Vitamin K Abstracts 6

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Dietary phylloquinone and menaquinones intakes and risk of type 2 diabetes.
            (Beulens et al., 2010) Download
OBJECTIVE:  To investigate whether dietary phylloquinone and menaquinones intakes are related to risk of type 2 diabetes. RESEARCH DESIGN AND METHODS:  We used data from a prospective cohort study in 38,094 Dutch men and women, aged 20-70 years. Dietary phylloquinone and menaquinones intakes were assessed using a validated food frequency questionnaire. Diabetes case patients were ascertained mainly via self-report and verified against medical records. RESULTS:  During 10.3 years of follow-up, 918 incident cases of diabetes were documented. In a multivariate model adjusting for diabetes risk factors and dietary factors, phylloquinone intake tended to be associated (P = 0.08) with a reduced risk of type 2 diabetes with a hazard ratio (HR) of 0.81 (95% CI 0.66-0.99) for the highest versus the lowest quartile. For menaquinones intake, a linear, inverse association (P = 0.038) with risk of type 2 diabetes was observed with an HR of 0.93 (0.87-1.00) for each 10-microg increment in the multivariate model. CONCLUSIONS:  This study shows that both phylloquinone and menaquinones intakes may be associated with a reduced risk of type 2 diabetes.

Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age.
            (Braam et al., 2003) Download
Although several observational studies have demonstrated an association between vitamin K status and bone mineral density (BMD) in postmenopausal women, no placebo-controlled intervention trials of the effect of vitamin K1 supplementation on bone loss have been reported thus far. In the trial presented here we have investigated the potential complementary effect of vitamin K1 (1 mg/day) and a mineral + vitamin D supplement (8 microg/day) on postmenopausal bone loss. The design of our study was a randomized, double-blind, placebo-controlled intervention study; 181 healthy postmenopausal women between 50 and 60 years old were recruited, 155 of whom completed the study. During the 3-year treatment period, participants received a daily supplement containing either placebo, or calcium, magnesium, zinc, and vitamin D (MD group), or the same formulation with additional vitamin K1 (MDK group). The main outcome was the change in BMD of the femoral neck and lumbar spine after 3 years, as measured by DXA. The group receiving the supplement containing additional vitamin K1 showed reduced bone loss of the femoral neck: after 3 years the difference between the MDK and the placebo group was 1.7% (95% Cl: 0.35-3.44) and that between the MDK and MD group was 1.3% (95% Cl: 0.10-3.41). No significant differences were observed among the three groups with respect to change of BMD at the site of the lumbar spine. If co-administered with minerals and vitamin D, vitamin K1 may substantially contribute to reducing postmenopausal bone loss at the site of the femoral neck.

Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study.
            (Braam et al., 2004) Download
Matrix-Gla Protein (MGP) is a strong inhibitor of vascular calcification, the expression of which is vitamin D dependent. MGP contains five gamma-carboxyglutamic acid (Gla)-residues which are formed in a vitamin K-dependent carboxylation step and which are essential for its function. Hence vascular vitamin K-deficiency will result in undercarboxylated, inactive MGP which is a potential risk factor for calcification. In the present study we describe the effects of vitamin K1 and D supplementation on vascular properties in postmenopausal women. In a randomized placebo-controlled intervention study, 181 postmenopausal women were given either a placebo or a supplement containing minerals and vitamin D (MD-group), or the same supplement with vitamin K1 (MDK-group). 150 participants completed the study and analysis was performed on 108 participants. At baseline and after three years, vessel wall characteristics, including compliance coefficient (CC), distensibility coefficient (DC), intima-media thickness (IMT) and the Young's Modulus (E) were measured to assess the effect of the supplements on the change of these parameters. The results showed that the elastic properties of the common carotid artery in the MDK-group remained unchanged over the three-year period, but decreased in the MD- and placebo-group. Comparing the MDK- and placebo-group, there were significant differences in decrease of DC (8.8%; p<0.05), CC (8.6%; p<0.05), and in increase of PP (6.3%; p<0.05) and E (13.2%, p<0.01). There were no significant differences between the MD-group and placebo. No significant differences were observed in the change of IMT between the three groups. It is concluded that a supplement containing vitamins K1 and D has a beneficial effect on the elastic properties of the arterial vessel wall.

