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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2019 May 9;85(7):1443–1453. doi: 10.1111/bcp.13913

Acute interaction between oral glucose (75 g as Lucozade) and inorganic nitrate: Decreased insulin clearance, but lack of blood pressure‐lowering

Christopher N Floyd 1,2,[Link], Satnam Lidder 1,2,[Link], Joanne Hunt 1,2, Sami A Omar 1,2, Karen McNeill 1,2, Andrew J Webb 1,2,✉
PMCID: PMC6595348  PMID: 30845346

Abstract

Aims

Dietary inorganic nitrate (NO3 −) lowers peripheral blood pressure (BP) in healthy volunteers, but lacks such effect in individuals with, or at risk of, type 2 diabetes mellitus (T2DM). Whilst this is commonly assumed to be a consequence of chronic hyperglycaemia/hyperinsulinaemia, we hypothesized that acute physiological elevations in plasma [glucose]/[insulin] blunt the haemodynamic responses to NO3 −, a pertinent question for carbohydrate‐rich Western diets.

Methods

We conducted an acute, randomized, placebo‐controlled, double‐blind, crossover study on the haemodynamic and metabolic effects of potassium nitrate (8 or 24 mmol KNO3) vs. potassium chloride (KCl; placebo) administered 1 hour prior to an oral glucose tolerance test in 33 healthy volunteers.

Results

Compared to placebo, there were no significant differences in systolic or diastolic BP (P = 0.27 and P = 0.30 on ANOVA, respectively) with KNO3, nor in pulse wave velocity or central systolic BP (P = 0.99 and P = 0.54 on ANOVA, respectively). Whilst there were significant elevations from baseline for plasma [glucose] and [C‐peptide], no differences between interventions were observed. A significant increase in plasma [insulin] was observed with KNO3 vs. KCl (n = 33; P = 0.014 on ANOVA) with the effect driven by the high‐dose cohort (24 mmol, n = 13; P < 0.001 on ANOVA; at T = 0.75 h mean difference 210.4 pmol/L (95% CI 28.5 to 392.3), P = 0.012).

Conclusions

In healthy adults, acute physiological elevations of plasma [glucose] and [insulin] result in a lack of BP‐lowering with dietary nitrate. The increase in plasma [insulin] without a corresponding change in [C‐peptide] or [glucose] suggests that high‐dose NO3 − decreases insulin clearance. A likely mechanism is via NO‐dependent inhibition of insulin‐degrading enzyme.

Keywords: blood pressure, cardiology, cardiovascular, nitric oxide, nutrition, physiology

What is already known about this subject

  • Inorganic nitrate lowers blood pressure and pulse wave velocity in healthy individuals.

  • These effects are absent in those with, or at risk of, T2DM.

  • This is assumed to be a consequence of chronic hyperglycaemia/hyperinsulinaemia.

What this study adds

  • Acute physiological elevations of plasma [glucose] and [insulin] result in a lack of BP‐lowering with dietary nitrate.

  • High‐dose inorganic nitrate reduced insulin clearance, probably via NO‐dependent inhibition of insulin‐degrading enzyme.

1. INTRODUCTION

The role of dietary inorganic nitrate (NO3 −) as an alternative source of nitric oxide (NO) via the enterosalivary nitrate–nitrite–NO pathway is recognized as a physiological mediator of blood pressure (BP), endothelial function and platelet aggregation.1, 2, 3 In both healthy individuals and those with chronic cardiovascular conditions, NO3 − supplementation has been shown to increase exercise capacity.4, 5, 6, 7, 8 This beneficial effect is thought to arise from the action of NO on skeletal muscle where it modulates excitation‐contraction coupling, mitochondrial respiration, autoregulation of blood flow, and glucose homeostasis.9 However, individuals with, or at risk of, type 2 diabetes mellitus (T2DM) fail to exhibit a reduction in peripheral BP or pulse wave velocity (PWV) in response to NO3 − supplementation.10, 11, 12 There are a number of mechanisms that might contribute to this lack of effect including dysfunctional NO synthesis, increased NO scavenging and altered redox balance.13 To what extent this is a consequence of acute or chronic hyperglycaemia/hyperinsulinaemia is unknown.

Carbohydrate (CHO) ingestion also has established benefits on exercise performance.14 However, the effects of concurrent NO3 − and CHO intake on cardiovascular haemodynamics and glucose homeostasis (both important determinants of exercise capacity) have not been studied in detail.

