 1 diabetic patients
HbA1c inversely correlated with tOCN in obese children and adolescents
Body fat mass (BFM)
Schafer et al. 29
Kanazawa et al5
Kindblom et al7
Yeap et al11
Garanty-Bogacka et al19
Pittas et al26
Polgreen et al27
Body weight (BW)
Schafer et al. 29
Kindblom et al7
Pittas et al26
Polycystic Ovarian Syndrome Pepene CE17
(PCOS)
Schwetz et al18
In overweight children
Pollock et al10
Garanty-Bogacka et al19
Effect of exercise
Adiponectin
Testosterone levels
Levinger et al3
Levinger et al4
Schafer et al. 29
Prats-Puig et al25
Polgreen et al27
Chen et al 1
Kanazawa et al30
Liao et al31
Pepene CE17
BFM inversely correlated with ucOCN
% trunk fat negatively correlated with tOCN in T2DM patients
% trunk fat negatively correlated with ucOCN in male T2DM patients
Visceral/subcutaneous fat ratio negatively correlated with ucOCN in male T2DM patients
BFM inversely correlated with tOCN
Waist circumference inversely associated with tOCN
Waist circumference inversely associated with tOCN in obese children and adolescents
Adiposity markers inversely associated with tOCN in obese children and adolescents
Body fat mass inversely correlated with tOCN in adults 65 years and older
Waist circumference inversely associated with tOCN in young adults
BW inversely correlated with ucOCN
BMI inversely correlated with tOCN
BMI inversely correlated with tOCN in adults 65 years and older
Lean but not overweight women with polycystic ovarian syndrome have higher ucOCN than
controls
Glucose load lowers tOCN and ucOCN in non-insulin resistant PCOS patients but not in insulin
resistant PCOS patients
Overweight children with prediabetes have lower ucOCN than overweight children with
normoglycemia
Insulin resistance, HbA1c, adiposity markers, triglycerides, waist circumference, C-reactive
protein (CRP) negatively correlated with tOCN in obese children and adolescents
Post acute exercise positively correlated with ucOCN
Post acute exercise positively correlated with ucOCN
Adiponectin positively correlated with ucOCN
Adiponectin positively associated with with higher ucOCN/cOCN ratio in healthy but heavy
children
Adiponectin positively correlated with cOCN in young adults
Serum testosterone negatively correlated with tOCN
Serum testosterone positively associated with ucOCN and ucOCN/tOCN ratio in diabetic male
patients
Serum total, free and bioavailable testosterone positively associated with serum osteocalcin
Serum total and free testosterone positively correlated with ucOCN in lean but not obese women
with PCOS
Cholesterol
Chen et al 1
Kanazawa et al28
Garanty-Bogacka et al19
Alfadda32
Vascular calcification
Ogawa-Furuya et al33
Kanazawa et al28
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Total cholesterol negatively correlated with ucOCN
Triglycerides negatively correlated with tOCN
HDL cholesterol positively correlated with tOCN
Triglycerides negatively correlated with tOCN in obese children and adolescents
HDL cholesterol positively correlated with tOCN in obese children and adolescents
Triglycerides negatively correlated with tOCN in patients with Metabolic Syndrome
HDL cholesterol positively correlated with ucOCN in patients with Metabolic Syndrome
Aortic calcification inversely associated with tOCN and ucOCN in male T2DM patients but not
females
Baseline plaque score positively associated with tOCN
Changes in plaque score negatively associated with tOCN
Chen, X., Wu, Y., Liu, L., Tian, H. & Yu, X. Osteocalcin is inversely associated with glucose levels in middle-aged Tibetan men with
different degrees of glucose tolerance. Diabetes/metabolism research and reviews (2013).
Wang, Q., Zhang, B., Xu, Y., Xu, H. & Zhang, N. The Relationship between Serum Osteocalcin Concentration and Glucose Metabolism in
Patients with Type 2 Diabetes Mellitus. Int J Endocrinol 2013, 842598 (2013).
Levinger, I., et al. The effect of acute exercise on undercarboxylated osteocalcin in obese men. Osteoporos Int 22, 1621-1626 (2011).
Levinger, I., et al. The Effect of Acute Exercise on Undercarboxylated Osteocalcin and Insulin Sensitivity in Obese Men. J Bone Miner Res
(2014).
Kanazawa, I., et al. Serum osteocalcin level is positively associated with insulin sensitivity and secretion in patients with type 2 diabetes.
Bone 48, 720-725 (2011).
Kanazawa, I., et al. Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2
diabetes mellitus. Osteoporos Int 22, 187-194 (2011).
Kindblom, J.M., et al. Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Miner Res
24, 785-791 (2009).
Lu, C., et al. Serum osteocalcin is not associated with glucose but is inversely associated with leptin across generations of nondiabetic
women. J Clin Endocrinol Metab 97, 4106-4114 (2012).
