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Effect of vitamin K supplementation on insulin sensitivity: a meta-analysis

Authors Suksomboon N, Poolsup N, Darli Ko Ko H

Received 20 March 2017

Accepted for publication 6 April 2017

Published 2 May 2017 Volume 2017:10 Pages 169—177


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Ming-Hui Zou

Naeti Suksomboon,1 Nalinee Poolsup,2 Htoo Darli Ko Ko1

1Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 2Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon-Pathom, Thailand

Objective: To perform a systematic review and meta-analysis of randomized, placebo-controlled trials to assess the effect of vitamin K supplementation on insulin sensitivity.
Data sources: MEDLINE, the Cochrane Library, CINAHL, Web of Science, Scopus,, and were searched up to January 2017. Reference lists of related papers were also scanned.
Study selection: Randomized controlled trials were selected if they compared vitamin K supplementation with placebo or no treatment and reported homeostasis model assessment of insulin resistance, fasting plasma glucose, fasting plasma insulin, C-reactive protein, adiponectin, leptin, or interleukin-6 levels.
Data extraction: Data extraction and study quality assessment were performed independently by two investigators using a standardized data extraction form. Any inconsistencies were resolved by a third reviewer. Effect estimates were pooled using inverse-variance weighted method. Heterogeneity was assessed by the I2 and Q statistic.
Results: A total of eight trials involving 1,077 participants met the inclusion criteria. A wide variety of participants were enrolled, including older men, postmenopausal women, prediabetic premenopausal women, and participants with a history of diabetes, hypertension, or vascular disease. Vitamin K1 and vitamin K2 (MK-4 and MK-7 subtypes) were assessed. Supplementation period ranged from 4 weeks to 3 years. Vitamin K supplementation did not affect insulin sensitivity as measured by homeostasis model assessment of insulin resistance, fasting plasma glucose, fasting plasma insulin, C-reactive protein, adiponectin, leptin, and interleukin-6 levels.
Conclusion: Our analysis suggests no effect of vitamin K supplementation on insulin sensitivity.

Keywords: vitamin K, insulin resistance, meta-analysis, systematic review


Bone has been well established as an endocrine organ.1,2 Its noncollagenous skeleton hormone named osteocalcin has been positively associated with physical activity3 and insulin sensitivity.4,5 Reduced serum concentration of osteocalcin has been linked to an increased risk of diabetes,6,7 which, in turn, has been linked to an increased risk of fracture.810 Vitamin K represents a group of naphthoquinone derivatives (isoprenoid quinones) that are well known for their role in hemostasis. Various forms of vitamin K can be obtained mainly from diet. Leafy greens contain high amount of vitamin K1 (phylloquinone). Dairy products, cheese, and fermented food contain vitamin K2 (menaquinone). Notably, the Japanese food “natto” is extremely rich in vitamin K2 (MK-7 subtype). All forms of vitamin K act as a cofactor for posttranslational modification of proteins.11,12 Apart from cofactor function, vitamin K also plays putative roles in osteoporosis, vascular calcification, cancer, glucose metabolism, and insulin resistance.13 Several studies have reported the beneficial effects of vitamin K on insulin sensitivity, metabolic syndrome, glucose homeostasis, and in reducing the risk of diabetes.1420 Moreover, vitamin K has been demonstrated to decrease cytokines and inflammatory markers, which are implicated in the pathology of insulin sensitivity.2124 The underlying mechanisms of vitamin K on insulin sensitivity have not yet been well established. It has been postulated that vitamin K-dependent bone protein osteocalcin, also known as bone γ-carboxyglutamic acid protein, functions as a mediator in the endocrine pathway. This could influence insulin sensitivity by acting directly on pancreatic β cells, increasing their proliferation and insulin secretion. Bone γ-carboxyglutamic acid protein can increase energy expenditure and adiponectin secretion from adipocytes.2528 Clinical trials of vitamin K supplementation have reported conflicting results on its effect on insulin sensitivity.20,29,3037 We therefore perform a systematic review and meta-analysis of randomized controlled trials to evaluate the effect of vitamin K supplementation on insulin sensitivity.