Vascular calcification: the price to pay for anticoagulation therapy with vitamin K-antagonists.
            (Chatrou et al., 2012) Download
Vitamin K-antagonists (VKA) are the most widely used anti-thrombotic drugs with substantial efficacy in reducing risk of arterial and venous thrombosis. Several lines of evidence indicate, however, that VKA inhibit not only post-translational activation of vitamin K-dependent coagulation factors but also synthesis of functional extra-hepatic vitamin K-dependent proteins thereby eliciting undesired side-effects. Vascular calcification is one of the recently revealed side-effects of VKA. Vascular calcification is an actively regulated process involving vascular cells and a number of vitamin K-dependent proteins. Mechanistic understanding of vascular calcification is essential to improve VKA-based treatments of both thrombotic disorders and atherosclerosis. This review addresses vitamin K-cycle and vitamin K-dependent processes of vascular calcification that are affected by VKA. We conclude that there is a growing need for better understanding of the effects of anticoagulants on vascular calcification and atherosclerosis.

Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials.
            (Cockayne et al., 2006) Download
BACKGROUND:  Observational and some experimental data suggest that low intake of vitamin K may be associated with an increased risk of fracture. OBJECTIVE:  To assess whether oral vitamin K (phytonadione and menaquinone) supplementation can reduce bone loss and prevent fractures. DATA SOURCES:  The search included the following electronic databases: MEDLINE (1966 to June 2005), EMBASE (1980 to June 2005), the Cochrane Library (issue 2, 2005), the ISI Web of Science (1945 to June 2005), the National Research Register (inception to the present), Current Controlled Trials, and the Medical Research Council Research Register. STUDY SELECTION:  Randomized controlled trials that gave adult participants oral phytonadione and menaquinone supplements for longer than 6 months were included in this review. DATA EXTRACTION:  Four authors extracted data on changes in bone density and type of fracture. All articles were double screened and double data extracted. DATA SYNTHESIS:  Thirteen trials were identified with data on bone loss, and 7 reported fracture data. All studies but 1 showed an advantage of phytonadione and menaquinone in reducing bone loss. All 7 trials that reported fracture effects were Japanese and used menaquinone. Pooling the 7 trials with fracture data in a meta-analysis, we found an odds ratio (OR) favoring menaquinone of 0.40 (95% confidence interval [CI], 0.25-0.65) for vertebral fractures, an OR of 0.23 (95% CI, 0.12-0.47) for hip fractures, and an OR of 0.19 (95% CI, 0.11-0.35) for all nonvertebral fractures. CONCLUSIONS:  This systematic review suggests that supplementation with phytonadione and menaquinone-4 reduces bone loss. In the case of the latter, there is a strong effect on incident fractures among Japanese patients.


 

Vitamin K intake and atherosclerosis.
            (Erkkilä and Booth, 2008) Download
PURPOSE OF REVIEW:  It has been hypothesized that insufficient intake of vitamin K may increase soft-tissue calcification owing to impaired gamma-carboxylation of the vitamin K-dependent protein matrix gamma-carboxyglutamic acid. The evidence to support this putative role of vitamin K intake in atherosclerosis is reviewed. RECENT FINDINGS:  In animal models, multiple forms of vitamin K have been shown to reverse the arterial calcification created by vitamin K antagonists. The human data, however, are less consistent. Phylloquinone, the primary dietary form, has not been associated consistently with the risk of cardiovascular diseases. High menaquinone intake may be associated with lower risk of coronary heart disease mortality, but this needs to be confirmed. SUMMARY:  The role of vitamin K in calcification remains controversial. Although biologically plausible, results from the human studies have not consistently supported this hypothesis.

Vitamin K intake and osteocalcin levels in women with and without aortic atherosclerosis: a population-based study.
            (Jie et al., 1995) Download
Protein-bound gamma-carboxyglutamate (Gla) has been demonstrated in calcified atherosclerotic plaques. Vitamin K is required for the formation of Gla-residues. As the biological activity of Gla-proteins appears to be strictly dependent on the presence of the Gla-residues, vitamin K status may be an important factor in the development and progression of atherosclerotic calcifications. We studied the association of vitamin K status, as assessed by nutritional vitamin K intake and the measurements of two circulating immunoreactive osteocalcin (irOC) fractions, with aortic atherosclerosis in a population-based study of 113 postmenopausal women. Women with calcified lesions (n = 34) had a 42.9 micrograms lower mean age-adjusted dietary vitamin K intake/day (95% C.I. -6.6 to 92.5) than those without calcifications (n = 79). Atherosclerotic women had higher irOC levels with a low affinity for hydroxyapatite (irOCfree): age-adjusted difference of 0.32 ng/ml (95% C.I. 0.03 to 0.61). In addition, the high affinity irOC levels expressed as a percentage (hydroxyapatite binding capacity, HBC) were 5.12% (95% C.I. 1.32 to 8.92) lower in women with calcifications. Our study indicates that women with aortic atherosclerosis have an impaired vitamin K status as reflected by a lower nutritional vitamin K intake, an increased irOCfree level and a reduced HBC level. An impaired vitamin K status in subjects with atherosclerosis is compatible with the view that vitamin K or Gla-containing proteins are involved in the development of calcification of the vessel wall.


