Biological Role of Vitamin K-With Particular Emphasis on Cardiovascular and Renal Aspects.

Vitamin K (VK) plays many important functions in the body. The most important of them include the contribution in calcium homeostasis and anticoagulation. Vascular calcification (VC) is one of the most important mechanisms of renal pathology. The most potent inhibitor of this process-matrix Gla protein (MGP) is VK-dependent. Chronic kidney disease (CKD) patients, both non-dialysed and hemodialysed, often have VK deficiency. Elevated uncarboxylated matrix Gla protein (ucMGP) levels indirectly reflected VK deficiency and are associated with a higher risk of cardiovascular events in these patients. It has been suggested that VK intake may reduce the VC and related cardiovascular risk. Vitamin K intake has been suggested to reduce VC and the associated cardiovascular risk. The role and possibility of VK supplementation as well as the impact of anticoagulation therapy on VK deficiency in CKD patients is discussed.

Fetal intracranial hemorrhage and maternal vitamin K deficiency induced by total parenteral nutrition: A case report.

RATIONALE: Fetal brain hemorrhage is rare. It is caused mainly by maternal trauma or fetal coagulation disorder, but in some cases, vitamin K deficiency may be the cause. PATIENT CONCERNS: We describe the case of a pregnant woman with bowel obstruction who was susceptible to vitamin K deficiency due to oral diet restriction, decreased intestinal absorption, and limited intravenous vitamin K supplementation. DIAGNOSIS: After 18 days of intermittent total parenteral nutrition, acute onset of severe fetal brain hemorrhage developed. INTERVENTIONS: After acute onset of fetal brain hemorrhage, the patient underwent an emergency cesarean section at 25 + 3 weeks of gestation due to fetal non-reassuring fetal monitoring. OUTCOMES: The Apgar score at birth was 0/0, and despite cardiopulmonary resuscitation, neonatal death was confirmed. After the baby was delivered, we checked the maternal upper abdominal cavity and found a massive adhesion in the small bowel to the abdominal wall near the liver and stomach with an adhesion band. The adhesion band, presumably a complication of previous hepatobiliary surgery, appeared to have caused small bowel obstruction. Adhesiolysis between the small bowel and abdominal wall was performed. LESSONS: This case demonstrates that even relatively short-term total parenteral nutrition can cause severe fetal brain hemorrhage. Vitamin K supplementation is required for mothers who are expected to be vitamin K deficient, especially if they are on total parenteral nutrition for more than 3 weeks.

Vitamin K and D Supplementation and Bone Health in Chronic Kidney Disease-Apart or Together?

Vitamin K (VK) and vitamin D (VD) deficiency/insufficiency is a common feature of chronic kidney disease (CKD), leading to impaired bone quality and a higher risk of fractures. CKD patients, with disturbances in VK and VD metabolism, do not have sufficient levels of these vitamins for maintaining normal bone formation and mineralization. So far, there has been no consensus on what serum VK and VD levels can be considered sufficient in this particular population. Moreover, there are no clear guidelines how supplementation of these vitamins should be carried out in the course of CKD. Based on the existing results of preclinical studies and clinical evidence, this review intends to discuss the effect of VK and VD on bone remodeling in CKD. Although the mechanisms of action and the effects of these vitamins on bone are distinct, we try to find evidence for synergy between them in relation to bone metabolism, to answer the question of whether combined supplementation of VK and VD will be more beneficial for bone health in the CKD population than administering each of these vitamins separately.

Dietary vitamin K is remodeled by gut microbiota and influences community composition.

