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Comparison of Exogenous Ketone Administration Versus Dietary Carbohydrate Restriction on Myocardial Glucose Suppression: A Crossover Clinical Trial.

ABSTRACT: The ketogenic diet (KD) is the standard of care to achieve myocardial glucose suppression (MGS) for assessing inflammation using ¹⁸F-FDG PET. However, failure to suppress physiologic glucose uptake remains a significant diagnostic barrier. Although extending the duration of KD may be effective, exogenously delivered ketones may provide a convenient, reliable, and same-day alternative. The aims of our study were to determine whether exogenous ketone administration is noninferior to the KD to achieve MGS and whether serum β-hydroxybutyrate (BHB) levels can predict MGS. Methods: KEETO-CROSS (Ketogenic Endogenous versus Exogenous Therapies for myoCaRdial glucOse SuppresSion) is a crossover, noninferiority trial of the KD (endogenous ketosis) versus ketone ester ([KE] exogenous ketosis) drink. Twenty healthy participants were enrolled into 3 arms: weight-based KE drink, 24-h KD, and 72-h KD (n = 18 completed all arms). The primary outcome was achievement of complete MGS on PET (noninferiority margin 5%). The area under receiver-operating-characteristics (AUROC) of endogenous BHB levels (analyzed in a laboratory and by point-of-care device) for predicting MGS was analyzed in 37 scans completed on the KD. Results: The mean age was 30 ± 7 y, 50% were women, and 45% were nonwhite. The median achieved BHB levels (mmol/L) were 3.82 (25th-75th percentile, 2.55-4.97) (KE drink), 0.77 (25th-75th percentile, 0.58-1.02) (25th-75th percentile, 24-h KD), and 1.30 (25th-75th percentile, 0.80-2.24) (72-h KD). The primary outcome was achieved in 44% (KE drink), 78% (24-h KD), and 83% (72-h KD) of participants (noninferiority P = 0.97 and 0.98 for KE vs. 24-h and 72-h KD). Endogenous BHB levels robustly predicted MGS (AUROC, 0.88; 95% CI 0.71, 1.00). A BHB of 0.58 or more correctly classified 92% of scans. A point-of-care device provided comparable predictive value. Conclusion: In healthy volunteers, KE was inferior to KD for achieving MGS. Serum BHB is a highly predictive biomarker for MGS and can be clinically implemented upstream of ¹⁸F-FDG PET, with rapid facilitation by point-of-care testing, to reduce false-positive scans.

SUBMITTER: Selvaraj S

PROVIDER: S-EPMC9051592 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Comparison of Exogenous Ketone Administration Versus Dietary Carbohydrate Restriction on Myocardial Glucose Suppression: A Crossover Clinical Trial.

Selvaraj Senthil S Margulies Kenneth B KB Dugyala Supritha S Schubert Erin E Tierney Ann A Arany Zoltan Z Pryma Daniel A DA Shah Svati H SH Rame J Eduardo JE Kelly Daniel P DP Bravo Paco E PE

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20211021 5

The ketogenic diet (KD) is the standard of care to achieve myocardial glucose suppression (MGS) for assessing inflammation using <sup>18</sup>F-FDG PET. However, failure to suppress physiologic glucose uptake remains a significant diagnostic barrier. Although extending the duration of KD may be effective, exogenously delivered ketones may provide a convenient, reliable, and same-day alternative. The aims of our study were to determine whether exogenous ketone administration is noninferior to the ...[more]

PMID: 34675108

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Project description:BackgroundInterest in therapeutic applications of exogenous ketones has grown significantly, spanning patients with heart failure to endurance athletes. Exogenous ketones engender significant effects on cardiac function in heart failure and provide an ergogenic benefit in athletes. The aim of this study was to assess the effects of exogenous ketones on cardiac function in healthy participants.MethodsIn a single-arm intervention study, 20 fasting, healthy participants underwent comprehensive echocardiography (two-dimensional, Doppler, and strain) before and 30 min after weight-based oral ketone ester administration. The relationship between changes in log-transformed biomarker levels and change in absolute global longitudinal strain (GLS) was assessed using linear regression.ResultsThe mean age was 30 ± 7 years, 50% were women, 45% were nonwhite, and the average body mass index was 24.3 ± 3.1 kg/m2. Ketone ingestion acutely elevated β-hydroxybutyrate levels from a median of 0.13 mmol/L (interquartile range, 0.10-0.37 mmol/L) to 3.23 mmol/L (interquartile range, 2.40-4.97 mmol/L) (P < .001). After ketone ester consumption, systolic blood pressure, heart rate, biventricular function, left ventricular GLS, and left atrial (LA) strain all augmented, while systemic vascular resistance decreased. Displayed as mean change, increases in ejection fraction (3.1%; 95% CI, 2.0%-4.2%; P < .001), GLS (2.0%; 95% CI, 1.4%-2.7%; P < .001), right ventricular S' (1.1 cm/sec; 95% CI, 0.4-1.8 cm/sec; P = .004), LA reservoir strain (7%; 95% CI, 3%-12%; P = .005), and LA contractile strain (4%; 2%-6%; P = .001) were observed. During robustly achieved ketosis, change in GLS was inversely associated with change in nonesterified fatty acids (P = .019).ConclusionsIn a single-arm study, systolic blood pressure, heart rate, biventricular function, and LV and LA strain acutely augmented after ketone ester ingestion in healthy, fasting participants, similar to several effects observed in the failing heart. These data may provide supporting data for the ergogenic benefits observed in athletes and may become increasingly relevant with exogenous ketone consumption across a variety of cardiovascular and noncardiovascular applications.

