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-Carboxylation of osteocalcin and insulin resistance in older men and women^1,2,3,4

¹ From the USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (MKS, ES, GED, PFJ, MY, and SLB); the Department of Orthopaedics, Yale University School of Medicine, New Haven, CT (CMG); and the General Medicine Division and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (JBM).

² Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the US Department of Agriculture.

³ Supported by the USDA Agricultural Research Service under cooperative agreement no. 58-1950-7-707, the National Institutes of Health (grant nos. AG14759, HL69272, AR38460, and T32 HL69772-01A1), and the American Heart Association (grant no. 0515605T). JBM was supported by National Institute of Diabetes and Digestive and Kidney Diseases (grant no. K24 DK080140).

⁴ Address correspondence to SL Booth, USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA 02111. E-mail: sarah.booth{at}tufts.edu.

Background: The skeletal protein osteocalcin is -carboxylated by vitamin K. High serum uncarboxylated osteocalcin reflects low vitamin K status. In vitro and animal studies indicate that high uncarboxylated osteocalcin is associated with reduced insulin resistance. However, associations between osteocalcin and measures of insulin resistance in humans are less clear.

Objective: Our aim was to examine cross-sectional and longitudinal associations between circulating forms of osteocalcin (total, uncarboxylated, and carboxylated) and insulin resistance in older men and women.

Design: Cross-sectional associations between serum measures of total osteocalcin, carboxylated osteocalcin, and uncarboxylated osteocalcin and insulin resistance were examined in 348 nondiabetic men and women (mean age: 68 y; 58% female) by using the homeostasis model assessment of insulin resistance (HOMA-IR). Associations between each form of osteocalcin at baseline and 3-y change in HOMA-IR were examined in 162 adults (mean age: 69 y; 63% female) who did not receive vitamin K supplementation.

Results: Lower circulating uncarboxylated osteocalcin was not associated with higher HOMA-IR at baseline or at 3-y follow-up. Those in the lowest tertiles of total osteocalcin and carboxylated osteocalcin at baseline had higher baseline HOMA-IR (P = 0.006 and P = 0.02, respectively). The concentration of carboxylated osteocalcin at baseline was inversely associated with a 3-y change in HOMA-IR (P = 0.002).

Conclusions: In older adults, circulating uncarboxylated osteocalcin was not associated with insulin resistance. In contrast, elevated carboxylated osteocalcin and total osteocalcin were associated with lower insulin resistance, which supports a potential link between skeletal physiology and insulin resistance in humans. The role of vitamin K status in this association remains unclear and merits further investigation. This trial is registered at clinicaltrials.gov as NCT00183001.