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Vitamin K deficiency is common among kidney transplant recipients (KTRs) and likely contributes to progressive vascular calcification and stiffness. In this single-center, randomized, double-blind, placebo-controlled trial, we aimed to investigate the effects of vitamin K supplementation on the primary end point, serum calcification propensity (calciprotein particle maturation time, T50), and secondary end points arterial stiffness (pulse wave velocity [PWV]) and vitamin K status in 40 vitamin K-deficient KTRs (plasma dephosphorylated uncarboxylated matrix Gla protein [dp-ucMGP] ≥500 pmol/L). Participants (35% female; age, 57 ± 13 years) were randomized 1:1 to vitamin K2 (menaquinone-7, 360 μg/day) or placebo for 12 weeks. Vitamin K supplementation had no effect on calcification propensity (change in T50 vs baseline +2.3 ± 27.4 minutes) compared with placebo (+0.8 ± 34.4 minutes; Pbetween group = .88) but prevented progression of PWV (change vs baseline -0.06 ± 0.26 m/s) compared with placebo (+0.27 ± 0.43 m/s; Pbetween group = .010). Vitamin K supplementation strongly improved vitamin K status (change in dp-ucMGP vs baseline -385 [-631 to -269] pmol/L) compared with placebo (+39 [-188 to +183] pmol/L; Pbetween group < .001), although most patients remained vitamin K-deficient. In conclusion, vitamin K supplementation did not alter serum calcification propensity but prevented progression of arterial stiffness, suggesting that vitamin K has vascular effects independent of calciprotein particles. These results set the stage for longer-term intervention studies with vitamin K supplementation in KTRs.TRIAL REGISTRY: EU Clinical Trials Register (EudraCT Number: 2019-004906-88) and the Dutch Trial Register (NTR number: NL7687).

Context The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood. Objective This study investigates potential crosstalk between FGF23 and glucose homeostasis. Methods First, we investigated the effect of glucose loading on plasma C-terminal FGF23 levels and its temporal relationship with changes in plasma phosphate in 45 overweight (body mass index [BMI] 25-30) individuals using time-lag analyses. Second, we studied cross-sectional associations of plasma C-terminal FGF23 levels with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI > 30) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI. Results After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag = .04). In the population-based cohort (N = 5482; mean age 52 years, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (β = .13 [.03-.23]; P = .01), insulin (β = .10 [.03-.17]; P < .001), and proinsulin (β = .06 [0.02-0.10]; P = .01) at baseline. On longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events [4%]; fully adjusted hazard ratio [HR] 1.66 [95% CI, 1.06-2.60]; P = .03) and development of obesity (241 events [6%]; fully adjusted HR 1.84 [95% CI, 1.34-2.50]; P < .001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI. Conclusion Glucose loading has phosphate-independent effects on FGF23 and, vice versa, FGF23 is associated with glucose, insulin and proinsulin levels, and obesity. These findings suggest crosstalk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.

Objective: Vascular calcification contributes to the cause of cardiovascular disease. The calciprotein particle maturation time (T 50 ) in serum, a measure of calcification propensity, has been linked with adverse outcomes in patients with chronic kidney disease, but its role in the general population is unclear. We investigated whether serum T 50 is associated with cardiovascular mortality in a large general population-based cohort. Approach and Results: The relationship between serum T 50 and cardiovascular mortality was studied in 6231 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) cohort. All-cause mortality was the secondary outcome. Mean (±SD) age was 53±12 years, 50% were male, and mean serum T 50 was 329±58 minutes. A shorter serum T 50 is indicative of a higher calcification propensity. Serum T 50 was inversely associated with circulating phosphate, age, estimated glomerular filtration rate, and alcohol consumption, whereas plasma magnesium was positively associated with serum T 50 ( P R 2 =0.281). During median (interquartile range) follow-up for 8.3 (7.8–8.9) years, 364 patients died (5.8%), of whom 95 (26.1%) died from a cardiovascular cause. In multivariable Cox proportional hazard models, each 60 minutes decrease in serum T 50 was independently associated with a higher risk of cardiovascular mortality (fully adjusted hazard ratio [95% CI], 1.22 [1.04–1.36], P =0.021). This association was modified by diabetes mellitus; stratified analysis indicated a more pronounced association in individuals with diabetes mellitus. Conclusions: Serum T 50 is independently associated with an increased risk of cardiovascular mortality in the general population and thus may be an early and potentially modifiable risk marker for cardiovascular mortality.