Vitamins have well-established roles in bacterial metabolism. Menaquinones (MKn, n = prenyl units in sidechain) are bacterially produced forms of vitamin K produced by the gut microbiota and consumed in the diet. Little is known about the influence of dietary vitamin K quinones on gut microbial composition and MKn production. Here, male and female C57BL6 mice were fed a vitamin K deficient diet or vitamin K sufficient diets containing phylloquinone (PK, plant-based vitamin K form), MK4, and/or MK9. DNA was extracted from cecal contents and 16S sequencing conducted to assess microbial composition. Cecal microbial community composition was significantly different in vitamin K deficient female mice compared to females on vitamin K sufficient diets (all p < .007). Parallel trends were seen in male mice, but were not statistically significant (all p > .05 but <0.1). Next, stable isotope-labeled vitamin K quinones were supplemented to male and female C57BL6 mice (2H7PK, 13C11MK4, 2H7MK7, 2H7MK9) and to an in vitro fermentation model inoculated with human stool (2H7PK, 2H7MK4, 2H7MK9, or vitamin K precursor 2H8-menadione). Vitamin K quinones in feces and culture aliquots were measured using LC-MS. In vivo, supplemented vitamin K quinones were remodeled to other MKn (2H7- or 13C6-labeled MK4, MK10, MK11, and MK12), but in vitro only the precursor 2H8-menadione was remodeled to 2H7MK4, 2H7MK9, 2H7MK10, and 2H7MK11. These results suggest that dietary vitamin K deficiency alters the gut microbial community composition. Further studies are needed to determine if menadione generated by host metabolism may serve as an intermediate in dietary vitamin K remodeling in vivo.

Randomised Controlled Trial of Nutritional Supplement on Bone Turnover Markers in Indian Premenopausal Women.

Young Indian women may be at risk of poor bone health due to malnutrition. The aim of this study was to examine the effects on bone metabolism of a nutritional supplement in women aged 25 to 44. The nutritional supplement was a protein-rich beverage powder fortified with multi-micronutrients including calcium (600 mg), vitamin D (400 IU), and vitamin K (55 mcg) per daily serving, while a placebo supplement was low-protein non-fortified isocaloric beverage powder. This 6-month randomised, controlled trial showed favorable changes in bone turnover markers (decreased) and calcium homeostasis; such changes in older adults have been associated with slowing of bone loss and reduced fracture risk. For example, serum CTX decreased by about 30% and PINP by about 20% as a result of the increase in calcium intake. There were also changes in the ratio of carboxylated to undercarboxylated osteocalcin and such changes have been linked to a slowing of bone loss in older subjects. For example, the ratio increased by about 60% after 3 months as a result in the improvement in vitamin K status. Finally, there were improvements in the status of B vitamins, and such changes have been associated with reductions in homocysteine, but it is uncertain whether this would affect fracture risk. The product was generally well tolerated. This study shows the nutritional supplement holds promise for improved bone health among young Indian women.

Efficacy and safety of sorafenib plus vitamin K treatment for hepatocellular carcinoma: A phase II, randomized study.

The previous retrospective study suggested that dosing vitamin K may enhance the anticancer action of sorafenib against hepatocellular carcinoma. To confirm it, we performed a phase II, randomized, open-label study. Patients with hepatocellular carcinoma were randomly assigned to receive sorafenib + vitamin K2 (menatetrenone, 45 mg daily, orally) or sorafenib only. Between 1 May 2012 and 1 May 2016, 68 patients were screened. Forty-four eligible patients were assigned at a 1:1 ratio to each cohort. The objective response rate in the vitamin K-dosed group was significantly higher than that in the sorafenib only group (27.3% vs 4.5%, respectively; p = 0.039). The median time of progression-free survival was significantly extended in the vitamin K-dosed group compared with the sorafenib only group (4.9 months vs 2.7 months, respectively; hazard ratio (HR), 0.44; 95% confidence interval (CI): 0.21-0.89; p = 0.018). Although there was no significant difference between the two groups in the median time of overall survival, patients in the vitamin K-dosed group with a complete response or partial response achieved a significantly extended median time of overall survival compared with the other patients in the vitamin K-dosed group or the patients in the sorafenib only group (26.1 months vs 9.0 months; HR, 0.34; 95% CI: 0.11-0.95; p = 0.046 or 11.5 months; HR, 0.16; 95% CI: 0.034-0.70; p = 0.006, respectively). Dosing vitamin K could augment the anticancer action of sorafenib against HCC.