Type two diabetes mellitus is a condition associated with excess CHO intake,15 although the aetiology of the condition is more complex.16 It has been observed that in both healthy individuals and those with T2DM, plasma [nitrate] and [nitrite] fall acutely in response to an oral glucose tolerance test (OGTT),17, 18 likely reflecting an increase in NO consumption. However, there is a lack of agreement with regard to basal plasma [nitrate] and [nitrite], with conflicting results reported.17, 19 This lack of agreement regarding basal concentrations may be the result of the use of the Griess test, which measures combined plasma [nitrate/nitrite] and is not sufficiently sensitive to measure physiological plasma [nitrite].

Systemic inhibition of NO synthesis results in a deterioration in glucose tolerance in non‐diabetic individuals in response to an OGTT, accompanied by an elevation in BP.20, 21 However, the effects of NO3 − supplementation on glucose homeostasis are less clear. In healthy individuals, NO3 − supplementation appears to result in lower plasma [glucose] post‐exercise,22, 23 but without changing homeostatic responses to glucose at rest.24, 25, 26 In those with, or at risk of T2DM, studies are heterogeneous in their design and report either an improvement or null effect of nitrate on insulin sensitivity following glucose administration.26, 27, 28, 29

In studies investigating the haemodynamic effects of NO3 − supplementation in individuals with T2DM there is greater consistency, as neither peripheral BP nor exercise tolerance are improved10, 11, 12; although we have demonstrated a lowering of central SBP with 6 months' dietary nitrate [24], with a decrease in left ventricular volumes.30 This lack of effect in those with impaired glucose tolerance may be due to impaired insulin‐mediated vasodilation,31, 32, 33 but whether this is a consequence of acute or chronic hyperglycaemia/hyperinsulinaemia has not been established.

The purpose of this study was to determine whether there is an interaction between NO3 − and glucose on BP and glucose homeostasis in healthy individuals. We hypothesized that acute physiological elevations in plasma [glucose] and [insulin] would blunt the haemodynamic responses to NO3 −. This study was therefore conducted to address two complementary questions: (i) is the BP response to NO3 − supplementation affected by concurrent glucose ingestion? and (ii) is the metabolic response to an OGTT affected by NO3 − supplementation?

2. METHODS

2.1. Participants

Participants were healthy, normotensive volunteers aged 18–45 years. All participants had a body mass index (BMI) 18–35 kg/m2, no current or recent illness and were not taking systemic medication other than the oral contraceptive pill. A negative urine dipstick result for nitrite was required on the morning of each visit.

The study was approved by the South East London Research Ethics Committee (10/H0802/52). Written informed consent was obtained from all participants.

2.2. Study protocol

We conducted an acute, randomized, placebo‐controlled, double‐blind, crossover study of potassium nitrate (KNO3) vs. potassium chloride (KCl; placebo) (both Martindale Pharma) followed by an OGTT performed 1 hour later. The study consisted of two independent cohorts based on the dose of KNO3/KCl ingested: (i) a ‘high‐dose’ cohort received 24 mmol, and (ii) a ‘low‐dose’ cohort received 8 mmol. Each study visit lasted 4 hours and was separated by a minimum of 7 days. The allocation to KNO3 or KCl for each participant was performed using a random, computer‐generated order produced by an independent researcher.

Participants were asked to fast overnight (>12 hours) and to avoid nitrate‐rich foods, strenuous exercise, smoking and the use of mouthwash for 24 hours before the study. To minimize any dietary confounders, participants were asked to consume the same meals for the day prior to each arm of the study.

On the day of the study and following an hour's equilibration period during which baseline measurements were taken (see below), participants were randomized to receive KNO3 vs. KCl at Time −1 h. Both were administered with low‐nitrate water (300 ml; Buxton Water) and an antacid (10–20 mL repeated if necessary; Gaviscon, GSK) to minimize gastrointestinal discomfort from the potassium supplement. A standard OGTT (75 g glucose as Lucozade, GSK) was performed at Time 0 h. A schematic of the events is presented in Figure 1.

Figure 1.