We read with interest the comment by Janssen et al. [...]

Purpose Circulating and dietary magnesium have been shown to be inversely associated with the prevalence of cardiovascular disease (CVD) and mortality in both high and low-risk populations. We aimed to examine the association between dietary magnesium intake and several measures of vascular structure and function in a prospective cohort. Methods We included 789 participants who participated in the vascular screening sub-cohort of the Hoorn Study, a population-based, prospective cohort study. Baseline dietary magnesium intake was estimated with a validated food frequency questionnaire and categorised in energy-adjusted magnesium intake tertiles. Several measurements of vascular structure and function were performed at baseline and most measurements were repeated after 8 years of follow-up (n = 432). Multivariable linear and logistic regression was performed to study the cross-sectional and longitudinal associations of magnesium intake and intima-media thickness (IMT), augmentation index (Aix), pulse wave velocity (PWV), flow-mediated dilatation (FMD), and peripheral arterial disease (PAD). Results Mean absolute magnesium intake was 328 ± 83 mg/day and prior CVD and DM2 was present in 55 and 41% of the participants, respectively. Multivariable regression analyses did not demonstrate associations between magnesium intake and any of the vascular outcomes. Participants in the highest compared to the lowest magnesium intake tertile demonstrated in fully adjusted cross-sectional analyses a PWV of −0.21 m/s (95% confidence interval −1.95, 1.52), a FMD of −0.03% (−0.89, 0.83) and in longitudinal analyses an IMT of 0.01 mm (−0.03, 0.06), an Aix of 0.70% (−1.69, 3.07) and an odds ratio of 0.84 (0.23, 3.11) for PAD Conclusion We did not find associations between dietary magnesium intake and multiple markers of vascular structure and function, in either cross-sectional or longitudinal analyses.

Background Phosphate (Pi) toxicity is a strong determinant of vascular calcification development in chronic kidney disease (CKD). Magnesium (Mg2+) may improve cardiovascular risk via vascular calcification. The mechanism by which Mg2+ counteracts vascular calcification remains incompletely described. Here we investigated the effects of Mg2+ on Pi and secondary crystalline calciprotein particles (CPP2)-induced calcification and crystal maturation. Methods Vascular smooth muscle cells (VSMCs) were treated with high Pi or CPP2 and supplemented with Mg2+ to study cellular calcification. The effect of Mg2+ on CPP maturation, morphology and composition was studied by medium absorbance, electron microscopy and energy dispersive spectroscopy. To translate our findings to CKD patients, the effects of Mg2+ on calcification propensity (T50) were measured in sera from CKD patients and healthy controls. Results Mg2+ supplementation prevented Pi-induced calcification in VSMCs. Mg2+ dose-dependently delayed the maturation of primary CPP1 to CPP2 in vitro. Mg2+ did not prevent calcification and associated gene and protein expression when added to already formed CPP2. Confirmatory experiments in human serum demonstrated that the addition of 0.2 mmol/L Mg2+ increased T50 from healthy controls by 51 ± 15 min (P Conclusions Our results demonstrate that crystalline CPP2 mediates Pi-induced calcification in VSMCs. In vitro, Mg2+ delays crystalline CPP2 formation and thereby prevents Pi-induced calcification.

BACKGROUND: Observational studies suggest that high dairy intake is associated with a lower blood pressure (BP).OBJECTIVE: We aimed to investigate the effect of a high-dairy diet (HDD) as compared with a low-dairy diet (LDD) on BP in overweight middle-aged adults.METHODS: Fifty-two overweight men and women were included in a randomized crossover intervention study. Each subject consumed 2 isocaloric diets for 6 wk, an LDD (≤1 dairy portion per day) and an HDD (6 or 5 reduced-fat dairy portions for men and women, respectively), with a 4-wk washout period in between the diets during which the subjects consumed their habitual diet. BP was measured at the start and at the end of the intervention diets. The effect of the intervention study was evaluated by 2-sample t tests. Mixed-model analyses were used for adjustment for the potential influence of changes in dietary protein and mineral intake and risk factors for hypertension including body weight and plasma cholesterol.RESULTS: Consumption of an HDD as compared with an LDD resulted in a reduction of both systolic BP (mean ± SD: 4.6 ± 11.2 mm Hg, P < 0.01) and diastolic BP (3.0 ± 6.7 mm Hg, P < 0.01). In further analyses, these reductions appeared dependent on the concomitant increase in calcium intake.CONCLUSIONS: This intervention study shows that an HDD results in a reduction of both systolic and diastolic BP in overweight middle-aged men and women. If the results of our study are reproduced by other studies, advice for high dairy intake may be added to treatment and prevention of high BP. This trial was registered at trialregister.nl as NTR4899.

