Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Recent animal studies have demonstrated that undercarboxylated osteocalcin upregulates insulin secretion via osteoblast-insulin signaling. However, it remains unclear whether such a pathway exists in humans. This study showed that serum undercarboxylated osteocalcin levels were inversely associated with fasting plasma glucose, hemoglobin A1c, and homeostasis model assessment of insulin resistance (HOMA-IR) levels in community-dwelling elderly Japanese men.

Introduction

Undercarboxylated osteocalcin (ucOC) was reported to increase insulin secretion and improve glucose tolerance via osteoblast-insulin signaling in animal-based studies. Whether this pathway also exists in humans is unknown. We aimed to clarify whether serum ucOC levels are associated with glycemic status and insulin resistance in the general Japanese population.

Methods

We included 2,174 Japanese men (≥65 years) who were able to walk without aid from others and lived at home in four cities of Nara Prefecture. We excluded participants with a history of diseases or medications that affect bone metabolism, other than type 2 diabetes mellitus (T2DM). Fasting plasma glucose, glycated hemoglobin A1c, and HOMA-IR levels were determined as outcome measures.

Results

Of the 1,597 participants included in the analysis, both intact OC (iOC) and ucOC levels showed significant inverse correlations with all outcome measures, even after adjusting for potential confounders. Mean values of outcome measures showed a significant decreasing trend with higher quintiles of iOC or ucOC after adjusting for confounders. This trend remained significant for ucOC quintiles after further adjustment for iOC levels, but was not significant for iOC quintiles after adjusting for ucOC levels. These results were attenuated, but still apparent, after excluding participants receiving drug therapy for T2DM.

Conclusions

Levels of ucOC, but not iOC, were inversely associated with glycemic index and insulin resistance in a population of Japanese men. These findings will need to be confirmed with longitudinal studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan J, Committee of Scientific Advisors of the International Osteoporosis Foundation (2000) The use of biochemical markers of bone turnover in osteoporosis. Osteoporos Int 11(Suppl 6):S2–17

    Article  PubMed  Google Scholar 

  2. Christiansen C, Riis BJ, Rodbro P (1990) Screening procedure for women at risk of developing postmenopausal osteoporosis. Osteoporos Int 1:35–40

    Article  PubMed  CAS  Google Scholar 

  3. Iki M, Morita A, Ikeda Y, Sato Y, Akiba T, Matsumoto T, Nishino H, Kagamimori S, Kagawa Y, Yoneshima H, JPOS Study Group (2006) Biochemical markers of bone turnover predict bone loss in perimenopausal women but not in postmenopausal women—the Japanese Population-based Osteoporosis (JPOS) Cohort Study. Osteoporos Int 17:1086–1095

    Article  PubMed  CAS  Google Scholar 

  4. Garnero P, Sornay-Rendu E, Duboeuf F, Delmas PD (1999) Markers of bone turnover predict postmenopausal forearm bone loss over 4 years: the OFELY study. J Bone Miner Res 14:1614–1621

    Article  PubMed  CAS  Google Scholar 

  5. Luukinen H, Käkönen SM, Pettersson K, Koski K, Laippala P, Lövgren T, Kivelä SL, Väänänen HK (2000) Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin. J Bone Miner Res 15:2473–2478

    Article  PubMed  CAS  Google Scholar 

  6. Sarkar S, Reginster JY, Crans GG, Diez-Perez A, Pinette KV, Delmas PD (2004) Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res 19:394–401

    Article  PubMed  Google Scholar 

  7. Inukai T, Fujiwara Y, Tayama K, Aso Y, Takemura Y (1997) Alterations in serum levels of 1 alpha 25(OH)2 D3 and osteocalcin in patients with early diabetic nephropathy. Diab Res Clin Pract 38:53–59

    Article  CAS  Google Scholar 

  8. Akin O, Göl K, Aktürk M, Erkaya S (2003) Evaluation of bone turnover in postmenopausal patients with type 2 diabetes mellitus using biochemical markers and bone mineral density measurements. Gynecol Endocrinol 17:19–29

    PubMed  CAS  Google Scholar 

  9. Dobnig H, Piswanger-Sölkner JC, Roth M, Obermayer-Pietsch B, Tiran A, Strele A, Maier E, Maritschnegg P, Sieberer C, Fahrleitner-Pammer A (2006) Type 2 diabetes mellitus in nursing home patients: effects on bone turnover, bone mass, and fracture risk. J Clin Endocrinol Metab 91:3355–3363