This review was conducted and presented as recommended by PRISMA statement.

Data sources

Clinical studies of vitamin K were identified through electronic databases including MEDLINE, The Cochrane Library, CINAHL, Web of Science, Scopus,, and The databases were searched from inception to the end of January 2017 without language restriction. A historical search of reference lists of relevant papers was also conducted. The following MeSH terms were used: vitamin K, phylloquinone, menaquinone, naphthoquinone, insulin resistance, and randomized controlled trials. This was followed by the search terms: [vitamin K or naphthoquinone or phylloquinone or menaquinone] AND [insulin resistance or HOMA-IR or fasting plasma glucose or fasting plasma insulin or C-reactive protein or adiponectin or leptin or interleukin-6].

Study selection

To be included in the systematic review, a study had to be a randomized controlled trial comparing vitamin K supplementation against placebo or no treatment, reporting homeostasis model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (FPG), fasting plasma insulin (FPI), C-reactive protein (CRP), adiponectin, leptin, or interleukin-6 (IL-6) levels as outcomes.

Data extraction and quality assessment

Data were extracted from individual studies independently by two reviewers using a standardized form. Any discrepancies were resolved by a third reviewer. The data extracted were publication year, country of origin, study characteristics, duration of intervention, dosage and form of vitamin K, sample size, and outcome measures, ie, HOMA-IR, FPG, FPI, adiponectin, leptin, IL-6, or CRP levels. The methodological quality was assessed using the scale developed by Jadad et al.38 The studies with a score of at least three out of five points were considered high quality.

Statistical analysis

The outcome measures were HOMA-IR, FPI, FPG, adiponectin, leptin, IL-6, and CRP levels. Treatment effect was estimated with a mean difference in the change from baseline value (HOMA-IR, FPI, and FPG) or in the final value (adiponectin, leptin, IL-6, and CRP) between the treatment and the control groups, depending on extractable data. Statistical heterogeneity was assessed using the Q statistic and I2 statistic. Data was combined using the fixed-effects model if heterogeneity was nonsignificant and the random-effects model was used if Q statistic for heterogeneity was significant at the level of 0.1. The inverse variance-weighted method was used for the pooling of mean difference and the estimation of a 95% confidence interval (CI).39 Review Manager Software (RevMan 5.3.5, Cochrane Community, London, UK) provided by the Cochrane Collaboration (Oxford, UK) was used for analyzing data. The significant level was set at P<0.05. Funnel plot to assess publication bias was not performed due to a small number of studies included in the meta-analysis.


Search results and study characteristics

We identified 326 reports through database searching, and 20 papers were retrieved for detailed evaluation. Ten reports were excluded as they were not randomized controlled trials. One randomized controlled trial was further excluded as vitamin K, D, and calcium cosupplementation was compared against placebo.40 The remaining nine randomized, placebo-controlled trials29,3037 met the inclusion criteria. However, two papers29,32 were duplicate reports. The paper reporting more complete data32 was included, leaving eight randomized controlled trials in the systematic review and meta-analysis3037 (Figure 1). Of the eight trials, two30,35 enrolled the same group of participants, but reported different outcomes. Data from these two studies were separately analyzed. Studies were conducted in England, the USA, Iran, Japan, the Netherlands, and Denmark. The number of participants ranged from 42 to 452. The study duration varied from 4 weeks to 3 years. Vitamin K was compared with placebo or no treatment, although in some studies participants in both the treatment and the control groups were similarly treated with vitamin D36; vitamin D and calcium31; or vitamin D, calcium, and multivitamin.30,35 Five studies3032,35,36 evaluated vitamin K1 ranging from 500 to 1,000 µg/d. Two trials33,34 used vitamin K2 (MK-4) 1.5 and 45 mg/d, and one trial37 assessed vitamin K2 (MK-7) 100 µg/d. Subjects were older men or postmenopausal women who did not have diabetes at baseline.30,31,3336 One trial each enrolled premenopausal women with prediabetes32 and participants with history of diabetes, hypertension, or vascular disease.37 The characteristics of all the trials are tabulated in Table 1. All the studies were regarded as high quality. Table 2 summarizes the outcomes reported by individual studies.

