The major finding of this study was that daily supplementation with 500 μg of phylloquinone for 36 months had a protective effect on progression of insulin resistance in older men.
In an animal study, rats fed a low vitamin K diet had impaired early insulin response and subsequent increased insulin secretion after intravenous administration of glucose (1
). Higher vitamin K intake was cross-sectionally associated with reduced insulin resistance in both men and women in the Framingham Offspring cohort (3
). A metabolic study of young men showed a significant association between vitamin K and post–glucose challenge measures, but not fasting measures (2
). In our study, a beneficial effect of vitamin K supplementation for 36 months was observed using fasting measures of insulin resistance. The effect of this intervention on post–glucose challenge measures of insulin resistance was not tested in our study.
Recent studies proposed that the uncarboxylated form of osteocalcin, a vitamin K–dependent bone protein, may improve insulin sensitivity and increase β-cell insulin secretion partially through the enhancement of β-cell proliferation, energy expenditure, and adiponectin expression in mice (16
). In our study, men receiving vitamin K supplementation had less uncarboxylated osteocalcin than the control group, which does not support the findings of the animal studies. Alternatively, it is plausible that vitamin K may improve insulin sensitivity through suppression of inflammation. In vivo and in vitro studies have shown that vitamin K reduced lipopolysaccharide-induced inflammation (18
). More recently, it was reported that biochemical and dietary measures of vitamin K status were inversely associated with inflammatory markers in an observational study (20
The beneficial effect of vitamin K on insulin resistance was limited to men in this study. However in a recent observational study, the inverse association between vitamin K intake and insulin resistance was observed in men and women (3
). In a previous metabolic study, only young men were studied (2
), and there are no other studies with which to make a comparison. Although adjustment of BMI in the statistical model did not change our finding in women, one potential explanation for this lack of protective effect of vitamin K on insulin resistance in women is the role of adipose tissue in modulating the response to vitamin K supplementation. In our study, overweight or obesity, which are major determinants of insulin resistance (21
), was more prevalent in women who received vitamin K supplementation than in those who did not. Furthermore, there was an inverse association between plasma phylloquinone concentrations and BMI in the women, which is suggestive of an impaired response to vitamin K supplementation. It may be plausible that adipose tissue stores the fat-soluble vitamin K, which may render the vitamin K unavailable for peripheral organs. In the absence of data on the role of adipose tissue in vitamin K metabolism, this suggestion is currently speculative. Alternatively, it is plausible that our study was statistically underpowered to detect statistically significant differences in HOMA-IR in response to vitamin K supplementation among women.
The interpretation of these findings is limited by several factors. First, this study was based on the analyses of data obtained from a study designed to determine the effect of vitamin K supplementation on changes in bone mineral density and vascular calcification in older men and women. Our findings may not be representative of the general population owing to the exclusion criteria of the parent study, and measures presented in this study were not necessarily obtained by optimal techniques. We acknowledge that use of the hyperinsulinemic-euglycemic clamp would have provided a more direct measure of insulin secretion and sensitivity than HOMA-IR, which only provides an indirect estimate of insulin resistance. Likewise, our assessment of body composition was limited to BMI and percent body fat as measured by dual- energy X-ray absorptiometry and did not provide information on regional adiposity. We also had limited statistical power to detect differences in HOMA-IR in response to vitamin K supplementation, which may explain the null findings in women. Finally, most of our participants were Caucasians; thus, our findings need to be examined in other populations.
In summary, 36 months of vitamin K supplementation had a beneficial effect on insulin resistance in older men but not in older women. As the parent study was not designed to test this hypothesis, these findings need to be replicated in a study designed specifically to test the hypothesis that vitamin K plays a protective role in insulin resistance in older adults.