 

Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study.
            (Jie et al., 1996) Download
Gammacarboxyglutamate (Gla) is an uncommon amino acid formed by vitamin K action. Increasing evidence indicates that Gla-proteins are involved in the regulation of calcification processes in both bone tissue and atherosclerotic vessel wall. In a population-based study we have previously shown that in a group of 113 postmenopausal women the presence of abdominal aortic calcifications is associated with a reduced vitamin K status. In the present study we investigated whether this reduced vitamin K status was also associated with differences in bone mass or circulating calciotropic hormone levels. Serum immunoreactive osteocalcin with low affinity for hydroxyapatite (irOCfree) was used as a marker for vitamin K status. After correction for age it was found that women with atherosclerotic calcifications had a 7% lower bone mass as measured by metacarpal radiogrammetry (mean difference: 3.2 mm2, 95% CI: -0. 2-6.5, P = 0.06). No differences between both groups of women were observed for serum intact parathyroid hormone (PTH) and serum 25-hydroxyvitamin D levels. In the atherosclerotic women (n = 34), markers for vitamin K status were inversely associated with bone mass (r = -0.47, P = 0.013), whereas no such association was found in the nonatherosclerotic women (n = 79). It is concluded that the atherosclerotic women in this study may be at higher risk for osteoporotic fractures as evidenced by their lower bone mass and higher serum irOCfree levels. The finding that in atherosclerotic women vitamin K status is associated with bone mass supports our hypothesis that vitamin K status affects the mineralization processes in both bone and in atherosclerotic plaques.

Association between dietary phylloquinone intake and peripheral metabolic risk markers related to insulin resistance and diabetes in elderly subjects at high cardiovascular risk.
            (Juanola-Falgarona et al., 2013) Download
BACKGROUND:  Vitamin K has been related to glucose metabolism, insulin sensitivity and diabetes. Because inflammation underlies all these metabolic conditions, it is plausible that the potential role of vitamin K in glucose metabolism occurs through the modulation of cytokines and related molecules. The purpose of the study was to assess the associations between dietary intake of vitamin K and peripheral adipokines and other metabolic risk markers related to insulin resistance and type 2 diabetes mellitus. METHODS:  Cross-sectional and longitudinal assessments of these associations in 510 elderly participants recruited in the PREDIMED centers of Reus and Barcelona (Spain). We determined 1-year changes in dietary phylloquinone intake estimated by food frequency questionnaires, serum inflammatory cytokines and other metabolic risk markers. RESULTS:  In the cross-sectional analysis at baseline no significant associations were found between dietary phylloquinone intake and the rest of metabolic risk markers evaluated, with exception of a negative association with plasminogen activator inhibitor-1. After 1-year of follow-up, subjects in the upper tertile of changes in dietary phylloquinone intake showed a greater reduction in ghrelin (-15.0%), glucose-dependent insulinotropic peptide (-12.9%), glucagon-like peptide-1 (-17.6%), IL-6 (-27.9%), leptin (-10.3%), TNF (-26.9%) and visfatin (-24.9%) plasma concentrations than those in the lowest tertile (all p<0.05). CONCLUSION:  These results show that dietary phylloquinone intake is associated with an improvement of cytokines and other markers related to insulin resistance and diabetes, thus extending the potential protection by dietary phylloquinone on chronic inflammatory diseases. TRIAL REGISTRATION:  http://www.controlled-trials.com as ISRCTN35739639.