Figure 1 Flow of study selection.

Table 1 Characteristics of the studies included in the systematic review

Abbreviations: bd, twice daily; BMI, body mass index; C, control; CO, crossover; CRP, C-reactive protein; DB, double-blind; FPG, fasting plasma glucose; FPI, fasting plasma insulin; HOMA-IR, homeostasis model assessment of insulin resistance; IFG, impaired fasting glucose; IGT, impaired glucose test; IL-6, interleukin-6; LSM, lifestyle modification; MK-4, menaquinone-4; NOF, National Osteoporosis Foundation; P, parallel; VK, vitamin K; PLB, placebo; NR, not reported; MK-7, menaquinone-7.

Table 2 Summary of outcomes reported in the studies included in the meta-analysis

Abbreviations: CRP, C-reactive protein; FPG, fasting plasma glucose; FPI, fasting plasma insulin; HOMA-IR, homeostasis model assessment of insulin resistance; IL-6, interleukin-6.

Meta-analysis of effects on HOMA-IR, FPG, and FPI

Three studies3032 with a total of 479 subjects (244 in the vitamin K and 235 in the control groups) reported results on HOMA-IR, FPG, and FPI. Vitamin K supplementation had no effect on HOMA-IR, FPG, and FPI. The pooled mean differences were −0.14 (95% CI: −0.35 to 0.07, P=0.19), 0.30 mg/dL (0.02 mmol/L; 95% CI: −3.11 to 3.70, P=0.86), and −0.34 µIU/mL (95% CI: −1.13 to 0.45, P=0.40) for HOMA-IR, FPG, and FPI, respectively (Figure 2).

Meta-analysis of effect on leptin

Two studies32,33 contributed data on the effect of vitamin K supplementation on leptin. Again, leptin did not change with vitamin K supplementation (mean difference =0.77 ng/mL; 95% CI: −1.32 to 2.86; Figure 2).

Figure 2 Mean difference (95% CI) in HOMA-IR, FPG, FPI, leptin, IL-6, and CRP.

Abbreviations: CI, confidence interval; CRP, C-reactive protein; FPG; fasting plasma glucose; FPI, fasting plasma insulin; HOMA-IR, homeostasis model of insulin resistance; IL-6, interleukin-6.

Meta-analysis of effects on IL-6 and CRP

Vitamin K supplementation failed to show a significant effect on IL-6 or CRP levels. The pooled mean differences were 0.14 pg/mL (95% CI: −0.69 to 0.97) and −0.49 mg/L (95% CI: −1.18 to 0.20) for IL-6 and CRP, respectively (Figure 2).

Meta-analysis of effect on adiponectin

Three studies3234 involving a total of 294 subjects (152 in the vitamin K and 142 in the control groups) provided poolable data on adiponectin. No effect of vitamin K supplementation was observed. The pooled mean difference was 0.82 µg/mL (95% CI: −0.89 to 2.53; Figure 3).

Figure 3 Mean difference (95% CI) in adiponectin.

Abbreviation: CI, confidence interval.


Several studies have reported vitamin K supplements and its effect on insulin sensitivity. The proposed mechanism is through bone pathway. In in vitro studies, osteocalcin, which is a vitamin K-dependent bone protein, in its uncarboxylated form can increase β cell mass and insulin concentration and promote the release of adiponectin by acting directly on adipocytes,2,25 resulting in an increase in sensitivity to insulin. In humans, both carboxylated and uncarboxylated forms of osteocalcin can be presented in circulation. This is the first meta-analysis of the effect of vitamin K supplementation on insulin sensitivity. We focused on both vitamin K1 and vitamin K2 and reported on HOMA-IR, FPG, FPI, adiponectin, leptin, IL-6, and CRP. HOMA-IR developed by Matthews et al41 is an easy and efficient method used in clinical practice. It can be easily calculated from FPG and FPI. The results of the meta-analysis showed that vitamin K supplementation has no effect on HOMA-IR, FPG, or FPI levels. Heterogeneity was detected in the meta-analysis of FPG (I2=64%, P=0.06). This became nonsignificant when the study by Kumar et al31 was excluded (I2=0%, P=0.80). This study enrolled patients with low level of FPG at baseline (mean ± SD: 78.64±9.4 mg/dL), whereas the others3032 included participants with baseline FPG of 93.55–107.66 mg/dL. Variability in treatment interventions may also introduce heterogeneity. Two studies used vitamin K1 500 µg/d30 and 1 mg/d31 in addition to calcium and vitamin D for the treatment group and placebo plus calcium and vitamin D for the control group. The other32 used vitamin K1 1,000 µg/d.