Project description:Recently developed ketone (monoester or salt) supplements acutely elevate blood β-hydroxybutyrate (BHB) exogenously without prolonged periods of fasting or carbohydrate restriction. Previous (small-scale) studies have found a blood glucose-lowering effect of exogenous ketones. This study aimed to systematically review available evidence and conduct meta-analyses of studies reporting on exogenous ketones and blood glucose. We searched 6 electronic databases on 13 December 2021 for randomized and nonrandomized trials of any length that reported on the use of exogenous ketones. We calculated raw mean differences (MDs) in blood BHB and glucose in 2 main analyses: 1) after compared with before acute ingestion of exogenous ketones and 2) following acute ingestion of exogenous ketones compared with a comparator supplement. We pooled effect sizes using random-effects models and performed prespecified subgroup analyses to examine the effect of potential explanatory factors, including study population, exercise, blood BHB, and supplement type, dosing, and timing. Risk of bias was examined using Cochrane's risk-of-bias tools. Studies that could not be meta-analyzed were summarized narratively. Forty-three trials including 586 participants are summarized in this review. Following ingestion, exogenous ketones increased blood BHB (MD = 1.73 mM; 95% CI: 1.26, 2.21 mM; P < 0.001) and decreased mean blood glucose (MD = -0.54 mM; 95% CI: -0.68, -0.40 mM; P < 0.001). Similarly, when compared with placebo, blood BHB increased (MD = 1.98 mM; 95% CI: 1.52, 2.45 mM; P < 0.001) and blood glucose decreased (MD = -0.47 mM; 95% CI: -0.57, -0.36 mM; P < 0.001). Across both analyses, significantly greater effects were seen with ketone monoesters compared with salts (P < 0.001). The available evidence indicates that acute ingestion of exogenous ketones leads to increased blood BHB and decreased blood glucose. Limited evidence on prolonged ketone supplementation was found.

Project description:Low-carbohydrate diets and intermittent energy restriction may offer metabolic advantages in fuel utilisation, that are independent of weight loss. The underlying mechanisms for these effects are unclear but may involve extensions of the catabolic phase and/or attenuation of insulin secretion. To address this gap, we aimed to investigate the independent acute metabolic effect of carbohydrate restriction at varying energy levels. Twelve, (six female) healthy overweight/obese participants (27.3 ± 1.8 years; 25.2 ± 1.6 kg/m2) completed this three-way study. Volunteers followed three diets for one day (36 h, covering the intervention day and overnight fasting), separated by 5-day washout: a normal carbohydrate, energy-balanced diet (nEB, 55% CHO), a low-carbohydrate, energy-balanced diet (LCEB, 50 g/day CHO), and a low-carbohydrate, energy-restricted diet (LC25, 50 g/day CHO with 75% energy restriction). Fasting and serial postprandial (360 min) measurements to a mixed test meal were collected the following morning. Additionally, subjective appetite responses and two-day subsequent ad libitum food intake was assessed. Both low-carbohydrate with and without energy restriction diets induced comparable decrease in triacylglycerol iAUC (p = 0.02, p = 0.04, respectively), and respiratory quotient (both p < 0.01) along with increase in non-esterified fatty acids (both p < 0.01) and 3-hydroxybutyrate (p = 0.001, p = 0.01, respectively) levels. Compared to a non-restricted carbohydrate, energy-balanced diet, postprandial glucose levels significantly increased in the LCEB arm (p = 0.024) and showed a rising trend in the LC25 arm (p = 0.07). Neither insulin responses nor resting, and diet-induced thermogenesis were significantly altered by variations in energy or carbohydrate content. These findings demonstrate that carbohydrate restriction, without altering energy intake, can elicit effects similar to those observed in short-term fasting. As such we propose a strategy of repeated carbohydrate restriction cycles alone may be an emerging alternative approach for the enhancement of cardiometabolic health, warranting further investigation.

Dataset Information

Comparison of Exogenous Ketone Administration Versus Dietary Carbohydrate Restriction on Myocardial Glucose Suppression: A Crossover Clinical Trial.

Publications

Comparison of Exogenous Ketone Administration Versus Dietary Carbohydrate Restriction on Myocardial Glucose Suppression: A Crossover Clinical Trial.

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