Figure 1

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Schematic of events. After acclimatization (−2 h to −1 h), participants received KNO3 or KCl tablets (Time −1 h) followed by an oral glucose tolerance test (OGTT; 75 mg glucose) at Time 0 h. Blood pressure (BP) measurement, blood tests and urine collection occurred as indicated

2.3. Measurements

Blood pressure and heart rate (HR) readings were taken in triplicate every 15 min using an oscillometric BP monitor (Omron 705CP, UK) according to guidelines. The average of the second and third readings was used for analysis to diminish the impact of any alerting response. Central systolic blood pressure (cSBP), pulse wave velocity (PWV) and augmentation index (AIx) were measured (Time −1 h and Time 2 h) using Finometer (Finopress Medical Systems, Netherlands) and Vicorder (SMT Medical, Germany) devices according to manufacturers' instructions.

Blood samples were taken from a cannula in the antecubital vein at time intervals shown in Figure 1. An initial 2 mL of blood was discarded, before 6 mL of blood was collected and transferred into chilled lithium heparin blood collection tubes. Blood samples were immediately centrifuged at a relative centrifugal force of 2,000× g for 5 min at 4°C (Hettich Mikro 220R, Germany). Plasma was stored in duplicate in 1 mL aliquots at −80°C prior to analysis.

Plasma concentrations of glucose, insulin and C‐peptide were measured using standardized clinical assays (Viapath, St Thomas' Hospital). Nitrate and nitrite concentrations in urine and plasma were measured by ozone‐based chemiluminescence as previously described.1, 34 The coefficient of variation was <10% for both nitrite and nitrate quantification. Exhaled NO (eNO) was measured using a NObreath monitor (Bedfont Scientific, UK), according to the manufacturer's instructions.

Insulin sensitivity during each study arm was calculated via the Matsuda index, where a higher value represents greater insulin sensitivity.35

2.4. Data and statistical analyses

All data were analysed with GraphPad Prism software (v7.03), and are expressed as mean ± SEM unless otherwise stated. Repeated‐measures two‐way ANOVA with Sidak's post‐test was used for comparison of the data between the two interventions. Repeated‐measures one‐way ANOVA with Dunn's post‐test was used for comparison with baseline. Correlation was assessed using Pearson's correlation. Where data were non‐parametric, appropriate equivalent statistical tests were used. P < 0.05 was considered statistically significant.

2.5. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY,36 and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18.37, 38

3. RESULTS

Thirty‐three participants completed both parts of the study, of which 13 received high‐dose (24 mmol) and 20 received low‐dose (8 mmol) KNO3/KCl. Mild gastrointestinal discomfort lasting <15 min was reported by 42.4% (14/33) of participants following dosing, with no significant difference between dose or intervention. Demographic data for participants are summarized in Table 1.

Table 1.

Demographic data for participants

All participants Subgroups
24 mmol 8 mmol
Number of participants (n) 33 13 20
Gender (n male) 15 6 9
Age (years) 27.1 ± 6.5 27.8 ± 7.2 26.5 ± 6.0
Weight (kg) 70.1 ± 13.9 69.4 ± 9.9 70.5 ± 16.1
Height (m) 1.7 ± 0.1 1.7 ± 0.1 1.7 ± 0.1
BMI (kg/m2) 23.3 ± 2.9 23.7 ± 3.2 23.1 ± 2.8
SBP (mmHg) 113.4 ± 10.1 115.0 ± 11.1 112.4 ± 9.6
DBP (mmHg) 71.2 ± 5.8 72.0 ± 5.3 70.7 ± 6.2
HR (bpm) 67.9 ± 9.4 69.4 ± 10.3 67.1 ± 8.0
Fasting glucose (mmol/L) 4.7 ± 0.6 4.7 ± 0.4 4.7 ± 0.7
Fasting insulin (pmol/L) 44.1 ± 22.2 39.9 ± 16.2 46.9 ± 25.3
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Data expressed as mean ± SD. BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate.

3.1. Nitrate metabolism

The metabolism of ingested NO3 − was confirmed by a significant time‐dependent increase in plasma and urinary [nitrate] and [nitrite] and eNO following KNO3 compared to KCl (Figure 2). In the high‐dose cohort, plasma [nitrite] was significantly increased for KNO3 vs. KCl at both the time of the OGTT (Time 0 h, 399 ± 104 vs. 81 ± 16 nmol/L; P < 0.01) and at peak plasma [glucose] (Time 1 h, 721 ± 95 vs. 60 ± 13 nmol/L; P < 0.001); see Figure 2.