[Complex management of type 2 heparin-induced thrombocytopenia in patients with major bleeding tendency: two case report]. / Prise en charge de la thrombopénie induite par l'héparine immuno-allergique de type 2 au travers de deux cas cliniques chez des patients à risque hémorragique majeur.

Type 2 heparin-induced thrombocytopenia (HIT 2) is a rare pro-thrombotic disorder occurring in patients treated with heparin. It is defined as a clinical-biological syndrome associating the sudden onset of a thrombocytopenia, characterized by a drop of more than 50% of the initial platelet count, and thrombosis. We report two cases of HIT 2 occurring in patients with major bleeding tendency. The first HIT occurred in a patient whose management, in accordance with current guidelines, made it possible to control the thrombocytopenia and the anticoagulation despite the complexity of adapting and monitoring treatments in the context of recent cerebral hemorrhage. The second refers to an autoimmune HIT, which occurred in a patient whose management required the use of alternative therapies to the standard treatments suggested for HIT 2, to correct the severe refractory thrombocytopenia.

Effect of Fat-Soluble Vitamins A, D, E and K on Vitamin Status and Metabolic Profile in Patients with Fat Malabsorption with and without Urolithiasis.

Patients with intestinal fat malabsorption and urolithiasis are particularly at risk of acquiring fat-soluble vitamin deficiencies. The aim of the study was to evaluate the vitamin status and metabolic profile before and after the supplementation of fat-soluble vitamins A, D, E and K (ADEK) in 51 patients with fat malabsorption due to different intestinal diseases both with and without urolithiasis. Anthropometric, clinical, blood and 24-h urinary parameters and dietary intake were assessed at baseline and after ADEK supplementation for two weeks. At baseline, serum aspartate aminotransferase (AST) activity was higher in stone formers (SF; n = 10) than in non-stone formers (NSF; n = 41) but decreased significantly in SF patients after supplementation. Plasma vitamin D and E concentrations increased significantly and to a similar extent in both groups during intervention. While plasma vitamin D concentrations did not differ between the groups, vitamin E concentrations were significantly lower in the SF group than the NSF group before and after ADEK supplementation. Although vitamin D concentration increased significantly in both groups, urinary calcium excretion was not affected by ADEK supplementation. The decline in plasma AST activity in patients with urolithiasis might be attributed to the supplementation of ADEK. Patients with fat malabsorption may benefit from the supplementation of fat-soluble vitamins ADEK.

Beneficial Effects of Vitamin K Status on Glycemic Regulation and Diabetes Mellitus: A Mini-Review.

Type 2 diabetes mellitus is a chronic disease that is characterized by hyperglycemia, insulin resistance, and dysfunctional insulin secretion. Glycemic control remains a crucial contributor to the progression of type 2 diabetes mellitus as well as the prevention or delay in the onset of diabetes-related complications. Vitamin K is a fat-soluble vitamin that plays an important role in the regulation of the glycemic status. Supplementation of vitamin K may reduce the risk of diabetes mellitus and improve insulin sensitivity. This mini-review summarizes the recent insights into the beneficial effects of vitamin K and its possible mechanism of action on insulin sensitivity and glycemic status, thereby suppressing the progression of diabetes mellitus.

Causes of Vitamin K Deficiency in Patients on Haemodialysis.