Adiponectin is an adipocyte-secreted hormone and has a role as an insulin sensitizer.4244 Again, vitamin K supplementation did not affect adiponectin level. However, significant heterogeneity existed (I2=73%, P=0.03). This may be due to differences in the characteristics of participants and in the forms and dosages of vitamin K used. Heterogeneity became nonsignificant when the study by Rasekhi et al32 was excluded (I2=0%, P=0.89). In this study, adiponectin level was significantly increased with vitamin K supplementation.32 The observed effect may be attributable to osteocalcin, which acts directly on adipocytes, resulting in adiponectin secretion.2528 This study enrolled participants aged between 22 and 45 years and used vitamin K1 1,000 µg/d,32 while two other studies included participants aged 50–65 and 55–75 years and used vitamin K2 (MK-4) 1.5 and 45 mg/d, respectively.33,34 It was reported that elderly women have higher uncarboxylated osteocalcin concentration than younger women,45,46 and the amount of vitamin K required for carboxylation of proteins with glutamic acid domains may be higher in older subjects.47 This may be due to either an age-related decrease in the number of osteoblasts or the enzymatic activity of γ-carboxylase in osteoblasts.47 Vitamin K2 (MK-4) is known to be more lipophilic and is transported to extrahepatic tissues faster than vitamin K1. Vitamin K1 can be converted to vitamin K2 (MK-4) at any rate in extrahepatic tissues, such as pancreas, arterial walls, and testis, by replacing the phytyl side chain with isoprene residues.12 Long-chain menaquinone, MK-7, has a higher efficacy in carboxylation process and a higher bioavailability compared to MK-448 and is simply more potent than vitamin K1. MK-7-rich food (natto) intake was restricted to once or twice a week in one of our included studies33 as it may add to the effect of vitamin K supplementation. Clinical trials of MK-7 and insulin sensitivity are currently lacking.

Leptin plays an important role in inflammation, insulin secretion, and insulin sensitivity.49 Elevated leptin concentrations are implicated in the etiology of obesity-associated insulin resistance.50 CRP is a marker of systemic inflammation. Its causative role in the development of insulin resistance has been suggested.51,52 IL-6 is a proinflammatory mediator that suppresses adiponectin transcription and can induce insulin resistance.53,54 Again, meta-analysis results demonstrated no effect of vitamin K on leptin, IL-6, and CRP. Heterogeneity was also detected when analyzing IL-6 data (I2=61%, P=0.11). This may be due to variations in study design and intervention between these two studies (Table 1). The available data on leptin and IL-6 are scarce.

It is worth noting that some of the studies included in our meta-analysis were not specifically designed to evaluate the effect of vitamin K on insulin sensitivity. For example, one investigated whether vitamin K2 (MK-4) supplement improved bone metabolism.33 The other assessed the effect of phylloquinone on blood lipids and inflammatory and fibrinolytic markers.36 In addition, seven30,31,3337 out of the eight included trials enrolled postmenopausal women or elderly men. As insulin sensitivity is known to decrease with age,50 this may partly explain an absence of effect of vitamin K supplement observed in our meta-analysis.