Figure 2.

Figure 2

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Effect of 24 mmol KNO3 versus KCl (n = 13) on: A, plasma [nitrate], B, plasma [nitrite], C, urine [nitrate], D, urine [nitrite] and E, exhaled nitric oxide (NO). Effect of 8 mmol KNO3 versus KCl (n = 20) on F, exhaled NO. Data expressed as mean ± SEM. Significance shown as: †P < 0.05, ††P < 0.01, †††P < 0.001 on ANOVA, and *P < 0.05, **P < 0.01, ***P < 0.001, Sidak's post‐test of KNO3 vs. KCl. OGTT, oral glucose tolerance test

3.2. Haemodynamic response

Haemodynamic parameters pre‐intervention (Time −2 h to −1 h) were similar for KNO3 vs. KCl interventions (Table 2). There were no significant differences in BP or HR for KNO3 vs. KCl throughout the study (Time −2 h to +2 h; SBP P = 0.27; DBP P = 0.30; PP P = 0.74; HR P = 0.12) (Figure 3). Similarly, there were no significant differences in PWV, cSBP or AIx pre‐ and post‐OGTT (Time −1 h vs. +2 h; all P > 0.05; Figure 4).

Table 2.

Baseline haemodynamic parameters. Time −2 h to −1 h

KNO 3 KCl
SBP (mmHg) 113.1 ± 10.0 113.2 ± 10.9
DBP (mmHg) 70.8 ± 6.7 71.1 ± 6.4
PP (mmHg) 42.3 ± 7.3 41.2 ± 7.6
HR (bpm) 66.0 ± 7.2 65.7 ± 6.1
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Data expressed as mean ± SD. SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; HR, heart rate.

Figure 3.

Figure 3

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Effect of KNO3 vs. KCl (n = 33) on A, systolic blood pressure (SBP), B, diastolic blood pressure (DBP), C, pulse pressure (PP) and D, heart rate (HR). Data expressed as mean ± SEM. OGTT, oral glucose tolerance test

Figure 4.

Figure 4

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Effect of KNO3 vs. KCl (n = 29) on A, pulse wave velocity (PWV), B, central systolic blood pressure (cSBP) and C, augmentation index (AIx). Plots show range, median and 25th to 75th percentiles

Subgroup analyses of high‐dose (24 mmol) and low‐dose (8 mmol) cohorts also revealed similar haemodynamic parameters at baseline (data not shown). However, in contrast to the main analysis, significant differences in HR were observed between interventions within each cohort. In the high‐dose cohort, HR was reduced with KNO3 vs. KCl (mean 67.29 ± 0.55 vs. 68.36 ± 0.56 mmHg; P = 0.01) (Figure 5).

Figure 5.

Figure 5

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Effect of 24 mmol KNO3 vs. KCl (n = 13) on A, systolic blood pressure (SBP), B, diastolic blood pressure (DBP), C, pulse pressure (PP) and D, heart rate (HR). Data expressed as mean ± SEM. Significance shown as: †P < 0.05 on ANOVA. OGTT, oral glucose tolerance test

For the low‐dose cohort, the opposite effect was observed with a significantly higher HR with KNO3 vs. KCl (mean 65.89 ± 0.62 vs. 64.40 ± 0.40 mmHg; P < 0.01) (Figure 6). There were no significance differences in ΔPWV, ΔcSBP or ΔAIx for the interventions within either cohort (all P > 0.05; data not shown).

Figure 6.

Figure 6

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Effect of 8 mmol KNO3 vs. KCl (n = 20) on A, systolic blood pressure (SBP), B, diastolic blood pressure (DBP), C, pulse pressure (PP) and D, heart rate (HR). Data expressed as mean ± SEM. Significance shown as: †††P < 0.001 on ANOVA. OGTT: oral glucose tolerance test

3.3. Glucose homeostasis

There were no significant differences between interventions for plasma [glucose] (P = 0.58) or [C‐peptide] (P = 0.84), but significantly higher plasma [insulin] was observed for KNO3 vs. KCl (P = 0.01) (Figure 7). Insulin sensitivity, as represented by the Matsuda index, was not significantly different for KNO3 vs. KCl (mean 4.26 ± 0.48 vs. 4.37 ± 0.48; P = 0.59).

Figure 7.