    Article  PubMed  CAS  Google Scholar 

  10. Im JA, Yu BP, Jeon JY, Kim SH (2008) Relationship between osteocalcin and glucose metabolism in postmenopausal women. Clin Chim Acta 396:66–69

    Article  PubMed  CAS  Google Scholar 

  11. Zhou M, Ma X, Li H, Pan X, Tang J, Gao Y, Hou X, Lu H, Bao Y, Jia W (2009) Serum osteocalcin concentrations in relation to glucose and lipid metabolism in Chinese individuals. Eur J Endocrinol 161:723–729

    Article  PubMed  CAS  Google Scholar 

  12. Okazaki R, Totsuka Y, Hamano K, Ajima M, Miura M, Hirota Y, Hata K, Fukumoto S, Matsumoto T (1997) Metabolic improvement of poorly controlled noninsulin-dependent diabetes mellitus decreases bone turnover. J Clin Endocrinol Metab 82:2915–2920

    Article  PubMed  CAS  Google Scholar 

  13. Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T (2009) Adiponectin is associated with changes in bone markers during glycemic control in type 2 diabetes mellitus. J Clin Endocrinol Metab 94:3031–3037

    Article  PubMed  CAS  Google Scholar 

  14. Rosato MT, Schneider SH, Shapses SA (1998) Bone turnover and insulin-like growth factor I levels increase after improved glycemic control in noninsulin-dependent diabetes mellitus. Calcif Tissue Int 63:107–111

    Article  PubMed  CAS  Google Scholar 

  15. Sayinalp S, Gedik O, Koray Z (1995) Increasing serum osteocalcin after glycemic control in diabetic men. Calcif Tissue Int 57:422–425

    Article  PubMed  CAS  Google Scholar 

  16. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130:456–469

    Article  PubMed  CAS  Google Scholar 

  17. Ferron M, Hinoi E, Karsenty G, Ducy P (2008) Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci USA 105:5266–5270

    Article  PubMed  CAS  Google Scholar 

  18. Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Kurioka S, Yano S, Sugimoto T (2009) Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes mellitus. J Clin Endocrinol Metab 94:45–49

    Article  PubMed  CAS  Google Scholar 

  19. Pittas AG, Harris SS, Eliades M, Stark P, Dawson-Hughes B (2009) Association between serum osteocalcin and markers of metabolic phenotype. J Clin Endocrinol Metab 94:827–832

    Article  PubMed  CAS  Google Scholar 

  20. Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U, Mellström D (2009) Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Miner Res 24:785–791

    Article  PubMed  CAS  Google Scholar 

  21. Yeap BB, Chubb SA, Flicker L, McCaul KA, Ebeling PR, Beilby JP, Norman PE (2010) 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

    Article  PubMed  CAS  Google Scholar 

  22. Shea MK, Gundberg CM, Meigs JB, Dallal GE, Saltzman E, Yoshida M, Jacques PF, Booth SL (2009) γ-carboxylation of osteocalcin and insulin resistance in older men and women. Am J Clin Nutr 90:1230–1235

    Article  PubMed  CAS  Google Scholar 

  23. Hwang YC, Jeong IK, Ahn KJ, Chung HY (2009) The uncarboxylated form of osteocalcin is associated with improved glucose tolerance and enhanced beta-cell function in middle-aged male subjects. Diab Metab Res Rev 25:768–772

    Article  CAS  Google Scholar 

  24. Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T (2010) Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus. Osteoporos Int. doi:10.1007/s00198-101-1184-7

    Google Scholar 

  25. Iki M, Fujita Y, Tamaki J, Kouda K, Yura A, Kadowaki E, Sato Y, Moon JS, Okamoto N, Kurumatani N, Study Group for Functioning Capacity and Quality of Life in Elderly Japanese (Fujiwara-kyo Study Group) (2009) Design and baseline characteristics of a prospective cohort study for determinants of osteoporotic fracture in community-dwelling elderly Japanese men: the Fujiwara-kyo osteoporosis risk in men (FORMEN) study. BMC Musculoskelet Disord 10:165

    Article  PubMed  Google Scholar 

  26. Ikeda Y, Iki M, Morita A, Kajita E, Kagamimori S, Kagawa Y, Yoneshima H (2006) Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study. J Nutr 136:1323–1328