Dietary reference intake of vitamin K ranges between 1 and 1.5 µg/kg body weight/d.12 Adequate intake of vitamin K1 has been estimated to be 120 µg/d for men and 90 µg/d for women.55 These recommended ranges are set according to the needs of liver for normal blood coagulation system. Therapeutic dose of vitamin K supplement to protect bone health in elderly women varies from 1.5 to as high as 45 mg/d, which is well tolerated.33,34 Nevertheless, therapeutic dosage for bone health still cannot ensure full carboxylation of osteocalcin. Although the doses of vitamin K supplement used in the studies included in the meta-analysis are far higher than dietary reference intake, varying from 500 µg/d to 1.5 mg/d, it remains to be determined whether they are sufficient for improving insulin sensitivity. Oral supplementation of vitamin K13032,35,36 or vitamin K233,34 was relatively nontoxic. Adverse events were only reported in one study in which falls, musculoskeletal side effects, and gastrointestinal disturbances were more common in subjects receiving vitamin K2 (MK-7) 100 µg/d compared with placebo.37 However, serious adverse events or death did not differ between the two groups.37 Currently, the tolerable upper intake level of vitamin K has not been determined.

Our meta-analysis is not free from limitations. First, only published trials were included. Funnel plot and Egger’s test were not conducted as the number of studies included in each meta-analysis was too small to permit reasonable use of those methods. Thus, publication bias cannot be ruled out. Secondly, the number of included studies was small. The estimates of effect may be imprecise. Substantial heterogeneity was detected in the meta-analysis of FPG, adiponectin, and IL-6. Doses and forms of vitamin K varied from one trial to another. Subgroup analysis to separate the effect of vitamin K1 from vitamin K2 was not performed as the number of studies was too small. Characteristics of participants and variation in cointerventions may also have a role to play. In the analysis of fasting plasma glucose, for example, one trial included prediabetes premenopausal women,32 while the others enrolled postmenopausal women.30,31 Although these studies were aimed to evaluate the effect of vitamin K supplementation, some of them added multivitamin, vitamin D, and/or calcium to both the treatment and the control groups,30,31,35,36 while the others used vitamin K alone.3234,37 It was therefore difficult to interpret the results and establish the sole effect of vitamin K supplementation.


In conclusion, this systematic review as well as meta-analysis suggests a lack of effect of vitamin K supplementation on insulin sensitivity. Given the limited evidence available and the heterogeneity in the study results, further well-designed, large sample size randomized controlled trials are warranted. Different forms and doses of vitamin K should be explored in various populations, and other surrogate markers for insulin sensitivity should be measured to better establish any beneficial effects and their clinical relevance.


This research was supported by grants from Thailand Research Fund (TRF) and Faculty of Pharmacy, Mahidol University, Thailand (IRG5780007).

Author contributions

NS and NP contributed to the design, analysis, and interpretation of data and drafted the manuscript. HDKK contributed to the conception, analysis, and interpretation of data and drafted the manuscript. All the authors read and approved the final manuscript.


The authors report no conflicts of interest in this work.



Booth SL, Centi AJ, Gundberg C. Bone as an endocrine organ relevant to diabetes. Curr Diab Rep. 2014;14:1–8.


Patti A, Gennari L, Merlotti D, et al. Endocrine actions of osteocalcin. Int J Endocrinol. 2013:2013.


Chahla SE, Frohnert BI, Thomas W, et al. Higher daily physical activity is associated with higher osteocalcin levels in adolescents. Prev Med Rep. 2015;2:568–571.


Hwang YC, Jeong IK, Ahn KJ, Chung HY. Circulating osteocalcin level is associated with improved glucose tolerance, insulin secretion and sensitivity independent of the plasma adiponectin level. Osteoporos Int. 2012;23:1337–1342.


Shea MK, Gundberg CM, Meigs JB, et al. Gamma-carboxylation of osteocalcin and insulin resistance in older men and women. Am J Clin Nutr. 2009;90:1230–1235.


Ngarmukos C, Chailurkit LO, Chanprasertyothin S, et al. A reduced serum level of total osteocalcin in men predicts the development of diabetes in a long-term follow-up cohort. Clin Endocrinol (Oxf). 2012;77:42–46.


Díaz-López A, Bulló M, Juanola-Falgarona M, et al. Reduced serum concentrations of carboxylated and undercarboxylated osteocalcin are associated with risk of developing type 2 diabetes mellitus in a high cardiovascular risk population: a nested case-control study. J Clin Endocrinol Metab. 2013;98:4524–4531.


Starup-Linde J, Lykkeboe S, Gregersen S, et al. Differences in biochemical bone markers by diabetes type and the impact of glucose. Bone. 2015;83:149–155.


