title: Endocrine Actions of Osteocalcin 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. Effect of vitamin K on vascular health and physical function in older people with vascular disease–a randomised controlled trial Vitamin K, circulating cytokines, and bone mineral density in older men and women. Effect of Vitamin K Supplementation on Insulin Resistance in Older Men and Women Dietary Phylloquinone and Menaquinones Intakes and Risk of Type 2 Diabetes Phylloquinone supplementation improves glycemic status independent of the effects of adiponectin levels in premonopause women with prediabetes: a double-blind randomized controlled clinical trial 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. The effect of vitamin K1 supplementation on sensitivity and insulin resistance via osteocalcin in prediabetic women: a double-blind randomized controlled clinical trial Six weeks phylloquinone supplementation produces undesirable effects on blood lipids with no changes in inflammatory and fibrinolytic markers in postmenopausal women
abstract: Osteocalcin is the most abundant noncollagenous protein of bone matrix . Once transcribed , this protein undergoes posttranslational modifications within osteoblastic cells before its secretion , including the carboxylation of three glutamic residues in glutamic acid , which is essential for hydroxyapatite binding and deposition in the extracellular matrix of bone . Recent provocative data from experimental observations in mice showed that the circulating undercarboxylated fraction of osteocalcin increases insulin secretion and sensitivity , lowers blood glucose , and decreases visceral fat in both genders , while it enhances testosterone production by the testes in males . Moreover , both total and undercarboxylated osteocalcins increase following physical activity with potential positive effects on glucose tolerance . Despite that these evidence s have been only in part confirmed in humans , further prospect i ve investigations are needed to definitively establish the endocrine role of osteocalcin both in the general population and cohorts of patients with diabetes or other metabolic disorders Adiponectin , the most abundant adipose-specific protein , has been found to be negatively associated with degree of adiposity and positively associated with insulin sensitivity in Pima Indians and other population s. Moreover , adiponectin administration to rodents has been shown to increase insulin-induced tyrosine phosphorylation of the insulin receptor ( IR ) and also increase whole-body insulin sensitivity . To further characterize the relationship between plasma adiponectin concentration and insulin sensitivity in humans , we examined 1 ) the cross-sectional association between plasma adiponectin concentration and skeletal muscle IR tyrosine phosphorylation and 2 ) the prospect i ve effect of plasma adiponectin concentration at baseline on change in insulin sensitivity . Fasting plasma adiponectin concentration , body composition ( hydrodensitometry or dual energy X-ray absorptiometry ) , insulin sensitivity ( insulin-stimulated glucose disposal , hyperinsulinemic clamp ) , and glucose tolerance ( 75-g oral glucose tolerance test ) were measured in 55 Pima Indians ( 47 men and 8 women , aged 31 + /- 8 years , body fat 29 + /- 8 % [ mean + /- SD ] ; 50 with normal glucose tolerance , 3 with impaired glucose tolerance , and 2 with diabetes ) . Group 1 ( 19 subjects ) underwent skeletal muscle biopsies for the measurement of basal and insulin-stimulated tyrosine phosphorylation of the IR ( stimulated by 100 nmol/l insulin ) . The fold increase after insulin stimulation was calculated as the ratio between maximal and basal phosphorylation . Group 2 ( 38 subjects ) had follow-up measurements of insulin-stimulated glucose disposal .  