    PubMed  CAS  Google Scholar 

  27. Craig CL, Marshall AL, Sjostrom M, Bauman AE, Booth ML, Ainsworth BE, Pratt M, Ekelund U, Yngve A, Sallis JF, Oja P (2003) International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc 35:1381–1395

    Article  PubMed  Google Scholar 

  28. American Diabetes Association (2010) Diagnosis and classification of diabetes mellitus. Diab Care 33(Suppl 1):S62–S69

    Article  Google Scholar 

  29. Seino Y, Nanjo K, Tajima N, Kadowaki T, Kasiwaki A, Araki E, Ito C, Inagaki N, Iwamoto Y, Kasuga M, Hanafusa T, Naneda K, Ueki K, Japan Diabetes Society Committee for the Classification and Diagnostic Criteria of Diabetes Mellitus (2010) Committee Report. J Jpn Diabetes Soc 53:450–465, in Japanese

    Google Scholar 

  30. Kashiwagi A, Kadowaki T, Haneda K, Nawata H, Ito H, Tominaga M, Oikawa S, Noda M, Kawamura T, Sanke T, Namba M, Hasiramoto M, Sasahara T, Nishio Y, Takei I, Umemoto M, Kuwa K, Murakami M, Oguri T, Committee for Standardization of Diabetes-related Laboratory Measurements (2009) The Japanese deal to world-wide standardization of the hemoglobin A1c measurement. J Jpn Diabetes Soc 52:811–818, in Japanese

    CAS  Google Scholar 

  31. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419

    Article  PubMed  CAS  Google Scholar 

  32. Kawaguchi H, Matsumoto T, Kurokawa T, Orimo H, Mizunashi K, Takuwa Y, Niimi H, Shiraki M, Ohara T, Shishiba Y, Tsuchiya Y, Takahshi H, Takatsuki K, Seino Y, Morii H, Fujita T, Okamoto S, Ogata E (1990) Serum levels of BGP determined by two-site immunoradiometric assay (IRMA) using monoclonal antibodies. Clin Endocrinol 38:1291–1296 (in Japanese)

    Google Scholar 

  33. Nishimura J, Arai N, Tohmatsu J (2007) Measurement of serum undercarboxylated osteocalcin by electrochemiluminescence immunoassay with the “Picolumi ucOC” kit. Igaku to Yakugaku 57:523–535 (in Japanese)

    CAS  Google Scholar 

  34. Ishizawa Y, Inaba M, Ishii K, Yamashita H, Miki T, Goto H, Yamada S, Chaki O, Kurasawa K, Mochiduki Y (2005) Evaluation of newly developed kit for measurement of bone-specific tartrate-resistant acid phosphatase in blood. Igaku to Yakugaku 54:709–717 (in Japanese)

    Google Scholar 

  35. Fulzele K, Riddle RC, Digirolamo DJ, Cao X, Wan C, Chen D, Faugere MC, Aja S, Hussain MA, Brüning JC, Clemens TL (2010) Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142:309–319

    Article  PubMed  CAS  Google Scholar 

  36. Berkner KL (2005) The vitamin K-dependent carboxylase. Annu Rev Nutr 25:127–149

    Article  PubMed  CAS  Google Scholar 

  37. Yoshida M, Jacques PF, Meigs JB, Saltzman E, Shea MK, Gundberg C, Dawson-Hughes B, Dallal G, Booth SL (2008) Effect of vitamin K supplementation on insulin resistance in older men and women. Diab Care 31:2092–2096

    Article  CAS  Google Scholar 

  38. Yoshida M, Booth SL, Meigs JB, Saltzman E, Jacques PF (2008) Phylloquinone intake, insulin sensitivity, and glycemic status in men and women. Am J Clin Nutr 88:210–215

    PubMed  CAS  Google Scholar 

  39. Bouillon R, Bex M, Van Herck E, Laureys J, Dooms L, Lesaffre E, Ravussin E (1995) Influence of age, sex, and insulin on osteoblast function: osteoblast dysfunction in diabetes mellitus. J Clin Endocrinol Metab 80:1194–1202

    Article  PubMed  CAS  Google Scholar 

  40. Lumachi F, Camozzi V, Tombolan V, Luisetto G (2009) Bone mineral density, osteocalcin, and bone-specific alkaline phosphatase in patients with insulin-dependent diabetes mellitus. Ann NY Acad Sci 1173(Suppl 1):E64–67