Background: A low vitamin K status is common in patients on haemodialysis, and this is considered one of the reasons for the accelerated atherosclerosis in these patients. The vitamin is essential in activation of the protein Matrix Gla Protein (MGP), and the inactive form, dp-ucMGP, is used to measure vitamin K status. The purpose of this study was to investigate possible underlying causes of low vitamin K status, which could potentially be low intake, washout during dialysis or inhibited absorption capacity. Moreover, the aim was to investigate whether the biomarker dp-ucMGP is affected in these patients. Method: Vitamin K intake was assessed by a Food Frequency Questionnaire (FFQ) and absorption capacity by means of D-xylose testing. dp-ucMGP was measured in plasma before and after dialysis, and phylloquinine (vitamin K1) and dp-ucMGP were measured in the dialysate. Changes in dp-ucMGP were measured after 14 days of protein supplementation. Results: All patients had plasma dp-ucMGP above 750 pmol/L, and a low intake of vitamin K. The absorption capacity was normal. The difference in dp-ucMGP before and after dialysis was -1022 pmol/L (p < 0.001). Vitamin K1 was not present in the dialysate but dp-ucMGP was at a high concentration. The change in dp-ucMGP before and after protein supplementation was -165 pmol/L (p = 0.06). Conclusion: All patients had vitamin K deficiency. The reason for the low vitamin K status is not due to removal of vitamin K during dialysis or decreased absorption but is plausibly due to a low intake of vitamin K in food. dp-ucMGP is washed out during dialysis, but not affected by protein intake to a clinically relevant degree.

Vitamin K for kidney transplant organ recipients: investigating vessel stiffness (ViKTORIES): study rationale and protocol of a randomised controlled trial.

BACKGROUND: Renal transplant recipients (RTRs) exhibit increased vascular stiffness and calcification; these parameters are associated with increased cardiovascular risk. Activity of endogenous calcification inhibitors such as matrix gla protein (MGP) is dependent on vitamin K. RTRs commonly have subclinical vitamin K deficiency. The Vitamin K in kidney Transplant Organ Recipients: Investigating vEssel Stiffness (ViKTORIES) study assesses whether vitamin K supplementation reduces vascular stiffness and calcification in a diverse population of RTR. METHODS AND ANALYSIS: ViKTORIES (ISRCTN22012044) is a single-centre, phase II, parallel-group, randomised, double-blind, placebo-controlled trial of the effect of vitamin K supplementation in 90 prevalent RTR. Participants are eligible if they have a functioning renal transplant for >1 year. Those on warfarin, with atrial fibrillation, estimated glomerular filtration rate <15 mL/min/1.73 m2 or contraindications to MRI are excluded. Treatment is with vitamin K (menadiol diphosphate) 5 mg three times per week for 1 year or matching placebo. All participants have primary and secondary endpoint measures at 0 and 12 months. The primary endpoint is ascending aortic distensibility on cardiac MR imaging. Secondary endpoints include vascular calcification (coronary artery calcium score by CT), cardiac structure and function on MR, carotid-femoral pulse wave velocity, serum uncarboxylated MGP, transplant function, proteinuria and quality of life. The study is powered to detect 1.0×10-3 mm Hg-1 improvement in ascending aortic distensibility in the vitamin K group relative to placebo at 12 months. Analyses will be conducted as between-group differences at 12 months by intention to treat. DISCUSSION: This trial may identify a novel, inexpensive and low-risk treatment to improve surrogate markers of cardiovascular risk in RTR.

Effects of vitamin K dietary supplementation in pulmonary dysfunction induced by 7,12-dimethylbenz[a]anthracene in rat.

One of the well-known toxicants of the mammary tissue is 7,12-dimethylbenz[a]anthracene (DMBA). This study was carried out to investigate the possible prophylactic's role of increased dietary intake of vitamin K on the induction of toxicity in the lung tissue. Twenty-eight Wistar albino rats (120-150 g) were randomly divided into different groups. Group 1 served as the control and were fed with a normal diet (containing the recommended daily allowance of vitamin K (0.0075%)). Groups 2 and 3 received a single dose of DMBA (80 mg/kg body weight) intragastically. In addition, group 3 rats were maintained on surplus vitamin K diet (0.075% diet) as against the group 2 animals that were on a normal diet. Group 4 rats were on surplus vitamin K diet (0.075% diet) throughout the experimental period of 16 weeks. Our results revealed that supplementation of diet with surplus vitamin K significantly increased the activities of catalase. Superoxide dismutase, glutathione-S-transferase, and glutathione peroxidase were significantly increased in the serum and lungs when compared with the DMBA-treated group, which was maintained on a normal diet. Significant alterations in malondialdehyde, nitric oxide, granulocyte-macrophage colony-stimulating factor, and interleukin 17F were observed in rats challenged with DMBA-fed normal diets but were normalized in rats with surplus vitamin K. These alterations and reversal were confirmed by histopathology studies. This suggests the prophylactic benefit of increased dietary intake of vitamin K without any observed deleterious effect on DMBA-induced pulmonary toxicity.