Figure 7

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Effect of KNO3 vs. KCl (n = 33) on A, plasma [glucose], B, plasma [insulin] and C, plasma [C‐peptide]. Data expressed as mean ± SEM. Significance shown as: †P < 0.05 on ANOVA and *P < 0.05, Sidak's post‐test of KNO3 vs. KCl. ¥ P < 0.01 on ANOVA for KNO3 vs. baseline (−1 h) with Dunn's post‐test. ‡ P < 0.01 on ANOVA for KCl vs. baseline with Dunn's post‐test. OGTT, oral glucose tolerance test

Subgroup analyses of high‐dose (24 mmol) and low‐dose (8 mmol) cohorts revealed that the significant difference in plasma [insulin] was driven by the high‐dose cohort (P < 0.001 on ANOVA; at t = 0.75 h mean difference 210.4 pmol/L (95% CI 28.5–392.3), P = 0.012) (Figure 8). There was no significant difference in the Matsuda index for KNO3 vs. KCl with either 24 mmol (mean 5.42 ± 0.86 vs. 5.60 ± 0.75; P = 0.77) or 8 mmol (mean 3.50 ± 0.51 vs. 3.57 ± 0.57; P = 0.31). No significant correlation was observed between ΔSBP/DBP and Δ[insulin]/[glucose] at Time 1 h and 2 h (data not shown).

Figure 8.

Figure 8

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Effect of KNO3 vs. KCl (24 mmol, n = 13; A, C and E; 8 mmol, n = 20; B, D and F) on: A, and B, plasma [glucose], C, and D, plasma [insulin], and E, and F, plasma [C‐peptide]. Data expressed as mean ± SEM. Significance shown as: †††P < 0.001 on ANOVA, and *P < 0.05, Sidak's post‐test of KNO3 vs. KCl. OGTT, oral glucose tolerance test

4. DISCUSSION

This acute, crossover study investigated the effects of concurrent inorganic nitrate and glucose ingestion on blood pressure and glucose homeostasis in healthy individuals. The principal findings of this study were as follows: (i) physiological elevation of plasma [glucose] and [insulin] resulted in a lack of BP‐lowering with inorganic nitrate, despite elevated plasma [nitrite], and (ii) the increase in plasma [insulin] without a corresponding change in [C‐peptide] or [glucose] suggests that high‐dose NO3 − decreases insulin clearance.

A dose–response relationship has previously been demonstrated between NO3 − ingestion (as beetroot juice or nitrate capsules) and peripheral BP reduction.1, 39, 40 Doses as low as 5.1 mmol have been shown to cause significant SBP reductions,39, 40 with higher doses (up to 22 mmol as beetroot juice, and 24 mmol as potassium nitrate, as used here) resulting in SBP/DBP reductions of 10.4/8.0 mmHg, and 9.4/6.0 mmHg, respectively.1, 39 Reductions in arterial stiffness have also occurred with both acute and chronic dosing.41, 42 Whilst several studies in healthy individuals failed to show a peripheral BP decrease with NO3 − supplementation, this is the first study with a neutral effect for ≥12 mmol/d NO3 −. There is a strong correlation between PWV and PP, and so the lack of change in PWV is consistent with the peripheral measurements.43 Based on our previous work in those with, or at risk of, T2DM we would have expected to observe a reduction in cSBP following NO3 − ingestion through a selective dilatory effect on medium‐sized conduit vessels.12, 44 However, nitrate had no effect on cSBP with an acute glucose load.

The lack of effect on both peripheral and central haemodynamics suggests that normal, physiological responses to glucose are sufficient to prevent the BP‐lowering effects of NO3 − supplementation. The observed differences in HR between interventions were small and, as the magnitude of change was opposite to that expected for the two doses, their biological validity is uncertain. The lack of BP‐lowering is consistent with other studies that have demonstrated inhibition of NO‐dependent flow‐mediated dilatation of conduit and small resistance arteries following acute physiological elevations in plasma [glucose] and [insulin].45, 46, 47 Furthermore, in a study of overweight men, Joris et al. reported that co‐ingestion of beetroot juice (approximately 8 mmol NO3 −) counteracted the decrease in FMD associated with the intake of a mixed meal, without differences in PWV or peripheral BP between groups.48 Whilst our study was not designed to disentangle the relative contributions from glucose and insulin, we hypothesize that lack of effect was modulated by elevated plasma glucose given that insulin‐mediated vasodilatation within skeletal muscle is NO‐dependent.31 The elevated exhaled NO demonstrated an increase in systemic NO availability following nitrate supplementation, and that the lack of BP‐lowering was therefore unlikely due to interruption of the nitrate–nitrite–NO pathway.