Dietary intake of vitamin K is inversely associated with mortality risk.
            (Juanola-Falgarona et al., 2014) Download
Vitamin K has been related to cardiovascular disease and cancer risk. However, data on total mortality are scarce. The aim of the present study was to assess the association between the dietary intake of different types of vitamin K and mortality in a Mediterranean population at high cardiovascular disease risk. A prospective cohort analysis was conducted in 7216 participants from the PREDIMED (Prevención con Dieta Mediterránea) study (median follow-up of 4.8 y). Energy and nutrient intakes were evaluated using a validated 137-item food frequency questionnaire. Dietary vitamin K intake was calculated annually using the USDA food composition database and other published sources. Deaths were ascertained by an end-point adjudication committee unaware of the dietary habits of participants after they had reviewed medical records and linked up to the National Death Index. Cox proportional hazard models were fitted to assess the RR of mortality. Energy-adjusted baseline dietary phylloquinone intake was inversely associated with a significantly reduced risk of cancer and all-cause mortality after controlling for potential confounders (HR: 0.54; 95% CI: 0.30, 0.96; and HR: 0.64; 95% CI: 0.45, 0.90, respectively). In longitudinal assessments, individuals who increased their intake of phylloquinone or menaquinone during follow-up had a lower risk of cancer (HR: 0.64; 95% CI: 0.43, 0.95; and HR: 0.41; 95% CI: 0.26, 0.64, respectively) and all-cause mortality (HR: 0.57; 95% CI: 0.44, 0.73; and HR: 0.55; 95% CI: 0.42, 0.73, respectively) than individuals who decreased or did not change their intake. Also, individuals who increased their intake of dietary phylloquinone had a lower risk of cardiovascular mortality risk (HR: 0.52; 95% CI: 0.31, 0.86). However, no association between changes in menaquinone intake and cardiovascular mortality was observed (HR: 0.76; 95% CI: 0.44, 1.29). An increase in dietary intake of vitamin K is associated with a reduced risk of cardiovascular, cancer, or all-cause mortality in a Mediterranean population at high cardiovascular disease risk. This trial was registered at http://www.controlled-trials.com as ISRCTN35739639.


 

Growth inhibitory effects of vitamin K2 on colon cancer cell lines via different types of cell death including autophagy and apoptosis.
            (Kawakita et al., 2009) Download
Vitamin K2 (menaquinone-4: MK4) has been reported to inhibit cell growth and induce apoptosis in various tumor cells. We examined the effects of MK4 using three types of colon cancer cell lines: PMCO1, COLO201, and DLD-1. Exposure to MK4 was at concentrations from 5 to 50 microM, growth inhibitory effects were observed dose-dependently in COLO201 and PMCO1, whereas the growth inhibition observed in DLD-1 was minimal. Comparison of COLO201 and PMCO1 cells exhibiting distinct growth inhibitory effects showed that cell death via apoptosis accompanied by activation of caspase-3 was induced in PMCO1, while apoptosis was not induced in COLO201. On the contrary, immunoblot assay using an anti-LC3B antibody showed autophagy induction by addition of MK4 and incubation in all three types of colon cancer cell lines. Addition of 3-methyladenine (3-MA) attenuated the growth inhibitory effect of MK4 in COLO201, whereas no influence of 3-MA was noted in PCMO1. Electron microscopy images of COLO201 showed that addition of MK4 induced an increased number of cytoplasmic autophagosomes and autolysosomes as well as morphological changes including scantiness of cytoplasm accompanied by loss of cell organelles, nuclear shrinkage, and fragmentation of cytoplasmic membrane in some cells, indicating the induction of cell death via autophagy not accompanied by the formation of apoptotic bodies in COLO201 cells. These results suggested that the response to MK4 and the way of induction of cell death vary in different colon cancer cell lines.

Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women.
            (Knapen et al., 2013) Download
UNLABELLED:  We have investigated whether low-dose vitamin K2 supplements (menaquinone-7, MK-7) could beneficially affect bone health. Next to an improved vitamin K status, MK-7 supplementation significantly decreased the age-related decline in bone mineral density and bone strength. Low-dose MK-7 supplements may therefore help postmenopausal women prevent bone loss. INTRODUCTION:  Despite contradictory data on vitamin K supplementation and bone health, the European Food Safety Authorities (EFSA) accepted the health claim on vitamin K's role in maintenance of normal bone. In line with EFSA's opinion, we showed that 3-year high-dose vitamin K1 (phylloquinone) and K2 (short-chain menaquinone-4) supplementation improved bone health after menopause. Because of the longer half-life and greater potency of the long-chain MK-7, we have extended these investigations by measuring the effect of low-dose MK-7 supplementation on bone health. METHODS:  Healthy postmenopausal women (n = 244) received for 3 years placebo or MK-7 (180 μg MK-7/day) capsules. Bone mineral density of lumbar spine, total hip, and femoral neck was measured by DXA; bone strength indices of the femoral neck were calculated. Vertebral fracture assessment was performed by DXA and used as measure for vertebral fractures. Circulating uncarboxylated osteocalcin (ucOC) and carboxylated OC (cOC) were measured; the ucOC/cOC ratio served as marker of vitamin K status. Measurements occurred at baseline and after 1, 2, and 3 years of treatment. RESULTS:  MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC and BMD at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae. CONCLUSIONS:  MK-7 supplements may help postmenopausal women to prevent bone loss. Whether these results can be extrapolated to other populations, e.g., children and men, needs further investigation.