Time in Therapeutic Range for Dialysis Patients on Warfarin: Determination and the Effect of Dietary Intervention.

This study aimed to identify the time in therapeutic range (TTR) for dialysis patients on warfarin, and improve TTR with dietary review and intervention of interacting foods. We identified 151 patients undergoing hemodialysis in two units who were being treated with warfarin from January 1, 2010, through February 1, 2018, who were included in the overall TTR study. Of these, 15 patients were available to undergo the dietary intervention. International normalized ratio values were collected retrospectively for all eligible hemodialysis patients, and TTR was calculated for each period in which the patient was on hemodialysis. Patients who were available and agreed to the intervention underwent targeted dietician review of interacting foods, and their TTR post-treatment was calculated. The median (interquartile range [IQR]) TTR was 44 (IQR, 29 to 53) % among the 151 patients. Among the 15 patients who underwent the intervention, median (IQR) TTR was 52 (IQR, 32 to 56) pre-intervention and 51 (IQR, 38 to 69) post-intervention (P=0.53). TTR for dialysis patients is low in this overall cohort despite patients being seen at an integrated health care system. Focused improvement projects such as dietary review of interacting foods may help increase a patient's TTR.

Vitamin K supplementation for cystic fibrosis.

BACKGROUND: Malabsorption and deficiency of fat-soluble vitamins K may occur in cystic fibrosis, a genetic disorder affecting multiple organs. Vitamin K is known to play an important role in both blood coagulation and bone formation, hence the role of supplementation of vitamin K in this category needs to be reviewed. This is an updated version of the review. OBJECTIVES: To assess the effects of vitamin K supplementation in people with cystic fibrosis and to investigate the hypotheses that vitamin K will decrease deficiency-related coagulopathy, increase bone mineral density, decrease risk of fractures and improve quality of life in people with CF. Also to determine the optimal dose and route of administration of vitamin K for people with CF (for both routine and therapeutic use). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 12 August 2019. SELECTION CRITERIA: Randomised controlled trials of all preparations of vitamin K used as a supplement compared to either no supplementation (or placebo) at any dose or route and for any duration, in patients with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently screened papers, extracted trial details and assessed their risk of bias. The quality of the evidence was assessed using the GRADE criteria. MAIN RESULTS: Three trials (total 70 participants, aged 8 to 46 years) assessed as having a moderate risk of bias were included. One trial compared vitamin K to placebo, a second to no supplementation and the third compared two doses of vitamin K. No trial in either comparison reported our primary outcomes of coagulation and quality of life or the secondary outcomes of nutritional parameters and adverse events. Vitamin K versus control Two trials compared vitamin K to control, but data were not available for analysis. One 12-month trial (n = 38) compared 10 mg vitamin K daily or placebo in a parallel design and one trial (n = 18) was of cross-over design with no washout period and compared 5 mg vitamin K/week for four-weeks to no supplementation for four-weeks. Only the 12-month trial reported on the primary outcome of bone formation; we are very uncertain whether vitamin K supplementation has any effect on bone mineral density at the femoral hip or lumbar spine (very low-quality evidence). Both trials reported an increase in serum vitamin K levels and a decrease in undercarboxylated osteocalcin levels. The cross-over trial also reported that levels of proteins induced by vitamin K absence (PIVKA) showed a decrease and a return to normal following supplementation, but due to the very low-quality evidence we are not certain that this is due to the intervention. High-dose versus low-dose vitamin K One parallel trial (n = 14) compared 1 mg vitamin K/day to 5 mg vitamin K/day for four weeks. The trial did report that there did not appear to be any difference in serum undercarboxylated osteocalcin or vitamin K levels (very low-quality evidence). While the trial reported that serum vitamin K levels improved with supplementation, there was no difference between the high-dose and low-dose groups. AUTHORS' CONCLUSIONS: There is very low-quality evidence of any effect of vitamin K in people with cystic fibrosis. While there is no evidence of harm, until better evidence is available the ongoing recommendations by national CF guidelines should be followed.

