A critical review of the effects of vitamin K on glucose and lipid homeostasis: its potential role in the prevention and management of type 2 diabetes

Abstract

In recent years, our knowledge regarding the physiological role of vitamin K has expanded beyond regulation of coagulation to include many other aspects of human health. In the present review, we aimed to evaluate the existing evidence for beneficial effects of vitamin K on type 2 diabetes and components of the metabolic syndrome as risk factors for cardiovascular disease. Increased dietary intake of vitamin K has been linked to lower incidence of type 2 diabetes mellitus (T2DM), possibly through its enhancement of insulin production and sensitivity. Additionally, higher plasma levels of vitamin K1 have been associated with lower T2DM risk and decreased insulin resistance, and supplementation trials also suggest a positive influence of vitamin K on glucose regulation. Vitamin K might also beneficially affect serum lipids and lipid metabolism. However, the available data remain controversial. Additionally, different studies use different approaches to assess vitamin K status owing to the absence of a generally accepted marker, which further complicates data evaluation. In conclusion, vitamin K possibly improves glucose and lipid metabolism and could be an emerging target in the context of prevention and control of T2DM, insulin resistance, and dyslipidemia.

Introduction

Vitamin K is a lipophilic micronutrient that was initially studied for its role in blood coagulation [1, 2]. In living organisms, it is found in two forms, namely, vitamin K1 (phylloquinone) and vitamin K2 (menaquinone 4-13, according to the number of isoprenoid units contained in its molecule). Phylloquinone is widely present in plants, and menaquinone is synthesized by bacteria. Both take part in electron transfer processes. In humans, dietary intake of phylloquinone comes mainly from vegetables and vegetable oils, while menaquinone is sourced from animal products and foods that undergo bacterial fermentation [3, 4]. Menaquinone is also produced by intestinal flora and may be absorbed to some extent [5]. Although phylloquinone is the main form of vitamin K in the diet, it can be converted to menaquinone-4 in cells by the enzyme UbiA prenyltransferase domain-containing protein 1 [6]. Both forms have been detected in various body tissues such as the liver, kidneys, pancreas, lung, heart, brain, and fat [7].

Vitamin K acts as a cofactor for the enzyme γ-glutamyl carboxylase which modifies specific proteins through the carboxylation of glutamic acid residues to γ-carboxyglutamic acid [8, 9]. Vitamin K–dependent proteins (VKDPs) need γ-carboxyglutamic acid residues in order to interact with positively charged substances, such as Ca2+ ions, and perform their physiological functions [10, 11]. This group of proteins has recently expanded to include not only coagulation factors but also other factors, such as osteocalcin, matrix Gla protein (MGP), and growth arrest-specific 6 (Gas6) among others. As a result, there is renewed research interest in the role of vitamin K in human health and disease apart from hemostasis.

Several studies have reported on the possible effects of vitamin K on glucose levels, insulin secretion, and resistance. Moreover, reduced inflammation and body fat and improved serum lipid profile may coexist with these effects but are less well studied. Therefore, this article presents a critical review of the literature on the role of vitamin K in the prevention and treatment of type 2 diabetes, obesity, and dyslipidemia.

Methodology

Inclusion criteria

Studies fulfilling the following criteria were considered eligible for inclusion in the review:

  1. 1.

    Original research articles.

  2. 2.

    Studies investigating the relationship of vitamin K with type 2 diabetes and metabolic risk factors.

  3. 3.

    Full text written in English.

In this review, we chose not to use exclusion criteria and to take all existing relevant studies into consideration. This was done due to the small number of studies available.

Search strategy

A literature search based on PubMed listings up to 10 June 2020 using “vitamin K OR phylloquinone OR menaquinone” AND “diabetes OR insulin OR glucose OR metabolic OR fat OR adipose OR cholesterol OR lipids” as search terms identified 2848 articles. Moreover, after an examination of the reference list of these articles, the articles that were judged relevant were selected for inclusion in this review. Finally, only 29 studies were included in this study.

In vitro and animal studies

Studies investigating the effect of vitamin K on glucose-dependent insulin secretion have found increased insulin production in rat and mouse cell lines treated with vitamin K, and impaired response in rats fed with a low vitamin K diet [12, 13]. The administration of vitamin K in ovariectomized rats has shown beneficial effects similar to those of exercise as regards blood glucose and insulin levels [14]. In studies using rat models of T2DM, supplementation with vitamin K, either K1 or K2, appears to downregulate fasting blood glucose and reduce glycated hemoglobin (HbA1c) and insulin resistance [15, 16]. Additionally, vitamin K1 or K2 supplementation has been demonstrated to be associated with decreased body fat accumulation and lower serum triglyceride (TRG) levels in rats [17].

