Review| Volume 136, P39-51, February 2018

Effect of vitamin K2 on type 2 diabetes mellitus: A review

Published:November 28, 2017DOI:


      • Studies showed vitamin K2 intake reduced 7% T2DM risk with each 10-μg increment.
      • Vitamin K2 has a more significant effect than vitamin K1 on T2DM.
      • Vitamin K2 increased insulin sensitivity via osteocalcin metabolism.
      • Vitamin K2 improved IR via anti-inflammatory property and lipid-lowering effects.
      • Vitamin K2 suppresses inflammation via inactivating NF-κB signalling pathway.


      Type 2 diabetes mellitus (T2DM) continue to be a major public health problem around the world that frequently presents with microvascular and macrovascular complications. Individuals with T2DM are not only suffering from significant emotional and physical misery, but also at increased risk of dying from severe complications. In recent years, evidence from prospective observational studies and clinical trials has shown T2DM risk reduction with vitamin K2 supplementation. We thus did an overview of currently available studies to assess the effect of vitamin K2 supplementation on insulin sensitivity, glycaemic control and reviewed the underlying mechanisms. We proposed that vitamin K2 improved insulin sensitivity through involvement of vitamin K-dependent-protein osteocalcin, anti-inflammatory properties, and lipid-lowering effects. Vitamin K2 had a better effect than vitamin K1 on T2DM. The interpretation of this review will increase comprehension of the development of a therapeutic strategy to prevent and treat T2DM.