High circulating dephosphorylated (dp) uncarboxylated (uc) matrix Gla protein (MGP) and uc osteocalcin (OC) concentrations are regarded as markers of vitamin K-deficiency. However, because MGP and OC are small molecules, they may potentially pass the glomerulus, and their blood concentrations may strongly depend on kidney function. However, many studies with vitamin K-status parameters do not structurally adjust for baseline kidney function, and detailed studies on kidney function-dependence of vitamin K-status markers are lacking. We therefore measured plasma dp-ucMGP using a chemiluminescent assay in 578 kidney transplant recipients (41% females, age 56 ± 13y, 7.5 (3.2 to 13.7)y after transplantation, eGFR 49 ± 17 ml/min/1.73m2) participating in the prospective TransplantLines Cohort Studies. Additionally, dp-carboxylated MGP, ucOC and carboxylated OC were measured using ELISA in plasma of a subgroup of 60 participants. Finally, dp-ucMGP was measured in a separate cohort of 124 kidney transplant recipients before and three months after kidney transplantation. Dp-ucMGP positively correlated with creatinine, cystatin C, and negatively with eGFR (Spearman’s ρ 0.54, 0.60, and -0.54, respectively, p &lt, 0.001 for all), and each 10 mL/min/1.73m2 increase in eGFR was associated with a 14.0% lower dp-ucMGP. Additionally, dp-ucMGP strongly declined after kidney transplantation (pretransplantation: 1252 (868 to 1744) pmol/L to posttransplantation: 609 (451 to 914) pmol/L, p &lt, 0.001). Proportions of dp-ucMGP over total MGP and ucOC over total OC were not associated with eGFR. This study highlights that dp-ucMGP is strongly associated with kidney function, and that levels strongly decrease after kidney transplantation. We therefore propose adequate adjustment for kidney function, or the use of kidney function-independent parameters such as proportion of uncarboxylated MGP or OC in the assessment of vitamin K-status in clinical practice and research.

The influence of dairy on the gut microbiome has not been studied extensively. We performed a randomized cross-over study to analyze the effect of high dairy intake on the gut microbiome. Subjects were randomly assigned to a high-dairy diet (HDD) (5&ndash, 6 dairy portions per day) and a low-dairy diet (LDD) (&le, 1 dairy portion per day) for 6 weeks with a washout period of 4 weeks in between both diets. The gut microbiome was assessed using 16S rRNA gene sequencing. Compositionality and functionality of the gut microbiome was assessed using Quantitative Insights Into Microbial Ecology (QIIME) and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Stool consistency was evaluated using the Bristol stool chart. In total, 46 healthy overweight subjects (BMI range 25&ndash, 30 kg/m2) completed both intervention periods. During the HDD, there was a significantly higher abundance of the genera Streptococcus, Leuconostoc, and Lactococcus, and the species Streptococcus thermophilus, Erysipelatoclostridium ramosum and Leuconostoc mesenteroides (pFDR &lt, 0.10). Furthermore, during the HDD, there was a significantly lower abundance of the genera Faecalibacterium and Bilophila, and the species Faecalibacterium prausnitzii, Clostridium aldenense, Acetivibrio ethanolgignens, Bilophila wadsworthia and Lactococcus lactis (pFDR &lt, 0.10). There were eight subjects who became constipated during the HDD and these subjects all had a lower abundance of F. prausnitzii. This is the first cross-over study in which the effect of an HDD compared to an LDD on the gut microbiome has been studied. An HDD led to a significantly different composition of the gut microbiome, with a particularly lower abundance of F. prausnitzii and a higher abundance of S. thermophilus. Constipation was observed in several subjects during the HDD. Predicted metabolic pathways were not significantly altered due to an HDD.

