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. 2009 Nov;90(5):1230-5.
doi: 10.3945/ajcn.2009.28151. Epub 2009 Sep 23.

Gamma-carboxylation of Osteocalcin and Insulin Resistance in Older Men and Women

Free PMC article

Gamma-carboxylation of Osteocalcin and Insulin Resistance in Older Men and Women

M Kyla Shea et al. Am J Clin Nutr. .
Free PMC article


Background: The skeletal protein osteocalcin is gamma-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 as NCT00183001.


Mean (±SD) homeostasis model assessment of insulin resistance (HOMA-IR) according to tertiles of (A) uncarboxylated osteocalcin (OC), (B) percentage uncarboxylated OC, (C) total OC, and (D) carboxylated OC in men and women. *P for trend on the basis of ANCOVA and adjusted for age, sex, race, Physical Activity Score for the Elderly, smoking, serum 25-hydroxyvitamin D, and percentage body fat. ‖,¶Tertiles with different superscripts are significantly different, P < 0.05 (Tukey’s honestly significant difference adjustment for multiple comparisons).

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