Ma L, Oei L, Jiang L, et al. Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies. Eur J Epidemiol. 2012;27:319–332.


Pan H, Wu N, Yang T, He W. Association between bone mineral density and type 1 diabetes mellitus: a meta-analysis of cross-sectional studies. Diabetes Metab Res Rev. 2014;30:531–542.


Shearer MJ, Newman P. Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis. J Lipid Res. 2014;55:345–362.


Vermeer C, Knapen MH. Vitamin K and bone. In: Anderson JJ, Sanford C, editors. Diet, Nutrients, and Bone Health. Boca Raton, FL: CRC Press (Taylor & Francis Group); 2012:193–201.


DiNicolantonio JJ, Bhutani J, O’Keefe JH. The health benefits of vitamin K. Open Heart. 2015;2:e000300.


Pan Y, Jackson RT. Dietary phylloquinone intakes and metabolic syndrome in US young adults. J Am Coll Nutr. 2009;28:369–379.


Dam V, Dalmeijer GW, Vermeer C, et al. Association between vitamin K and the metabolic syndrome: a 10-year follow-up study in adults. J Clin Endocrinol Metab. 2015;100:2472–2479.


Beulens JW, van der A DL, Grobbee DE, et al. Dietary phylloquinone and menaquinones intakes and risk of type 2 diabetes. Diabetes Care. 2010;33:1699–1705.


Ibarrola-Jurado N, Salas-Salvadó J, Martínez-González MA, Bulló M. Dietary phylloquinone intake and risk of type 2 diabetes in elderly subjects at high risk of cardiovascular disease. Am J Clin Nutr. 2012;96:1113–1118.


Yoshida M, Booth SL, Meigs JB, et al. Phylloquinone intake, insulin sensitivity, and glycemic status in men and women. Am J Clin Nutr. 2008;88:210–215.


Sakamoto N, Nishiike T, Iguchi H, Sakamoto K. Possible effects of one week vitamin K (menaquinone-4) tablets intake on glucose tolerance in healthy young male volunteers with different descarboxy prothrombin levels. Clin Nutr. 2000;19:259–263.


Choi HJ, Yu J, Choi H, et al. Vitamin K2 supplementation improves insulin sensitivity via osteocalcin metabolism: a placebo-controlled trial. Diabetes Care. 2011;34:e147.


Juanola-Falgarona M, Salas-Salvadó J, Estruch R, et al. 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. 2013;12:1–9.


Shea MK, Booth SL, Massaro JM, et al. Vitamin K and vitamin D status: associations with inflammatory markers in the Framingham Offspring Study. Am J Epidemiol. 2008;167:313–320.


Reddi K, Henderson B, Meghji S, et al. Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds. Cytokine. 1995;7:287–290.


Ohsaki Y, Shirakawa H, Hiwatashi K, et al. Vitamin K suppresses lipopolysaccharide-induced inflammation in the rat. Biosci Biotechnol Biochem. 2006;70:926–932.


Ferron M, Hinoi E, Karsenty G, Ducy P. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci USA. 2008;105:5266–5270.


Sakamoto N, Wakabayashi I, Sakamoto K. Low vitamin K intake effects on glucose tolerance in rats. Int J Vitam Nutr Res. 1999;69:27–31.


Sogabe N, Maruyama R, Baba O, et al. Effects of long-term vitamin K(1) (phylloquinone) or vitamin K(2) (menaquinone-4) supplementation on body composition and serum parameters in rats. Bone. 2011;48:1036–1042.


Lee NK, Sowa H, Hinoi E, et al. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130:456–469.


Rasekhi H, Karandish M, Jalali MT, et al. The effect of vitamin K1 supplementation on sensitivity and insulin resistance via osteocalcin in prediabetic women: a double-blind randomized controlled clinical trial. Eur J Clin Nutr. 2015;69(8):891–895.


Yoshida M, Jacques PF, Meigs JB, et al. Effect of vitamin K supplementation on insulin resistance in older men and women. Diabetes Care. 2008;31:2092–2096.