Background: The consumption of products rich in cereal fiber and with a low glycemic index is implicated in a lower risk of metabolic diseases. Previously, we showed that the consumption of fiber-rich pasta compared with bread resulted in a lower rate of appearance of exogenous glucose and a lower glucose clearance rate quantified with a dual-isotope technique, which was in accordance with a lower insulin and glucose-dependent insulinotropic polypeptide response.Objective: To gain more insight into the acute metabolic consequences of the consumption of products resulting in differential glucose kinetics, postprandial metabolic profiles were determined.Methods: In a crossover study, 9 healthy men (mean +/- SEM age: 21 +/- 0.5 y; mean SEM body mass index (kg/m(2)): 22 +/- 0.5] consumed wheat bread (132 g) and fresh pasta (119 g uncooked) enriched with wheat bran (10%) meals. A total of 134 different metabolites in postprandial plasma samples (at -5, 30, 60, 90, 120, and 180 min) were quantified by using a gas chromatography mass spectrometry based metabolomics approach (secondary outcomes). Two-factor ANOVA and advanced multivariate statistical analysis (partial least squares) were applied to detect differences between both food products.Results: Forty-two different postprandial metabolite profiles were identified, primarily representing pathways related to protein and energy metabolism, which were on average 8% and 7% lower after the men consumed pasta rather than bread, whereas concentrations of arabinose and xylose were 58% and 53% higher, respectively. Arabinose and xylose are derived from arabinoxylans, which are important components of wheat bran. The higher bioavailability of arabinose and xylose after pasta intake coincided with a lower rate of appearance of glucose and amino acids. We speculate that this higher bioavailability is due to higher degradation of arabinoxylans by small intestinal microbiota, facilitated by the higher viscosity of arabinoxylans after pasta intake than after bread intake.Conclusion: This study suggests that wheat bran, depending on the method of processing, can increase the viscosity of the meal bolus in the small intestine and interfere with macronutrient absorption in healthy men, thereby influencing postprandial glucose and insulin responses. This trial was registered at www.controlled-trials.com as ISRCTN42106325.

Frequent high postprandial glucose concentrations could be a risk factor for the development of type 2 diabetes and/or cardiovascular disease. Starchy products can play a role in the prevention of these hyperglycemic events, if starch-derived glucose is released into the circulation in a more slow and attenuated manner (slowly available starch). In this chapter, we describe the mechanisms that operate to maintain normal plasma glucose levels and the causes and consequences of hyperglycemia. Secondly, possible targets to slow down the rate at which starch-derived glucose becomes available for absorption in the gastrointestinal tract are discussed in more detail. Thirdly, we give an overview over the methods to monitor starch digestion in vitro and in vivo and the current (nutritional) strategies to prevent hyperglycemia. We conclude by describing promising approaches to better characterize starchy food products and to extend the choice of products with slowly available starch.

Postprandial high glucose and insulin responses after starchy food consumption, associated with an increased risk of developing several metabolic diseases, could possibly be improved by altering food structure. We investigated the influence of a compact food structure; different wheat products with a similar composition were created using different processing conditions. The postprandial glucose kinetics and metabolic response to bread with a compact structure (flat bread, FB) was compared to bread with a porous structure (control bread, CB) in a randomized, crossover study with ten healthy male volunteers. Pasta (PA), with a very compact structure, was used as the control. The rate of appearance of exogenous glucose (RaE), endogenous glucose production, and glucose clearance rate (GCR) was calculated using stable isotopes. Furthermore, postprandial plasma concentrations of glucose, insulin, several intestinal hormones and bile acids were analyzed. The structure of FB was considerably more compact compared to CB, as confirmed by microscopy, XRT analysis (porosity) and density measurements. Consumption of FB resulted in lower peak glucose, insulin and glucose-dependent insulinotropic polypeptide (ns) responses and a slower initial RaE compared to CB. These variables were similar to the PA response, except for RaE which remained slower over a longer period after PA consumption. Interestingly, the GCR after FB was higher than expected based on the insulin response, indicating increased insulin sensitivity or insulin-independent glucose disposal. These results demonstrate that the structure of wheat bread can influence the postprandial metabolic response, with a more compact structure being more beneficial for health. Bread-making technology should be further explored to create healthier products.

Starchy food products differ in the rate of starch digestion, which can affect their metabolic impact. In this study, we examined how the in vivo starch digestibility is reflected by the glycemic response, because this response is often used to predict starch digestibility. Ten healthy male volunteers [age 21 60.5 y, BMI 23 60.6 kg/m 2 (mean6SEM)] participated in a cross-over study, receiving three different meals: pasta with normal wheat bran (PA) and bread with normal (CB) or purple wheat bran (PBB). Purple wheat bran was added in an attempt to decrease the rate of starch digestion. The meals were enriched in 13 C and the dual isotope technique was applied to calculate the rate of appearance of exogenous glucose (RaE). The 13 C-isotopic enrichment of glucose in plasma was measured with GC/combustion/isotope ratio MS (IRMS) and liquid chromatography/IRMS. Both IRMS techniques gave similar results. Plasma glucose concentrations [2-h incremental AUC (iAUC)] did not differ between the test meals. The RaE was similar after consumption of CB and PBB, showing that purple wheat bran in bread does not affect in vivo starch digestibility. However, the iAUC of RaE after men consumed PA was less than after they consumed CB (P , 0.0001) despite the similar glucose response. To conclude, the glycemic response does not always reflect the in vivo starch digestibility. This could have implications for intervention studies in which the glycemic response is used to characterize test products. J. Nutr. 142: 258‐263, 2012.