The proposed mechanism through which vitamin K affects glucose metabolism involves activation of the AMP-activated protein kinase/sirtuin 1 pathway in the liver, which in turn upregulates phosphoinositide 3-kinase and glucose transporter 2 to reduce insulin resistance and fasting glucose [16]. Moreover, the same pathway activates peroxisome proliferator-activated receptor alpha and increases lipid catabolism. Vitamin K may also lower insulin resistance by reducing inflammation and oxidative stress. Specifically, it has been found to decrease NF-κB activity and thus cytokine production, especially IL-6 [16, 18,19,20,21]. Furthermore, vitamin K–dependent carboxylation of Gas6 appears to be important for its functionality [22], and carboxylated Gas6 may thus lower insulin resistance either through the AMP-activated protein kinase/peroxisome proliferator-activated receptor alpha pathway in the liver, as mentioned above, or the phosphoinositide 3-kinase/Akt pathway in muscles [23,24,25,26]. In addition, osteocalcin, which is a VKDP, is likely to play a role in insulin secretion and glucose regulation. However, the effect of vitamin K–dependent carboxylation on osteocalcin function possibly differs between humans and animals and remains to be clarified [27, 28]. Although in vitro and animal studies suggest a causal beneficial effect of vitamin K on insulin resistance and diabetes mellitus, the extrapolation of this evidence to humans should be performed with appropriate caution.

Human studies

Glucose metabolism and T2DM

Dietary vitamin K intake

Convincing evidence coming from two studies points to a possible link between dietary vitamin K intake and incidence of diabetes. The first study investigated a large cohort of Dutch men and women. Dietary intake of vitamin K was assessed using a food frequency questionnaire, and newly diagnosed cases of T2DM were recorded for a median follow-up of 10.3 years [29]. Menaquinone intake was observed to be inversely associated with the incidence of T2DM, while the intake of phylloquinone showed a tendency towards a similar association [29]. The population of the second study consisted of elderly subjects with a high risk of cardiovascular disease. Phylloquinone intake was estimated annually using a food frequency questionnaire, and the incidence of T2DM was recorded for a median of 5.5 years [30]. The risk of incident T2DM was shown to be reduced by about 17% for every 100 μg per day higher phylloquinone consumption. Additionally, subjects who increased their phylloquinone intake during the follow-up period were 51% less likely to develop T2DM compared to those who did not [30].

The possible relationship between vitamin K intake and markers of glucose metabolism has also attracted increasing research interest. In a cohort of 2719 adult men and women, higher phylloquinone intake was related to better insulin sensitivity, as estimated by the insulin sensitivity index and a 2-h oral glucose tolerance test (2h-OGTT). However, no association was found with fasting glucose levels, homeostatic model assessment of insulin resistance (HOMA-IR), and HbA1c [31]. Sakamoto et al. found that healthy young volunteers with the largest reported vitamin K intake demonstrated improved acute insulin response in a 75-g OGTT [32]. In a recently published study, dietary phylloquinone intake was associated with lower blood glucose and insulin resistance among women [33]. Better insulin sensitivity was also reported in women and a subgroup of men. In study subjects with high fat mass index, however, phylloquinone intake was negatively correlated with the homeostatic model assessment of β-cell function (HOMA-β). This finding cannot be adequately explained in the context of the above study alone. An important limitation of the study is that participants were selected randomly and persons with metabolic disorders, whether treated or not, may have been enrolled. Furthermore, all three studies used a cross-sectional design, and thus, firm conclusions about causality cannot be reached. Additionally, these studies relied on dietary recall methods in order to calculate vitamin K intake, which are expected to result in some degree of inaccuracy due to the subjective nature of self-reported records for dietary habits in the past [34].

Based on the abovementioned considerations, increased dietary intake of vitamin K appears to be associated with lower incidence of T2DM, possibly through the augmentation of insulin production and sensitivity. However, an important limitation of these observational studies was that the results may have been influenced by the effects of various confounders linked to vitamin K intake. A diet rich in phylloquinone is most probably a plant-based diet also rich in other potentially beneficial nutrients and is more likely connected to a generally healthier lifestyle. On the other hand, such explanations would not be valid for menaquinone, which is mainly sourced from animal-based products in Western diets. Moreover, the exact mechanisms underlying the effects of dietary vitamin K on glucose homeostasis remain to be elucidated.

Plasma phylloquinone levels

With regard to the relationship between plasma phylloquinone levels and markers of glucose metabolism, the available studies indicate a possible inverse association between plasma phylloquinone levels and insulin resistance. Specifically, a small study found that plasma phylloquinone was lower in diabetics compared with healthy controls [16]. Among diabetics, plasma phylloquinone correlated negatively with fasting glucose and HOMA-IR [16]. In a cross-sectional study of 932 older men and women, a trend towards an inverse association of plasma phylloquinone with HOMA-IR was detected only in the subgroup of men with normal triglyceride levels. Such an effect was not demonstrated in women [35].