Kumar R, Binkley N, Vella A. Effect of phylloquinone supplementation on glucose homeostasis in humans. Am J Clin Nutr. 2010;92:1528–1532.


Rasekhi H, Karandish M, Jalali MT, et al. Phylloquinone supplementation improves glycemic status independent of the effects of adiponectin levels in premonopause women with prediabetes: a double-blind randomized controlled clinical trial. J Diabetes Metab Disord. 2015;14:1.


Koitaya N, Sekiguchi M, Tousen Y, et al. Low-dose vitamin K2 (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women. J Bone Miner Metab. 2014;32:142–150.


Knapen MH, Schurgers LJ, Shearer MJ, et al. Association of vitamin K status with adiponectin and body composition in healthy subjects: uncarboxylated osteocalcin is not associated with fat mass and body weight. Br J Nutr. 2012;108:1017–1024.


Shea MK, Dallal GE, Dawson-Hughes B, et al. Vitamin K, circulating cytokines, and bone mineral density in older men and women. Am J Clin Nutr. 2008;88:356–363.


Kristensen M, Kudsk J, Bügel S. Six weeks phylloquinone supplementation produces undesirable effects on blood lipids with no changes in inflammatory and fibrinolytic markers in postmenopausal women. Eur J Nutr. 2008;47:375–379.


Fulton RL, McMurdo ME, Hill A, et al. Effect of vitamin K on vascular health and physical function in older people with vascular disease – a randomised controlled trial. J Nutr Health Aging. 2016;20:325–333.


Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.


Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from:


Asemi Z, Raygan F, Bahmani F, et al. The effects of vitamin D, K and calcium co-supplementation on carotid intima-media thickness and metabolic status in overweight type 2 diabetic patients with CHD. Br J Nutr. 2016;116(2):286–293.


Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419.


Stefan N, Vozarova B, Funahashi T, et al. Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes. 2002;51:1884–1888.


Awazawa M, Ueki K, Inabe K, et al. Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6-dependent pathway. Cell Metab. 2011;13:401–412.


Kolumam G, Chen MZ, Tong R, et al. Sustained brown fat stimulation and insulin sensitization by a humanized bispecific antibody agonist for fibroblast growth factor receptor 1/βklotho complex. EBioMedicine. 2015;2:730–743.


Knapen MH, Hamulyák K, Vermeer C. The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern Med. 1989;111:1001–1005.


Plantalech L, Guillaumont M, Vergnaud P, et al. Impairment of gamma carboxylation of circulating osteocalcin (bone Gla protein) in elderly women. J Bone Miner Res. 1991;6:1211–1216.


Tsugawa N, Shiraki M, Suhara Y, et al. Vitamin K status of healthy Japanese women: age-related vitamin K requirement for γ-carboxylation of osteocalcin. Am J Clin Nutr. 2006;83:380–386.


Sato T, Schurgers LJ, Uenishi K. Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women. Nutr J. 2012;11:1–4.


Blüher M, Mantzoros CS. From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. Metabolism. 2015;64:131–145.


Krentz AJ. Insulin Resistance: A Clinical Handbook. Hoboken, NJ: Blackwell Science Ltd; 2002.


Xi L, Xiao C, Bandsma RH, et al. C-reactive protein impairs hepatic insulin sensitivity and insulin signaling in rats: role of mitogen-activated protein kinases. Hepatology. 2011;53:127–135.


Ndumele CE, Pradhan AD, Ridker PM. Interrelationships between inflammation, C-reactive protein, and insulin resistance. J Cardiometab Syndr. 2006;1:190–196.


Park T, Kim SJ. Insulin resistance and inflammatory singnaling pathways modulated by high-fat diet. In: Dong Z, Surh YJ, editors. Dietary Modulation of Cell Signaling Pathways. Boca Raton, FL: CRC Press; 2009:385–415.


Carey AL, Febbraio MA. Interleukin-6 and insulin sensitivity: friend or foe? Diabetologia. 2004;47:1135–1142.


Manna P, Kalita J. Beneficial role of vitamin K supplementation on insulin sensitivity, glucose metabolism, and the reduced risk of type 2 diabetes: a review. Nutrition. 2016;32:732–739.

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