Nutritional considerations for the prevention and treatment of postmenopausal osteoporosis.

Osteoporosis commonly affects postmenopausal women and accounts for 300,000 hip fractures in the United States each year. More women are deferring or discontinuing pharmacologic treatment because of intolerable adverse reactions or fear of long-term safety. Supplementing dietary intake of certain vitamins and minerals can have positive effects on bone parameters. Calcium is frequently recommended for osteoporotic patients but many not confer much benefit toward bone density. Certain forms of vitamins A and K have been shown to increase bone density. Isoflavones and phytates are phytochemicals found in soy foods that are comparable to bisphosphonates when consumed at certain levels. Lastly, increasing certain daily fruit and vegetable servings can improve bone health. Nutritional interventions are typically safe alternatives that should be considered for postmenopausal women who are seeking nonpharmacologic treatment options for osteoporosis.

Warfarin drug interaction with vitamin K and other foodstuffs / Interacción de la droga warfarina con la vitamina K y otros productos alimenticios

Vitamin K is found in higher concentrations in dark green plant and in vegetable oils. The adequate intake of vitamin K is 90 and 120ug/day for adult elderly men and women, respectively. The main function of vitamin K is to act as an enzymatic cofactor for hepatic prothrombin synthesis, blood coagulation factors, and anticoagulant proteins. Prominent among the many available anticoagulants is warfarin, an antagonist of vitamin K, which exerts its anticoagulant effects by inhibiting the synthesis of vitamin K1 and vitamin KH2. From the beginning of the therapy it is necessary that the patients carry out the monitoring through the prothrombin time and the international normalized ratio. However, it is known that very low intake and/or fluctuations in vitamin K intake are as harmful as high consumption. In addition, other foods can interact with warfarin, despite their content of vitamin K. The aim of this study was to gather information on the drug interaction of warfarin with vitamin K and with dietary supplements and other foods.

La vitamina K se encuentra en concentraciones más altas en plantas de color verde oscuro y en aceites vegetales. La ingesta adecuada de vitamina K es de 90 y 120 ug/día para hombres y mujeres adultos mayores, respectivamente. La función principal de la vitamina K es actuar como un cofactor enzimático para la síntesis de protrombina hepática, factores de coagulación de la sangre y proteínas anticoagulantes. Entre los muchos anticoagulantes disponibles destaca la warfarina, un antagonista de la vitamina K, que ejerce sus efectos anticoagulantes al inhibir la síntesis de la vitamina K1 y la vitamina KH2. Desde el inicio de la terapia, es necesario que los pacientes realicen el monitoreo a través del tiempo de protrombina y la proporción normalizada internacional. Sin embargo, se sabe que una ingesta muy baja y/o fluctuaciones en la ingesta de vitamina K son tan dañinas como un consumo alto. Además, otros alimentos pueden interactuar con la warfarina, a pesar de su contenido de vitamina K. El objetivo de este estudio fue recopilar información sobre la interacción de los medicamentos de la warfarina con la vitamina K y con los suplementos dietéticos y otros alimentos.

Quantifying dietary vitamin K and its link to cardiovascular health: a narrative review.