These study outcomes should be interpreted after taking into account the relatively short elimination half-life of phylloquinone and the possible fluctuations in plasma phylloquinone levels depending on the content of previous meals. Therefore, it remains uncertain whether plasma phylloquinone levels accurately reflect long-term dietary intake and vitamin K status [36,37,38,39,40]. However, it should be acknowledged that plasma phylloquinone levels reflect more directly and accurately the exposure of body tissues to vitamin K than measures of dietary vitamin K intake.

In a large, Mendelian randomization study, Zwakenberg et al. analyzed data from the EPIC-InterAct case cohort study, DIAGRAM, and the UK Biobank. Four single-nucleotide polymorphisms that are associated with circulating phylloquinone levels were examined. They showed that higher genetically predicted circulating phylloquinone may be associated with a lower risk of type 2 diabetes [41]. This finding is in agreement with and thus further supports the results of the aforementioned studies regarding the association of dietary vitamin K intake with the risk of incident diabetes. However, various other factors may affect circulating vitamin K levels, and more data would be necessary to confirm a causal relationship between vitamin K and its metabolic pathway and the development of type 2 diabetes (Table 1).

Table 1 Effect of vitamin K intake and vitamin K status on type 2 diabetes

Vitamin K supplementation and glucose homeostasis

Several studies have investigated the effects of phylloquinone supplementation on glucose metabolism in differing populations. The dosage and duration of administration also varied among them.

Centi et al. showed that supplementation of healthy individuals with 500 μg per day phylloquinone for 21 days did not cause any significant change in HOMA-IR despite a drop in the levels of undercarboxylated osteocalcin (ucOC), a marker of phylloquinone status [42]. Similar results were reported from a small placebo-controlled trial which enrolled postmenopausal women [43]. Twenty-one women received 1000 μg per day of phylloquinone and 21 received placebo for 12 months. UcOC decreased with supplementation but HOMA-IR did not change [43]. A randomized, double-blind trial investigated nondiabetic older men and women who received either a multivitamin formulation containing phylloquinone at a dose of 500 μg per day or the same formulation without phylloquinone for 36 months [44]. Insulin resistance, as assessed by HOMA-IR, decreased in men but not in women [44]. Interestingly, this finding is in agreement with the results of Centi et al., which may imply that older men with higher plasma phylloquinone are less insulin resistant [35]. In addition, women who received supplementation had a higher prevalence of overweight and obesity than those who did not [44]. Among these women, an inverse relation was observed between BMI and plasma phylloquinone levels, which might be the result of an impaired response of women with higher BMI to supplementation due to increased vitamin K sequestration in adipose tissue. Apart from that, the observed disparity could also be produced by hormonal differences between men and women. The exact nature of such an effect, however, remains unknown. In another randomized trial, 82 prediabetic women received either phylloquinone at a dose of 1000 μg per day or placebo for 4 weeks. Supplementation decreased serum levels of 2h-OGTT glucose and insulin and, as a result, increased the insulin sensitivity index. HOMA-IR and HOMA-β, which depend on fasting levels of glucose and insulin, did not change [45].

The results of the abovementioned studies indicate that older men and those with already impaired glucose metabolism may be more likely to benefit from an improved phylloquinone status. The mechanisms underlying this effect remain to be investigated. It is possible that these two groups present altered properties of their adipose tissue and plasma lipids or differences in baseline vitamin K status and utilization in body tissues. The presence of excessive, dysfunctional body fat may lead to lower plasma vitamin K levels and availability even after supplementation. Such populations could require higher dosages for longer time periods to reap benefits from supplementation.

On the other hand, the potential outcomes of vitamin K2 supplementation have only been examined in healthy young males. Forty-two healthy men received 30 mg per day of menaquinone-4 or placebo for 4 weeks. Supplementation led to a higher insulin sensitivity index and disposition index, but did not influence the acute insulin response, compared to placebo [46]. A higher dose of 90mg per day was administered to 12 healthy volunteers in another study. Serum levels of descarboxy prothrombin were used as a marker of vitamin K status. The authors reported improved glucose tolerance in a 2h-OGTT conducted after 1 week of intake. This effect was detected only in participants with higher plasma levels of descarboxy prothrombin at the beginning of the study, indicating a possible vitamin K insufficiency at baseline [47]. Despite being obviously underpowered, the results of this study suggest that baseline vitamin K status should be taken into account in the interpretation of supplementation outcomes (Table 2).