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        • Dam H.
        The antihaemorrhagic vitamin of the chick.
        Biochem J. 1935; 29: 1273-1285
        • Rees K.
        • Guraewal S.
        • Wong Y.L.
        • Majanbu D.L.
        • Mavrodaris A.
        • Stranges S.
        • et al.
        Is vitamin K consumption associated with cardio-metabolic disorders? A systematic review.
        Maturitas. 2010; 67: 121-128
        • Widhalm J.R.
        • Ducluzeau A.L.
        • Buller N.E.
        • Elowsky C.G.
        • Olsen L.J.
        • Basset 1, Gilles J.C.
        Phylloquinone (vitamin K1) biosynthesis in plants: two peroxisomal thioesterases of lactobacillales origin hydrolyze 1,4-dihydroxy-2-naphthoyl-coa.
        Plant J. 2012; 71: 205-215
        • Binkley S.B.
        • MacCorquodale D.W.
        • Thayer S.A.
        • Doisy E.A.
        The isolation of vitamin K1.
        J Biol Chem. 1939; : 219-234
        • Gundberg C.M.
        • Markowitz M.E.
        • Mizruchi M.
        • Rosen J.F.
        Osteocalcin in human serum: a circadian rhythm.
        J Clin Endocrinol Metab. 1985; 60: 736-739
        • Knapen M.H.
        • Braam L.A.
        • Drummen N.E.
        • Bekers O.
        • Hoeks A.P.
        • Vermeer C.
        Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial.
        Thromb Haemost. 2015; 113: 1135-1144
        • Yoshida M.
        • Jacques P.F.
        • Meigs J.B.
        • et al.
        Effect of vitamin K supplementation on insulin resistance in older men and women.
        Diabetes Care. 2008; 31: 2092-2096
        • Beulens
        • Joline W.J.
        • Van Der A.
        • et al.
        Dietary phylloquinone and menaquinones intakes and risk of type 2 diabetes.
        Diabetes Care. 2010; 33: 1699-1705
        • Choi H.J.
        • Yu J.
        • Choi H.
        • An J.H.
        • Kim S.W.
        • Park K.S.
        • et al.
        Vitamin K2 supplementation improves insulin sensitivity via osteocalcin metabolism: a placebo-controlled trial.
        Diabetes Care. 2011; 34: e147
        • Asemi Z.
        • Raygan F.
        • Bahmani F.
        • Rezavandi Z.
        • Talari H.R.
        • Rafiee M.
        • 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: 286-293
        • 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
        • Berkner K.L.
        The vitamin K-dependent carboxylase.
        Annu Rev Nutr. 2005; 25: 127-149
        • Dowd T.L.
        • Rosen J.F.
        • Li L.
        • Gundberg C.M.
        The three-dimensional structure of bovine calcium ion-bound osteocalcin using HNMR spectroscopy.
        Biochemistry. 2003; 42: 7769-7779
        • Booth S.L.
        • Centi A.
        • Smith S.R.
        • Gundberg C.
        The role of osteocalcin in human glucose metabolism: marker or mediator?.
        Nat Rev Endocrinol. 2013; 9: 43-55
        • Lee N.K.
        • Sowa H.
        • Hinoi E.
        • Ferron M.
        • Ahn J.D.
        • Confavreux C.
        • et al.
        Endocrine regulation of energy metabolism by the skeleton.
        Cell. 2007; 130: 456-469
        • Pittas A.G.
        • Harris S.S.
        • Eliades M.
        • Stark P.
        • Dawson-Hughes B.
        Association between serum osteocalcin and markers of metabolic phenotype.
        J Clin Endocrinol Metab. 2009; 94: 827-832
        • Saleem U.
        • Mosley Jr., T.H.
        • Kullo I.J.
        Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of metabolic syndrome.
        Arterioscler Thromb Vasc Biol. 2010; 30: 1474-1478
        • Gravenstein K.S.
        • Napora J.K.
        • Short R.G.
        • Ramachandran R.
        • Carlson O.D.
        • Metter E.J.
        • et al.
        Cross-sectional evidence of a signaling pathway from bone homeostasis to glucose metabolism.
        J Clin Endocrinol Metab. 2011; 96: E884-E890
        • Shea M.K.
        • Gundberg C.M.
        • Meugs J.B.
        • et al.
        Gamma-carboxylation of osteocalcin and insulin resistance in older men and women.
        Am J Clin Nutr. 2009; 90: 1230-1235
        • Hwang Y.
        • Jeong I.
        • Ahn K.
        • Chung H.Y.
        The uncarboxylated form of osteocalcin is associated with improved glucose tolerance and enhanced β-cell function in middle-aged male subjects.
        Diabetes/Metab Res Rev. 2009; 25: 768-772
        • Knapen M.H.
        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; : 1017-1024
        • Pollock N.K.
        • Bernard P.J.
        • Gower B.A.
        • et al.
        Lower uncarboxylated osteocalcin concentrations in children with prediabetes is associated with {beta}-cell function.
        J Clin Endocrinol Metab. 2011; 96: E1092-E1099
        • Desbois C.
        • Hogue D.A.
        • Karsenty G.
        The mouse osteocalcin gene cluster contains three genes with two separate spatial and temporal patterns of expression.
        J Biol Chem. 1994; 269: 1183-1190
        • Cousin W.
        • Courseaux A.
        • Ladoux A.
        • Dani C.
        • Peraldi P.
        Cloning of hOST-PTP: the only example of a protein-tyrosine-phosphatase the function of which has been lost between rodent and human.
        Biochem Biophys Res Commun. 2004; : 259-265
        • Gundberg C.M.
        • Nieman S.D.
        • Abrams S.
        • Rosen H.
        Vitamin K status and bone health: an analysis of methods for determination of undercarboxylated osteocalcin.
        J Clin Endocrinol Metab. 1998; 83: 3258-3266
        • Zhang Y.
        • Ma C.
        • Zhao J.
        • Xu H.
        • Hou Q.
        • Zhang H.
        Lactobacillus casei Zhang and vitamin K2 prevent intestinal tumorigenesis in mice via adiponectin-elevated different signaling pathways.
        Oncotarget. 2017; 8: 24719-24727
        • Weyer C.
        • Funahashi T.
        • Tanaka S.
        • et al.
        Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.
        J Clin Endocrinol Metab. 2001; 5: 1930-1935
        • Tschritter O.
        • Fritsche A.
        • Thamer C.
        • Haap M.
        • Shirkavand F.
        • Rahe S.
        • et al.
        Plasma adiponectin concentrations predict insulin sensitivity of both glucose and lipid metabolism.
        Diabetes. 2003; : 239-243
        • Matsubara M.
        • Katayose S.
        • Maruoka S.
        Decreased plasma adiponectin concentrations in nondiabetic women with elevated homeostasis model assessment ratios.
        Eur J Endocrinol. 2003; 148: 343-350
        • Cnop M.
        • Havel P.J.
        • Utzschneider K.M.
        • Carr D.B.
        • Sinha M.K.
        • Boyko E.J.
        • et al.
        Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex.
        Diabetologia. 2003; : 459-469
        • Lihn A.S.
        • Pedersen S.B.
        • Richelsen B.
        Adiponectin: action, regulation and association to insulin sensitivity.
        Obes Rev. 2005; : 13-21
        • Yamauchi T.
        • Kamon J.
        • Yusuke I.
        • Atsushi T.
        • Takehiko Y.
        • Shunhun K.
        • et al.
        Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.
        Nature. 2003; : 762-769
        • Feve B.
        • Bastard J.P.
        The role of interleukins in insulin resistance and type 2 diabetes mellitus.
        Nat Rev Endocrinol. 2009; 5: 305-311
        • Mofrad M.D.
        Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes.
        Trends Endocrinol Metab. 2000; : 212-217
        • Hotamisligil G.S.
        Inflammatory pathways and insulin action.
        Int J Obes Relat Metab Disord. 2003; 27: S53-S55
      1. Rehman K, Akash MSH. Mechanisms of inflammatory responses and development of insulin resistance: how are they interlinked? J Biomed Sci 2016;23:87.