The anticancer effects of vitamin K.
            (Lamson and Plaza, 2003) Download
Vitamin K, an essential nutrient often associated with the clotting cascade, has been the focus of considerable research demonstrating an anticancer potential. Much of this research has focused on vitamin K3, although vitamins K2 and K1 have also been shown to have anticancer effects. Early studies of vitamin K3 employed an oxidative model to explain the anticancer effects seen in both in vitro and in vivo studies; however, this model does not adequately address the action of vitamins K1 and K2. Recent research has demonstrated the anticancer action of vitamin K may act at the level of tyrosine kinases and phosphatases, modulating various transcription factors such as Myc and Fos. Tyrosine kinases associated with cyclins have also been shown to be affected by vitamin K, which can lead to cell cycle arrest and cell death.

The vitamin C:vitamin K3 system - enhancers and inhibitors of the anticancer effect.
            (Lamson et al., 2010) Download
The oxidizing anticancer system of vitamin C and vitamin K₃ (VC:VK₃, producing hydrogen peroxide via superoxide) was combined individually with melatonin, curcumin, quercetin, or cholecalciferol (VD₃) to determine interactions. Substrates were LNCaP and PC-3 prostate cancer cell lines. Three of the tested antioxidants displayed differences in cell line cytotoxicity. Melatonin combined with VC:VK₃ quenched the oxidizing effect, while VC:VK₃ applied 24 hours after melatonin showed no quenching. With increasing curcumin concentrations, an apparent combined effect of VC:VK₃ and curcumin occurred in LNCaP cells, but not PC-3 cells. Quercetin alone was cytotoxic on both cell lines, but demonstrated an additional 50-percent cytotoxicity on PC-3 cells when combined with VC:VK₃. VD₃ was effective against both cell lines, with more effect on PC-3. This effect was negated on LNCaP cells with the addition of VC:VK₃. In conclusion, a natural antioxidant can enhance or decrease the cytotoxicity of an oxidizing anticancer system in vitro, but generalizations about antioxidants cannot be made.

 


References

Beulens, JW, et al. (2010), ‘Dietary phylloquinone and menaquinones intakes and risk of type 2 diabetes.’, Diabetes Care, 33 (8), 1699-705. PubMed: 20424220
Braam, LA, et al. (2003), ‘Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age.’, Calcif Tissue Int, 73 (1), 21-26. PubMed: 14506950
Braam, LA, et al. (2004), ‘Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study.’, Thromb Haemost, 91 (2), 373-80. PubMed: 14961167
Chatrou, ML, et al. (2012), ‘Vascular calcification: the price to pay for anticoagulation therapy with vitamin K-antagonists.’, Blood Rev, 26 (4), 155-66. PubMed: 22520397
Cockayne, S, et al. (2006), ‘Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials.’, Arch Intern Med, 166 (12), 1256-61. PubMed: 16801507
Erkkilä, AT and SL Booth (2008), ‘Vitamin K intake and atherosclerosis.’, Curr Opin Lipidol, 19 (1), 39-42. PubMed: 18196985
Jie, KG, et al. (1996), ‘Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study.’, Calcif Tissue Int, 59 (5), 352-56. PubMed: 8849401
Jie, KS, et al. (1995), ‘Vitamin K intake and osteocalcin levels in women with and without aortic atherosclerosis: a population-based study.’, Atherosclerosis, 116 (1), 117-23. PubMed: 7488326
Juanola-Falgarona, M, et al. (2013), ‘Association between dietary phylloquinone intake and peripheral metabolic risk markers related to insulin resistance and diabetes in elderly subjects at high cardiovascular risk.’, Cardiovasc Diabetol, 12 7. PubMed: 23298335
Juanola-Falgarona, M, et al. (2014), ‘Dietary intake of vitamin K is inversely associated with mortality risk.’, J Nutr, 144 (5), 743-50. PubMed: 24647393
Kawakita, H, et al. (2009), ‘Growth inhibitory effects of vitamin K2 on colon cancer cell lines via different types of cell death including autophagy and apoptosis.’, Int J Mol Med, 23 (6), 709-16. PubMed: 19424596
Knapen, MH, et al. (2013), ‘Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women.’, Osteoporos Int, 24 (9), 2499-507. PubMed: 23525894
Lamson, DW and SM Plaza (2003), ‘The anticancer effects of vitamin K.’, Altern Med Rev, 8 (3), 303-18. PubMed: 12946240
Lamson, DW, et al. (2010), ‘The vitamin C:vitamin K3 system - enhancers and inhibitors of the anticancer effect.’, Altern Med Rev, 15 (4), 345-51. PubMed: 21194250