Osteocalcin: the relationship between bone metabolism and glucose homeostasis in diabetes mellitus
Keywords:osteocalcin, bone remodeling biomarkers, insulin secretion, diabetes mellitus, metabolic disorders, fracture risk, review
Recent studies have demonstrated the importance of bone as an endocrine organ that produces biologically active substances, which regulate both local bone metabolism and metabolic functions throughout the body. In the process of bone remodeling (formation/destruction), the active cells secrete specific biomarkers that help detect osteometabolic dysfunction. Among bone hormones, osteocalcin plays an important role as a coordinator of bone modeling processes, energy homeostasis, metabolism of glucose, lipids and minerals. Osteocalcin is a structural protein of the bone matrix, which is synthesized by osteoblasts and enters the bloodstream in the process of bone resorption. The level of osteocalcin in the serum is used as a specific marker of bone formation. Osteocalcin promotes pancreatic β-cell proliferation and insulin secretion, and also affects the insulin sensitivity of peripheral tissues. The inverse association of glycemia with the level of osteocalcin was revealed. Patients with type 2 diabetes mellitus usually have normal or even slightly elevated bone mineral density compared to age-appropriate controls. Decreased bone quality and increased risk of fractures are associated with changes in bone microarchitecture and local humoral environment. An imbalance in osteoblast/osteoclast activity may be due to oxidative stress and the accumulation of glycosylation end products, which contributes to chronic inflammation and bone resorbtion in patients with diabetes. It is shown that the level of osteocalcin in the blood serum is significantly reduced compared to healthy controls, both in patients with type 1 diabetes mellitus and, especially, in type 2 diabetes mellitus. Given the importance of developing new approaches to the diagnosis and correction of metabolic disorders in diabetic patients, the study of the influence of bone hormones on hormonal and metabolic parameters and bone status, including the risk of fractures, remains relevant in modern diabetology.
Kajimura D, Lee HW, Riley KJ, et al. Adiponectin regulates bone mass via opposite central and peripheral mechanisms through FoxO1. Cell Metab. 2013 Jun 4;17(6):901-915. doi: 10.1016/j.cmet.2013.04.009.
Abarrategi A, Mian SA, Passaro D, Rouault-Pierre K, Grey W, Bonnet D. Modeling the human bone marrow niche in mice: From host bone marrow engraftment to bioengineering approaches. J Exp Med. 2018 Mar 5;215(3):729-743. doi: 10.1084/jem.20172139.
Cai X, Xing J, Long C, Peng Q, Humphrey M. DOK3 modulates bone remodeling by negatively regulating osteoclastogenesis and positively regulating osteoblastogenesis. J Bone Min Res. 2017;32(11):2207-2218. doi: 10.1002/jbmr.3205.
Napoli N, Chandran M, Pierroz DD, Abrahamsen B, Schwartz AV, Ferrari SL; IOF Bone and Diabetes Working Group. Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol. 2017 Apr;13(4):208-219. doi: 10.1038/nrendo.2016.153.
Vasikaran S, Eastell R, Bruyère O, et al; IOF-IFCC Bone Marker Standards Working Group. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011 Feb;22(2):391-420. doi: 10.1007/s00198-010-1501-1.
Gupte AA, Sabek OM, Fraga D, et al. Osteocalcin protects against nonalcoholic steatohepatitis in a mouse model of metabolic syndrome. Endocrinology. 2014 Dec;155(12):4697-705. doi: 10.1210/en.2014-1430.
Saleem U, Mosley TH Jr, Kullo IJ. Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of metabolic syndrome. Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):1474-8. doi: 10.1161/ATVBAHA.110.204859.
Wei J, Ferron M, Clarke CJ, et al. Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation. J Clin Invest. 2014 Apr;124(4):1-13. doi: 10.1172/JCI72323.
Yeap BB, Alfonso H, Chubb SA, et al. Higher serum undercarboxylated osteocalcin and other bone turnover markers are associated with reduced diabetes risk and lower estradiol concentrations in older men. J Clin Endocrinol Metab. 2015 Jan;100(1):63-71. doi: 10.1210/jc.2014-3019.