Gower, B.A., et al. Associations of total and undercarboxylated osteocalcin with peripheral and hepatic insulin sensitivity and beta-cell
function in overweight adults. J Clin Endocrinol Metab 98, E1173-1180 (2013).
Pollock, N.K., et al. Lower uncarboxylated osteocalcin concentrations in children with prediabetes is associated with beta-cell function. J
Clin Endocrinol Metab 96, E1092-1099 (2011).
11.
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Yeap, B.B., et al. Reduced serum total osteocalcin is associated with metabolic syndrome in older men via waist circumference,
hyperglycemia, and triglyceride levels. Eur J Endocrinol 163, 265-272 (2010).
Iki, M., et al. Serum undercarboxylated osteocalcin levels are inversely associated with glycemic status and insulin resistance in an
elderly Japanese male population: Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Study. Osteoporos Int 23, 761-770 (2012).
Hwang, Y.C., Jeong, I.K., Ahn, K.J. & Chung, H.Y. The uncarboxylated form of osteocalcin is associated with improved glucose tolerance
and enhanced beta-cell function in middle-aged male subjects. Diabetes/metabolism research and reviews 25, 768-772 (2009).
Furusyo, N., et al. The serum undercarboxylated osteocalcin level and the diet of a Japanese population: results from the Kyushu and
Okinawa Population Study (KOPS). Endocrine 43, 635-642 (2013).
Thrailkill, K.M., et al. Determinants of undercarboxylated and carboxylated osteocalcin concentrations in type 1 diabetes. Osteoporos Int
23, 1799-1806 (2012).
Poomthavorn, P., Nantarakchaikul, P., Mahachoklertwattana, P., Chailurkit, L.O. & Khlairit, P. Effects of correction of vitamin D
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Pepene, C.E. Serum under-carboxylated osteocalcin levels in women with polycystic ovary syndrome: weight-dependent relationships
with endocrine and metabolic traits. J Ovarian Res 6, 4 (2013).
Schwetz, V., et al. Osteocalcin levels on oral glucose load in women being investigated for polycystic ovary syndrome. Endocr Pract 20, 514 (2014).
Garanty-Bogacka, B., et al. Association between serum osteocalcin, adiposity and metabolic risk in obese children and adolescents.
Endokrynol Pol 64, 346-352 (2013).
Bullo, M., Moreno-Navarrete, J.M., Fernandez-Real, J.M. & Salas-Salvado, J. Total and undercarboxylated osteocalcin predict changes in
insulin sensitivity and beta cell function in elderly men at high cardiovascular risk. Am J Clin Nutr 95, 249-255 (2012).
Mori, K., et al. Undercarboxylated osteocalcin does not correlate with insulin resistance as assessed by euglycemic hyperinsulinemic
clamp technique in patients with type 2 diabetes mellitus. Diabetology & metabolic syndrome 4, 53 (2012).
Shea, M.K., et al. Gamma-carboxylation of osteocalcin and insulin resistance in older men and women. Am J Clin Nutr 90, 1230-1235
(2009).
Diaz-Lopez, A., et al. Reduced serum concentrations of carboxylated and undercarboxylated osteocalcin are associated with risk of
developing type 2 diabetes mellitus in a high cardiovascular risk population: a nested case-control study. J Clin Endocrinol Metab 98,
4524-4531 (2013).
Lucey, A.J., et al. Young overweight and obese women with lower circulating osteocalcin concentrations exhibit higher insulin resistance
and concentrations of C-reactive protein. Nutrition research (New York, N.Y.) 33, 67-75 (2013).
Prats-Puig, A., et al. Carboxylation of osteocalcin affects its association with metabolic parameters in healthy children. Diabetes care 33,
661-663 (2010).
Pittas, A.G., Harris, S.S., Eliades, M., Stark, P. & Dawson-Hughes, B. Association between serum osteocalcin and markers of metabolic
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Schafer, A.L., et al. Change in Undercarboxylated Osteocalcin Is Associated with Changes in Body Weight, Fat Mass, and Adiponectin:
Parathyroid Hormone (1-84) or Alendronate Therapy in Postmenopausal Women with Osteoporosis (the PaTH Study). Journal of Clinical
Endocrinology & Metabolism 96, E1982-E1989 (2011).
Kanazawa, I., et al. Undercarboxylated osteocalcin is positively associated with free testosterone in male patients with type 2 diabetes
mellitus. Osteoporos Int 24, 1115-1119 (2013).
Liao, M., et al. Role of metabolic factors in the association between osteocalcin and testosterone in Chinese men. J Clin Endocrinol
Metab 98, 3463-3469 (2013).
Alfadda, A.A., Masood, A., Shaik, S.A., Dekhil, H. & Goran, M. Association between Osteocalcin, Metabolic Syndrome, and Cardiovascular
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Ogawa-Furuya, N., Yamaguchi, T., Yamamoto, M., Kanazawa, I. & Sugimoto, T. Serum osteocalcin levels are inversely associated with
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