Purpose Underlying mechanisms of the beneficial health effects of low glycemic index starchy foods are not fully elucidated yet. We varied the wheat particle size to obtain fiber-rich breads with a high and low glycemic response and investigated the differences in postprandial glucose kinetics and metabolic response after their consumption. Methods Ten healthy male volunteers participated in a randomized, crossover study, consuming 13C-enriched breads with different structures; a control bread (CB) made from wheat flour combined with wheat bran, and a kernel bread (KB) where 85 % of flour was substituted with broken wheat kernels. The structure of the breads was characterized extensively. The use of stable isotopes enabled calculation of glucose kinetics: rate of appearance of exogenous glucose, endogenous glucose production, and glucose clearance rate. Additionally, postprandial plasma concentrations of glucose, insulin, glucagon, incretins, cholecystokinin, and bile acids were analyzed. Results Despite the attempt to obtain a bread with a low glycemic response by replacing flour by broken kernels, the glycemic response and glucose kinetics were quite similar after consumption of CB and KB. Interestingly, the glucagon-like peptide-1 (GLP-1) response was much lower after KB compared to CB (iAUC, P

Starchy food products differ in the rate of starch digestion, which can affect their metabolic impact. In this study, we examined how the in vivo starch digestibility is reflected by the glycemic response, because this response is often used to predict starch digestibility. Ten healthy male volunteers [age 21 ± 0.5 y, BMI 23 ± 0.6 kg/m² (mean ± SEM)] participated in a cross-over study, receiving three different meals: pasta with normal wheat bran (PA) and bread with normal (CB) or purple wheat bran (PBB). Purple wheat bran was added in an attempt to decrease the rate of starch digestion. The meals were enriched in ¹³C and the dual isotope technique was applied to calculate the rate of appearance of exogenous glucose (RaE). The ¹³C-isotopic enrichment of glucose in plasma was measured with GC/combustion/isotope ratio MS (IRMS) and liquid chromatography/IRMS. Both IRMS techniques gave similar results. Plasma glucose concentrations [2-h incremental AUC (iAUC)] did not differ between the test meals. The RaE was similar after consumption of CB and PBB, showing that purple wheat bran in bread does not affect in vivo starch digestibility. However, the iAUC of RaE after men consumed PA was less than after they consumed CB (P0.0001) despite the similar glucose response. To conclude, the glycemic response does not always reflect the in vivo starch digestibility. This could have implications for intervention studies in which the glycemic response is used to characterize test products.

Background: Previously we observed that the consumption of pasta and bread resulted in a similar glycemic response, despite a slower intestinal influx rate of glucose from the pasta. Underlying mechanisms of this effect were not clear.Objective: The objective was to investigate the differences in glucose kinetics and hormonal response after consumption of products with slow and rapid in vivo starch digestibility but with a similar glycemic response.Design: Ten healthy male volunteers participated in a crossover study and consumed C-13-enriched wheat bread or pasta while receiving a primed-continuous D-[6,6-H-2(2)] glucose infusion. The dual-isotope technique enabled calculation of the following glucose kinetics: rate of appearance of exogenous glucose (RaE), endogenous glucose production, and glucose clearance rate (GCR). In addition, postprandial plasma concentrations of glucose, insulin, glucagon, and glucose-dependent insulinotropic polypeptide (GIP) were analyzed.Results: GIP concentrations after pasta consumption were lower than after bread consumption and strongly correlated with the RaE (r = 0.82, P Conclusions: Slower intestinal uptake of glucose from a starchy food product can result in lower postprandial insulin and GIP concentrations, but not necessarily in a lower glycemic response, because of a slower GCR. Even without being able to reduce postprandial glycemia, products with slowly digestible starch can have beneficial long-term effects. These types of starchy products cannot be identified by using the glycemic index and therefore another classification system may be necessary. This trial was registered at controlled-trials.com as ISRCTN42106325. Am J Clin Nutr 2012; 96: 1017-24.