    Article  PubMed  CAS  Google Scholar 

  41. Danielson KK, Elliott ME, LeCaire T, Binkley N, Palta M (2010) Poor glycemic control is associated with low BMD detected in premenopausal women with type 1 diabetes. Osteoporos Int 20:923–933

    Article  Google Scholar 

  42. Maggio AB, Ferrari S, Kraenzlin M, Marchand LM, Schwitzgebel V, Beghetti M, Rizzoli R, Farpour-Lambert NJ (2010) Decreased bone turnover in children and adolescents with well controlled type 1 diabetes. J Pediatr Endocrinol Metab 23:697–707

    Article  PubMed  CAS  Google Scholar 

  43. Botolin S, McCabe LR (2006) Chronic hyperglycemia modulates osteoblast gene expression through osmotic and non-osmotic pathways. J Cell Biochem 99:411–424

    Article  PubMed  CAS  Google Scholar 

  44. Balint E, Szabo P, Marshall CF, Sprague SM (2001) Glucose-induced inhibition of in vitro bone mineralization. Bone 28:21–28

    Article  PubMed  CAS  Google Scholar 

  45. Gundberg CM, Nieman SD, Abrams S, Rosen H (1998) Vitamin K status and bone health: an analysis of methods for determination of undercarboxylated osteocalcin. J Clin Endocrinol Metab 83:3258–3266

    Article  PubMed  CAS  Google Scholar 

  46. Grey A (2008) Skeletal consequences of thiazolidinedione therapy. Osteoporos Int 19:129–137

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The Fujiwara-kyo Study Group (chaired by Norio Kurumatani with Nozomi Okamoto as secretary general) comprising Nobuko Amano, Yuki Fujita, Akihiro Harano, Kan Hazaki, Masayuki Iki, Junko Iwamoto, Akira Minematsu, Masayuki Morikawa, Keigo Saeki, Noriyuki Tanaka, Kimiko Tomioka, and Motokazu Yanagi performed most non-skeletal measures in the present study and provided the data to the FORMEN Study. The FORMEN Study was supported by Grants-in-Aid for Scientific Research (#20659103: 2008–2009, #21390210: 2009–2011, #20590661: 2008–2010) from the Japanese Society for the Promotion of Science; a Grant-in-Aid for Young Scientists (#20790451: 2008–2010) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology; a grant-in-aid for Study on Milk Nutrition (2008) from the Japan Dairy Association; a grant (2007) from the Foundation for Total Health Promotion; a St. Luke’s Life Science Institute Grant-in-Aid for Epidemiological Research (2008); and a grant (2008) from the Physical Fitness Research Institute, MEIJIYASUDA Life Foundation of Health and Welfare. The funding bodies and collaborators had no role in designing the study, in analyzing and interpreting the data, in writing the manuscript, or in deciding where to submit the manuscript for publication. The authors acknowledge Eisai Co., Ltd. (Tokyo, Japan) and Sanko Junyaku Co., Ltd. (Tokyo, Japan) for their assistance in measuring serum ucOC, and SRL Inc. (Tokyo, Japan) for their technical assistance in laboratory measurements.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Public Health, Kinki University Faculty of Medicine, 377-2 Oono-higashi, Osaka-Sayama, Osaka, 589-8511, Japan

    M. Iki, J. Tamaki, Y. Fujita, K. Kouda, A. Yura & E. Kadowaki

  2. Department of Human Life, Jin-ai University, 3-1-1 Ohdecho, Echizen, Fukui, 915-8586, Japan

    Y. Sato

  3. Faculty of Human Sciences, Taisei Gakuin University, 1060-1 Hirao, Mihara-ku, Sakai, Osaka, 587-8555, Japan

    J. S. Moon

  4. Department of Community Health and Epidemiology, Nara Medical University School of Medicine, 840 Shijocho, Kashihara, Nara, 634-8521, Japan

    K. Tomioka, N. Okamoto & N. Kurumatani

Authors
  1. M. Iki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Tamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y. Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. Kouda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Yura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. Kadowaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y. Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. S. Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K. Tomioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. N. Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. N. Kurumatani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Iki.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iki, M., Tamaki, J., Fujita, Y. 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). https://doi.org/10.1007/s00198-011-1600-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-011-1600-7

Keywords

Search

Navigation