Gamma-carboxylation of osteocalcin and insulin resistance in older men and women.

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 clinicaltrials.gov as NCT00183001.