        • Kern P.A.
        • Ranganathan S.
        • Li C.
        • Wood L.
        • Ranganathan G.
        Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance.
        Am J Physiol: Endocrinol Metab. 2001; : E745
        • Emanuelli B.
        • Peraldi P.
        • Filloux C.
        • SawkaVerhelle D.
        • Hilton D.
        • Vanobberghen E.
        SOCS-3 is an insulin-induced negative regulator of insulin signaling.
        J Biol Chem. 2000; 275: 15985-15991
        • Chen G.
        • Goeddel D.V.
        TNF-R1 signaling: a beautiful pathway.
        Science. 2002; : 1634-1635
        • Fasshauer M.
        • Klein J.
        • Neumann S.
        • Eszlinger M.
        • Paschke R.
        Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes.
        Biochem Biophys Res Commun. 2002; : 1084-1089
        • Maeda N.
        • Takahashi M.
        • Funahashi T.
        • et al.
        PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein.
        Diabetes. 2001; 50: 2094-2099
        • Ohsaki Y.
        • Shirakawa H.
        • Miura A.
        • Giriwono P.E.
        • Sato S.
        • Ohashi A.
        • et al.
        Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor κB through the repression of IKKα/β phosphorylation.
        J Nutr Biochem. 2010; 21: 1120-1126
        • Reddi K.
        • Henderson B.
        • Meghji S.
        • Wilson M.
        • Poole S.
        • Hopper C.
        • et al.
        Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds.
        Cytokine. 1995; 7: 287-290
        • Assimacopoulos-Jeannet F.
        Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes.
        Int J Obes Relat Metab Disord. 2004; : S53-S57
        • Nagasawa Y.
        • Fujii M.
        • Kajimoto Y.
        • Imai E.
        • Hori M.
        Vitamin K2 and serum cholesterol in patients on continuous ambulatory peritoneal dialysis.
        Lancet (London, England). 1998; 351: 724
        • Kawashima H.
        • Nakajima Y.
        • Matubara Y.
        • Nakanowatari J.
        • Fukuta T.
        • Mizuno S.
        • et al.
        Effects of vitamin K2 (menatetrenone) on atherosclerosis and blood coagulation in hypercholesterolemic rabbits.
        Jpn J Pharmacol. 1997; 75: 135-143
        • Sogabe N.
        • Maruyama R.
        • Baba O.
        • Hosoi T.
        • Goseki-Sone M.
        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
        • Dam V.
        • Dalmeijer G.W.
        • Vermeer C.
        • Drummen N.E.
        • Knapen M.H.
        • van der Schouw Y.T.
        • 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
        • Iki M.
        • Tamaki J.
        • Fujita Y.
        • Kouda K.
        • Yura A.
        • Kadowaki E.
        • et al.
        Serum undercarboxylated osteocalcin levels are inversely associated with glycemic status and insulin resistance in an elderly Japanese male population: Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Study.
        Osteoporos Int. 2012; : 761-770
        • Trumbo P.
        • Yates A.A.
        • Schlicker S.
        • Poos M.
        Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc.
        J Acad Nutr Dietetics. 2001; 101: 294-301
        • European Food Safety Authority
        Vitamin K2 added for nutritional purposes in foods for particular nutritional uses, food supplements and foods intended for the general population and vitamin K2 as a source of vitamin K added for nutritional purposes to foodstuffs, in the context of Regulation (EC) No. 258/97 - Scientific Opinion of the Panel on Dietetic Products, Nutrition and Allergies.
        EFSA J. 2008; 6
        • 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