Table 2 Effect of vitamin K supplementation on type 2 diabetes

The relationship of vitamin K to body fat

Analysis of adipose tissue samples obtained from obese individuals [48] has revealed high concentrations of vitamin K, a finding that supports the hypothesis that adipose tissue is a site of binding or storage of this vitamin. The same authors provide evidence that in women, increased body fat may be associated with lower plasma concentrations of phylloquinone and higher descarboxy prothrombin levels, a marker indicating lower vitamin K status. However, another marker, the percentage of ucOC, did not change. These associations were not confirmed in men. A possible explanation for this could be the smaller proportion of body fat found in men, but additional factors may also play a role [48].

In a study conducted by Dam et al., improved vitamin K status was possibly associated with lower waist circumference in men and women [49]. The serum desphospho-uncarborxylated matrix-Gla protein level was used to assess vitamin K status in this study.

These data appear to be supported by a study of menaquinone administration in postmenopausal women [50]. At the start of the study, women with the highest waist circumference and android fat distribution also had the poorest vitamin K status (low carboxylated OC). After 3 years of menaquinone-7 supplementation, good responders, based on serum cOC concentrations, were characterized by reduced fat in the abdominal area compared to poor responders and controls. By contrast, in a large cross-sectional study, the amount of phylloquinone consumed by young adults was found to be associated with lower prevalence of metabolic syndrome, but this association was not driven by reduced central adiposity [51].

The relationship of vitamin K to serum lipids

Pan et al. found that in young adults, a diet rich in phylloquinone was associated with lower prevalence of decreased high-density lipoprotein cholesterol (HDL-C), high serum triglycerides, and hyperglycemia. However, after adjustment for dietary confounders the effect remained significant only for hyperglycemia [51]. In other observational studies, on the other hand, no correlation was found between the participants’ phylloquinone intake and lipid profile [29, 33, 49]. Favorable outcomes have been reported regarding the influence of dietary menaquinone intake on lipid profile. Dam et al. have recorded lower triglyceride concentrations in adults with high menaquinone intakes, both cross-sectionally and longitudinally [49]. Beulens et al. found a tendency towards higher HDL-C associated with higher menaquinone intake in a baseline sample of their cohort [29].

While it cannot be ruled out that vitamin K might have a direct beneficial effect on lipid metabolism, the connection between dietary vitamin K intake and improved HDL-C and TRG levels could also be mediated by its positive effect on insulin resistance [16]. This hypothesis is further supported by the fact that most studies detect changes in TRG rather than low-density lipoprotein cholesterol. The possibility of an association between vitamin K and lipoprotein(a) was not examined in the included studies. Considering the fact that both intervene in the process of thrombosis, such a relationship could be an important field of research.

Two randomized clinical studies failed to show a positive effect of phylloquinone administration on serum lipids. These included women with rheumatoid arthritis and postmenopausal women, respectively [52, 53]. In the latter study, in fact, higher serum triglycerides and possibly lower HDL-C were observed after administration. Long-term administration of menaquinone to patients undergoing peritoneal dialysis has led to favorable results in lipid profile, including a decrease in low-density lipoprotein cholesterol without any change in TRG and HDL-C [54]. This effect became significant beyond the first 6 months of menaquinone supplementation. Vitamin K deficiency seems to be more prevalent among chronic kidney disease patients than in the general population [55]. The results of these studies are not directly comparable since lipoprotein metabolism is altered in end-stage renal disease. Larger studies are needed, in several population groups, to define the relationship between vitamin K supplementation and lipid profile (Table 3).

Table 3 Effect of vitamin K on serum lipids, body fat, and METs

Conclusion

In conclusion, there are indications that vitamin K might beneficially regulate glucose and lipid metabolism. In this respect, improved vitamin K status could be an emerging treatment target in the prevention and management of T2DM. However, the available evidence is still inconclusive. New, better, and more accurate markers for long-term intake and status of vitamin K are needed. Recognition of specific population groups that are more likely to be vitamin deficient and larger, randomized trials are then required to assess the role of vitamin K supplementation in type 2 diabetes, insulin resistance, and dyslipidemia.

Abbreviations

T2DM:

Type 2 diabetes mellitus

FFQ:

Food frequency questionnaire

OGTT:

Oral glucose tolerance test

HOMA-IR:

Homeostatic model assessment-insulin resistance

HOMA-β:

Homeostatic model assessment-β cell function

ucOC:

Undercarboxylated osteocalcin

cOC:

Carboxylated osteocalcin

HbA1c:

Glycated hemoglobin

HDL-C:

High-density lipoprotein-cholesterol

TRG:

Triglycerides

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Varsamis, N.A., Christou, G.A. & Kiortsis, D.N. A critical review of the effects of vitamin K on glucose and lipid homeostasis: its potential role in the prevention and management of type 2 diabetes. Hormones (2021). https://doi.org/10.1007/s42000-020-00268-w

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Keywords

  • Vitamin K
  • Diabetes
  • Insulin
  • Metabolic syndrome
  • Body fat
  • Cholesterol