Association of vitamin K with insulin resistance and body composition.
evidence supports an association between the skeleton and energy metabolism. These
interactions are mediated by a variety of hormones, cytokines and nutrients. Osteocalcin
(OC), a vitamin K-dependent protein, may have a role in the regulation of glucose
metabolism and adiposity. To evaluate this role of OC in humans, one also needs to take
into consideration the effect of... read morevitamin K (VK). Because OC depends on VK for
carboxylation, and thus function, the percentage of OC that is not carboxylated (%ucOC)
has been used as a measure of VK status, with lower %ucOC representing higher
circulating VK. In mice, the uncarboxylated form of OC (ucOC) is active in glucose
metabolism and body composition. The data in humans are equivocal. Despite its
dependence on VK, very few human studies examining the association between OC and
insulin resistance (IR) or diabetes risk have taken VK status into account. To address
this shortcoming, we examined the associations between VK, OC, IR and body weight in
three well-characterized cohorts. Our specific aims were: 1: To determine if intentional
weight loss is associated with a decrease in the carboxylation of OC in post-menopausal
women when VK intake is held constant, 2: To determine if increased carboxylation of OC
through VK supplementation is associated with lower markers of IR in younger and older
men and women, and 3: To determine the cross-sectional associations between circulating
VK concentrations and markers of IR in older men and women. For specific aim 1, data
were obtained from healthy post-menopausal women (n=71) undergoing a twenty-week weight
loss program. Measures of body weight, body fat percentage, and serum OC forms were
assessed before and after the intervention. All participants lost weight (-10.9±3.9
kg) and body fat (-3.9±2.0 %), but their weight-loss was not associated with
changes in any form of serum OC (all p>0.31). For specific aim 2, data were obtained
from 42 healthy younger (age= 18-40y) and older (age= ±65y) men and women who
received a VK supplement for 21 days. Circulating measures of OC, VK, and markers of IR
were assessed before and after supplementation. With VK supplementation, circulating
uncarboxylated OC (ucOC) decreased (pre= 4.4±3.0, post= 1.1±2.1 ng/mL,
p<0.001) with no concomitant change in the homeostatic model of insulin resistance
(HOMA-IR, p=0.78). No significant correlation between any form of OC (total OC (tOC),
ucOC or %ucOC) and HOMA-IR was observed (p>0.12). For specific aim 3, data were
obtained from a large multi-center cohort of community dwelling older men and women (n=
932). Circulating measures of VK and IR were measured. Serum lipids were also measured
since VK is transported on triglyceride-rich lipoproteins. A trend for higher plasma VK
to be associated with lower measures of HOMA-IR was observed in men with normal
triglycerides only (β= -0.077, p=0.08). No significant associations were noted for
women, consistent with prior literature. The approach was limited to secondary analysis.
However, the data from three independent cohorts were consistent in that ucOC was not
associated with measures of IR or weight loss in community-dwelling men and women. In
contrast, there was a trend for higher circulating VK to be associated with lower
HOMA-IR cross-sectionally, particularly in older men with normal triglycerides.
Carefully designed studies are required to define the role of VK in the regulation of
glucose metabolism in humans.
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Sarah Booth.
Committee: Caren Gundberg, Edward Saltzman, and Kyla Shea.
Keyword: Nutrition.read less