González-García ZM, Kullo IJ, Coletta DK, Mandarino LJ, Shaibi GQ. Osteocalcin and type 2 diabetes risk in Latinos: a life course approach. Am J Hum Biol. 2015 Nov-Dec;27(6):859-61. doi: 10.1002/ajhb.22745.
Kunutsor SK, Apekey TA, Laukkanen JA. Association of serum total osteocalcin with type 2 diabetes and intermediate metabolic phenotypes: systematic review and meta-analysis of observational evidence. Eur J Epidemiol. 2015 Aug;30(8):599-614. doi: 10.1007/s10654-015-0058-x.
Confavreux CB, Szulc P, Casey R, Varennes A, Goudable J, Chapurlat RD. Lower serum osteocalcin is associated with more severe metabolic syndrome in elderly men from the MINOS cohort. Eur J Endocrinol. 2014 Aug;171(2):275-83. doi: 10.1530/EJE-13-0567.
Uchida T, Nakamura T, Hashimoto N, et al. Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. Nat Med. 2005 Feb;11(2):175-82. doi: 10.1038/nm1187.
Takahashi A, Mulati M, Saito M, et al. Loss of cyclin-dependent kinase 1 impairs bone formation, but does not affect the bone-anabolic effects of parathyroid hormone. J Biol Chem. 2018 Dec 14;293(50):19387-19399. doi: 10.1074/jbc.RA118.004834.
Bao YQ, Zhou M, Zhou J, et al. Relationship between serum osteocalcin and glycaemic variability in Type 2 diabetes. Clin Exp Pharmacol Physiol. 2011 Jan;38(1):50-4. doi: 10.1111/j.1440-1681.2010.05463.x.
Ehnert S, Rinderknecht H, Aspera-Werz RH, Häussling V, Nussler AK. Use of in vitro bone models to screen for altered bone metabolism, osteopathies, and fracture healing: challenges of complex models. Arch Toxicol. 2020 Dec;94(12):3937-3958. doi: 10.1007/s00204-020-02906-z.
Viljakainen H, Ivaska KK, Paldánius P, et al. Suppressed bone turnover in obesity: a link to energy metabolism? A case-control study. J Clin Endocrinol Metab. 2014 Jun;99(6):2155-63. doi: 10.1210/jc.2013-3097.
Tonks KT, White CP, Center JR, Samocha-Bonet D, Greenfield JR. Bone Turnover Is Suppressed in Insulin Resistance, Independent of Adiposity. J Clin Endocrinol Metab. 2017 Apr 1;102(4):1112-1121. doi: 10.1210/jc.2016-3282.
McCarthy AD, Etcheverry SB, Bruzzone L, Lettieri G, Barrio DA, Cortizo AM. Non-enzymatic glycosylation of a type I collagen matrix: effects on osteoblastic development and oxidative stress. BMC Cell Biol. 2001;2:16. doi: 10.1186/1471-2121-2-16.
Siris ES, Adler R, Bilezikian J, et al. The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int. 2014 May;25(5):1439-43. doi: 10.1007/s00198-014-2655-z.
Burghardt AJ, Issever AS, Schwartz AV, et al. High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010 Nov;95(11):5045-55. doi: 10.1210/jc.2010-0226.
Ishii S, Cauley JA, Crandall CJ, et al. Diabetes and femoral neck strength: findings from the Hip Strength Across the Menopausal Transition Study. J Clin Endocrinol Metab. 2012 Jan;97(1):190-7. doi: 10.1210/jc.2011-1883.
Urano T, Shiraki M, Kuroda T, et al. Low serum osteocalcin concentration is associated with incident type 2 diabetes mellitus in Japanese women. J Bone Miner Metab. 2018 Jul;36(4):470-477. doi: 10.1007/s00774-017-0857-0.
Takashi Y, Ishizu M, Mori H, et al. Circulating osteocalcin as a bone-derived hormone is inversely correlated with body fat in patients with type 1 diabetes. PLoS One. 2019 May 3;14(5):e0216416. doi: 10.1371/journal.pone.0216416.
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