Cardiovascular disease is the leading cause of death and disability worldwide. Recent work suggests a link between vitamin K insufficiency and deficiency with vascular calcification, a marker of advanced atherosclerosis. Vitamin K refers to a group of fat-soluble vitamins important for blood coagulation, reducing inflammation, regulating blood calcium metabolism, as well as bone metabolism, all of which may play a role in promoting cardiovascular health. Presently, there is a lack of a comprehensive vitamin K database on individual foods, which are required to accurately calculate vitamin K1 and K2 intake for examination in epidemiological studies. This has likely contributed to ambiguity regarding the recommended daily intake of vitamin K, including whether vitamin K1 and K2 may have separate, partly overlapping functions. This review will discuss the presence of: (i) vitamin K1 and K2 in the diet; (ii) the methods of quantitating vitamin K compounds in foods; and (iii) provide an overview of the evidence for the cardiovascular health benefits of vitamin K in observational and clinical trials.

Vitamin K as a Diet Supplement with Impact in Human Health: Current Evidence in Age-Related Diseases.

Vitamin K health benefits have been recently widely shown to extend beyond blood homeostasis and implicated in chronic low-grade inflammatory diseases such as cardiovascular disease, osteoarthritis, dementia, cognitive impairment, mobility disability, and frailty. Novel and more efficient nutritional and therapeutic options are urgently needed to lower the burden and the associated health care costs of these age-related diseases. Naturally occurring vitamin K comprise the phylloquinone (vitamin K1), and a series of menaquinones broadly designated as vitamin K2 that differ in source, absorption rates, tissue distribution, bioavailability, and target activity. Although vitamin K1 and K2 sources are mainly dietary, consumer preference for diet supplements is growing, especially when derived from marine resources. The aim of this review is to update the reader regarding the specific contribution and effect of each K1 and K2 vitamers in human health, identify potential methods for its sustainable and cost-efficient production, and novel natural sources of vitamin K and formulations to improve absorption and bioavailability. This new information will contribute to foster the use of vitamin K as a health-promoting supplement, which meets the increasing consumer demand. Simultaneously, relevant information on the clinical context and direct health consequences of vitamin K deficiency focusing in aging and age-related diseases will be discussed.

Gamma-glutamyl-carboxylated Gas6 mediates positive role of vitamin K on lowering hyperglycemia in type 2 diabetes.

The role of gamma-glutamyl-carboxylated growth arrest-specific 6 (cGas6) in mediating the beneficial effect of vitamin K (VK) on regulating glucose metabolism remains elusive. We took a three-pronged approach-evaluating human type 2 diabetes (T2D), high-fat diet (HFD)-fed mice, and in vitro cultured myotubes-to address this. Blood samples were collected from both T2D patients and control subjects; skeletal muscle and blood samples were collected from HFD-fed mice with or without VK supplementation (1, 3, and 5 µg/kg BW, 8 weeks); and the molecular mechanism of cGas6 was dissected using GGCX, Gas6, AXL, or IR siRNA-transfected cultured myotubes. Plasma cGas6 and VK were significantly lower in T2D patients compared with control; and cGas6 and the cGas6/Gas6 ratio were positively correlated with VK and inversely correlated with fasting glucose in T2D patients, suggesting an important role for plasma VK and cGas6 in maintaining glucose homeostasis in T2D. Animal studies revealed that VK supplementation dose-dependently upregulated plasma cGas6; stimulated the protein expression of cGas6, PI3K, pAKT, and GLUT4 in skeletal muscle; and reduced hyperglycemia in HFD-fed T2D mice. And in vitro mRNA knockdown studies demonstrated the requirement of cGas6 in mediating the positive effect of VK on glucose metabolism via stimulating the PI3K/pAKT/GLUT4 signaling pathway in high glucose-treated myotubes. These results demonstrate a significant involvement of cGas6 in mediating the beneficial effect of VK on regulating glucose homeostasis in T2D.