Cross-sectionally , plasma adiponectin concentration was positively associated with insulin-stimulated glucose disposal ( r = 0.58 , P < 0.0001 ) and negatively associated with percent body fat ( r = -0.62 , P < 0.0001 ) in the whole group . In group 1 plasma adiponectin was negatively associated with the basal ( r = -0.65 , P = 0.003 ) and positively associated with the fold increase in IR tyrosine phosphorylation ( r = 0.69 , P = 0.001 ) before and after the adjustment for percent body fat ( r = -0.58 , P = 0.01 and r = 0.54 , P = 0.02 , respectively ) . Longitudinally , after adjustment for age , sex , and percent body fat , low plasma adiponectin concentration at baseline was associated with a decrease in insulin sensitivity ( P = 0.04 ) . In conclusion , our cross-sectional data suggest a role of physiological concentration of fasting plasma adiponectin in the regulation of skeletal muscle IR tyrosine phosphorylation . Prospect ively , low plasma adiponectin concentration at baseline precedes a decrease in insulin sensitivity . Our data indicate that adiponectin plays an important role in regulation of insulin sensitivity in humans Background and Aims Vitamin K insufficiency is common and linked to an increased risk of cardiovascular disease and osteoporotic fractures . The aim of this study was to examine whether daily supplementation with oral vitamin K could improve vascular health and physical function in older people with established vascular disease . Methods and results A double blind , r and omised , placebo-controlled trial . Participants aged ≤ 70 years with a history of vascular disease were r and omised to receive 6 months of daily oral 100mcg vitamin K2 ( MK7 subtype ) or matching placebo with outcomes measured at 0 , 3 and 6 months . The primary outcome was between-group difference in endothelial function assessed using flow-mediated dilatation of the brachial artery at 6 months . Secondary outcomes included carotid-radial pulse wave velocity , augmentation index , blood pressure , carotid intima-media thickness , C-reactive protein , B-type natriuretic peptide , cholesterol and desphospho-uncarboxylated matrix Gla protein levels . H and grip strength and the Short Physical Performance Battery assessed physical function , while postural sway was measured using a 3-dimensional force platform . Results 80 participants were r and omised , mean age 77 ( SD 5 ) years ; 44/80 were male .  Vitamin K levels rose in the intervention arm compared to placebo ( + 48 pg/ml vs −6 pg/ml , p=0.03 ) at 6 months . Desphospho-uncarboxylated Matrix Gla protein levels fell in the intervention group compared to placebo at 6 months ( −130 [ SD 117 ] pmol/L vs + 13 [ SD 180 ] pmol/L , p<0.001 ) . No change was seen in endothelial function ( between group difference −0.3 % [ 95%CI −1.3 to 0.8 ] , p=0.62 ) . A modest , non-significant improvement in pulse wave velocity was seen in the vitamin K group ( −0.8 m/s [ 95%CI −1.8 to 0.3 ] , p=0.15 ) while all other vascular and physical function outcomes unchanged . Conclusions Six months of vitamin K2 supplementation did not improve markers of vascular health or physical function in older patients with vascular disease BACKGROUND Vitamin K modulates cytokines involved in bone turnover , including interleukin-6 ( IL-6 ) and osteoprotegerin in vitro . OBJECTIVE The objective of this study was to assess 1 ) associations between measures of vitamin K status [ plasma phylloquinone and serum percentage of undercarboxylated osteocalcin ( % ucOC ) ] and IL-6 , osteoprotegerin , and C-reactive protein ( CRP ) concentrations and 2 ) the effect of daily 500 mug phylloquinone supplementation for 3 y on cytokine concentrations . DESIGN Concentrations of IL-6 , osteoprotegerin , and CRP and bone mineral density ( BMD ) were measured at baseline and after 3 y of follow-up in 379 healthy men and women ( 60 - 81 y ; 58.5 % women ) participating in a r and omized trial that studied the effect of vitamin K supplementation on bone loss . RESULTS Cross-sectionally , plasma phylloquinone was inversely associated with IL-6 and CRP , whereas serum % ucOC was inversely associated with IL-6 . Osteoprotegerin was associated positively with plasma phylloquinone and inversely with % ucOC . No differences were observed in the 3-y change in IL-6 , osteoprotegerin , and CRP concentrations between participants who received phylloquinone supplementation and those who did not . Overall , no association was observed between the 3-y changes in circulating cytokines and BMD . CONCLUSIONS Poor vitamin K status was associated with high concentrations of cytokines involved in bone turnover , but vitamin K supplementation did not confer a decrease in cytokine concentrations . The healthy status of this cohort may explain a lack of effect of vitamin K supplementation on cytokine concentrations . This trial was registered with www . clinical trials.gov as NCT00183001 OBJECTIVE —Vitamin K has a potentially beneficial role in insulin resistance , but evidence is limited in humans . We tested the hypothesis that vitamin K supplementation for 36 months will improve insulin resistance in older men and women . RESEARCH DESIGN AND METHODS —This was an ancillary study of a 36-month , r and omized , double-blind , controlled trial design ed to assess the impact of supplementation with 500 μg/day phylloquinone on bone loss . Study participants were older nondiabetic men and women ( n = 355 ; aged 60–80 years ; 60 % women ) . The primary outcome of this study was insulin resistance as measured by homeostasis model assessment ( HOMA-IR ) at 36 months . Fasting plasma insulin and glucose were examined as the secondary outcomes . RESULTS —The effect of 36-month vitamin K supplementation  on HOMA-IR differed by sex ( sex × treatment interaction P = 0.02 ) . HOMA-IR was statistically significantly lower at the 36-month visit among men in the supplement group versus the men in the control group ( P = 0.01 ) after adjustment for baseline HOMA-IR , BMI , and body weight change . There were no statistically significant differences in outcome measures between intervention groups in women . CONCLUSIONS —Vitamin K supplementation for 36 months at doses attainable in the diet may reduce progression of insulin resistance in older men 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 prospect i ve cohort study in 38,094 Dutch men and women , aged 20–70 years .  Dietary phylloquinone and menaquinones intakes were assessed using a vali date d food frequency question naire . 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-μg 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 Background Vitamin K , as a cofactor in the gamma carboxylation of certain glutamic acid ( Gla ) residues , has been related to glucose metabolism and insulin sensitivity . Osteocalcin , also known as bone γ-carboxyglutamic acid , increases β-cell proliferation as well as insulin and adiponectin secretion , which improve glucose tolerance and insulin sensitivity . Thus , the purpose of the present study was to examine the possible role of adiponectin as a mediator of glucose homeostasis following phylloquinone supplementation in premonopause women with prediabetes . Methods Eighty two women were r and omized to consume vitamin k1 supplement ( n = 39 ) or placebo ( n = 43 ) for four weeks . Participants in vitamin K1 treatment group received one pearl softgel capsule containing 1000 micrograms phylloquinone while the placebo group received one placebo capsules daily for four weeks . The Blood sample s were collected at baseline and after a four-week intervention to quantify osteocalcin , adiponectin , leptin and relevant variables . Results Phylloquinone supplementation significantly increased serum adiponectin concentration ( 1.24 ± 1.90 compared with −0.27 ± 1.08 μg/ml ) , and did not alter total osteocalcin ( 0.50 ± 4.11 compared with 0.13 ± 1.85 ng/ml ) and leptin ( −0.29 ± 8.23 compared with −1.15 ± 5.25 ng/ml ) compared with placebo . Adjustments for total osteocalcin and adiponectin using analysis of covariance ( ANCOVA ) did not affect the association of glycemic status with related variables . Conclusions In conclusion our study demonstrated that phylloquinone supplementation  improved glycemic status in premonopausal prediabetic women independent of adiponectin . Trial registration This trial was registered in Iranian Registry of Clinical Trials with ID number of I RCT 2013120915724N1 CONTEXT AND OBJECTIVE Because it has been suggested that osteocalcin ( OC ) , an osteoblast-derived hormone , is a new link between bone and glucose metabolism , we tested whether serum carboxylated osteocalcin ( cOC ) and undercarboxylated osteocalcin ( ucOC ) levels are independently associated with the development of type 2 diabetes in subjects at high cardiovascular risk . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve , nested case-control study was conducted using data from the Prevención con Dieta Mediterránea ( PREDIMED ) study . We included 153 case subjects with newly diagnosed diabetes and 306 individually matched control subjects free of diabetes identified during a mean 5-year follow-up . Conditional logistic regression models were used to estimate matched odds ratios for incident diabetes according to categories of both forms of OC measured by ELISAs . RESULTS Baseline serum concentrations of both forms of OC were significantly lower in case subjects than in control subjects . In subjects with incident cases of diabetes , concentrations of cOC , but not of ucOC , were inversely and significantly associated with homeostasis model assessment of insulin resistance levels ( β = -0.335 ) and with fasting glucose concentrations ( β = -0.044 ) in control subjects , independent of other relevant confounders . In the conditional logistic model that took into account the matching factors , the odds ratios for diabetes incidence in the lowest vs the highest tertile of cOC and ucOC were 2.03 ( 95 % confidence interval , 1.32 - 3.13 ) and 1.88 ( 1.23 - 2.85 ) , respectively . Further adjustment for family history of diabetes , lifestyle , and other confounding factors did not appreciably change the magnitude of these associations . CONCLUSION In a population at high cardiovascular risk , low concentrations of serum cOC and ucOC were strongly associated with an increased risk of incident diabetes Background / Objectives : A relationship between osteocalcin ( OC ) levels and factors associated with energy metabolism and insulin resistance has been reported recently . The aim of this study was to investigate whether modulation of ostecalcin isoforms via vitamin K1 supplementation would affect glucose metabolism or insulin sensitivity in prediabetic and premenopause women . Subjects/ Methods : Eighty-two prediabetic women were r and omized to consume vitamin K1 supplement ( n=39 ) or placebo ( n=43 ) for 4 weeks . Participants in the vitamin K1 supplement group received one pearl softgel capsule containing 1000 μm of phylloquinone , and the placebo group received one placebo capsule daily for 4 weeks . Blood sample s were collected at baseline and after the 4-week intervention period to quantify carboxylated OC ( cOC ) , undercarboxylated OC ( ucOC ) and relevant variables . Results : Phylloquinone supplementation increased the serum levels of cOC and decreased ucOC , compared with placebo ( 12.53±5.95 compared with 7.43±4.85 ng/ml and 2.47±1.91 compared with 4.79±2.43 ng/ml , respectively ; P<0.001 ) . Furthermore , intake of phylloquinone supplement led to significant decreases in % ucOC ( 17.97±12.24 compared with 43.80±19.86 ) and 2-h post-oral glucose tolerance test ( OGTT ) glucose ( 7.32±1.50 compared with 8.62±1.45 mmol/l ) , and 2- h post-OGTT insulin level ( 80.34±42.24 compared with 112.43±53.19 μIU/ml ) and increased insulin sensitivity index ( 2.46±0.71 compared with 1.75±0.61 ) compared with placebo . Overall , a significant association was found between changes in % ucOC and changes in 2-h post-OGTT glucose ( r=0.308 , P=0.028 ) . Conclusions : The results of this study demonstrated that vitamin K1 supplementation for 4 weeks did not affect insulin resistance in premenopausal and prediabetic women but had beneficial effects on glycemic status and insulin sensitivity Background Cardiovascular disease is the major cause of death in the Western world , but some recent studies indicate that vitamin K may play a role in atherosclerosis protection . Aim of study The aim of this study was to evaluate the effect of phylloquinone supplementation on blood lipids , inflammatory markers and fibrinolytic activity in postmenopausal women . Methods Thirty-one postmenopausal women completed this placebo-controlled , r and omized crossover study and received 500 µg phylloquinone or placebo in addition to their habitual diet during two periods of 6 weeks ’ duration . Blood concentration of lipids , inflammatory markers and fibrinolytic parameters were measured after each period . Results Inflammatory markers , fibrinolytic parameters , total cholesterol and LDL-C were unaffected by the supplementation , whereas a 15 % increase was seen in triacylglycerols ( P = 0.015 ) and a 5 % decrease in HDL-C ( P = 0.06 ) . Conclusions Six weeks supplementation with a dose of phylloquinone similar to that obtainable from the diet induced a deterioration of the lipid profile with no improvement in any of the other risk markers analysed . Thus , these results do not support a cardioprotective effect of vitamin K as has been suggested by others
target: 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 .
  Our analysis suggests no effect of vitamin K supplementation on insulin sensitivity
background: OBJECTIVE To perform a systematic review and meta- analysis of r and omized , placebo-controlled trials to assess the effect of vitamin K supplementation on insulin sensitivity .