In agreement with previous studies, NO3 − supplementation did not lower resting plasma [glucose] or improve insulin sensitivity as assessed by the Matsuda index.24, 25, 26 However, in the high‐dose cohort we did observe an increase in plasma [insulin] without a corresponding increase in [C‐peptide], thus suggesting decreased insulin clearance. A change in plasma [insulin] without a corresponding change in [glucose] is consistent with the multifaceted mechanisms responsible for glucose homeostasis.49, 50 Dietary nitrate has been demonstrated to enhance glucose uptake in skeletal muscle independent of insulin via translocation of glucose transporter 4 (GLUT4).51 It is therefore possible that high‐dose dietary nitrate facilitated glucose uptake via insulin‐independent mechanisms, thus reducing insulin clearance at the same site. Our finding is also consistent with a previous study which showed that systemic inhibition of nitric oxide synthase (NOS) with N G‐monomethyl‐l‐arginine (l‐NMMA) in healthy volunteers increased insulin clearance without an effect on peripheral insulin sensitivity.21 The mechanism of increased insulin clearance following NOS inhibition was attributed to activation of the specific protease hepatic insulin‐degrading enzyme (IDE), which is largely responsible for whole‐body insulin clearance.52 IDE is dose‐dependently inhibited by NO in vitro and provides a plausible mechanism for our observation of decreased insulin clearance. Furthermore, as NO mediates glucose uptake by skeletal muscle in vitro through insulin‐independent mechanisms, decreased insulin clearance may also occur peripherally following NO3 − intake.53, 54

This study differs from those previously conducted with regard to the nitrate dose, glucose load and relative timing of ingestion. Our use of high‐dose nitrate, a full OGTT and coordination of peak plasma [glucose] with elevated [nitrite], optimized any interaction and may explain why other studies did not observe changes in plasma [insulin]. Furthermore, we opted to deliver NO3 − via capsules rather than beetroot juice, to avoid additional uncontrolled CHO ingestion (37.5 g sugar per 500 mL; James White Drinks Ltd). It is a limitation of this study that although Lucozade is routinely used to administer OGTTs in clinical practice, we cannot exclude confounders mediated by other ingredients. However, the ingredients of Lucozade are similar to those in many other sports drinks and so the potential impact on exercise may represent a “class effect”. Thus, the lack of an effect of concomitant administration of glucose with nitrate on BP suggests the possibility that glucose might also negate the beneficial effects of nitrate on exercise performance.

In summary, our findings describe decreased insulin clearance as a previously unidentified consequence of NO3 − supplementation and provide further information regarding how diet can acutely modulate blood pressure. Further investigation is required into the potentially antagonistic interaction between glucose and NO3 −.

COMPETING INTERESTS

A.J.W. holds shares in HeartBeet Ltd, which receive a royalty from James White Drinks Ltd who manufacture beetroot juice (source of dietary nitrate). The other authors have stated explicitly that there are no conflicts of interest in connection with this article.

CONTRIBUTORS

C.N.F., S.L., J.H., S.A.O., K.M., A.J.W. made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; and were involved in drafting the manuscript or revising it critically for important intellectual content; and gave final approval of the version to be published; and have participated sufficiently in the work to take public responsibility for appropriate portions of the content; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

ACKNOWLEDGEMENTS

There was no support from any external organization specifically for the submitted work. We acknowledge internal infrastructure financial support from King's College London British Heart Foundation Centre (pump‐priming funding); National Institute for Health Research (NIHR) Clinical Research Facility at Guy's & St Thomas' NHS Foundation Trust and NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Floyd CN, Lidder S, Hunt J, Omar SA, McNeill K, Webb AJ. Acute interaction between oral glucose (75 g as Lucozade) and inorganic nitrate: Decreased insulin clearance, but lack of blood pressure‐lowering. Br J Clin Pharmacol. 2019;85:1443–1453. 10.1111/bcp.13913

The authors confirm that the Principle Investigator for this paper is Dr A.J. Webb and that he had direct clinical responsibility for patients.

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