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

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.

Figure 1

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

Figure 2

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

Figure 3

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

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

Figure 5

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

Figure 6

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

Figure 7

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

Figure 8

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