Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats

Shannon L Kesl, Angela M Poff, Nathan P Ward, Tina N Fiorelli, Csilla Ari, Ashley J Van Putten, Jacob W Sherwood, Patrick Arnold, Dominic P D'Agostino, Shannon L Kesl, Angela M Poff, Nathan P Ward, Tina N Fiorelli, Csilla Ari, Ashley J Van Putten, Jacob W Sherwood, Patrick Arnold, Dominic P D'Agostino

Abstract

Background: Nutritional ketosis induced by the ketogenic diet (KD) has therapeutic applications for many disease states. We hypothesized that oral administration of exogenous ketone supplements could produce sustained nutritional ketosis (>0.5 mM) without carbohydrate restriction.

Methods: We tested the effects of 28-day administration of five ketone supplements on blood glucose, ketones, and lipids in male Sprague-Dawley rats. The supplements included: 1,3-butanediol (BD), a sodium/potassium β-hydroxybutyrate (βHB) mineral salt (BMS), medium chain triglyceride oil (MCT), BMS + MCT 1:1 mixture, and 1,3 butanediol acetoacetate diester (KE). Rats received a daily 5-10 g/kg dose of their respective ketone supplement via intragastric gavage during treatment. Weekly whole blood samples were taken for analysis of glucose and βHB at baseline and, 0.5, 1, 4, 8, and 12 h post-gavage, or until βHB returned to baseline. At 28 days, triglycerides, total cholesterol and high-density lipoprotein (HDL) were measured.

Results: Exogenous ketone supplementation caused a rapid and sustained elevation of βHB, reduction of glucose, and little change to lipid biomarkers compared to control animals.

Conclusions: This study demonstrates the efficacy and tolerability of oral exogenous ketone supplementation in inducing nutritional ketosis independent of dietary restriction.

Keywords: Appetite; Hyperketonemia; Ketogenic diet; Ketone ester; Ketone supplement; Triglycerides; β-hydroxybutyrate.

Figures

Fig. 1
Fig. 1
Effects of ketone supplementation on triglycerides and lipoproteins: Ketone supplementation causes little change in triglycerides and lipoproteins over a 4-week study. Graphs show concentrations at 4-weeks of total cholesterol (a), Triglycerides (b), LDL (c), and HDL (d). MCT supplemented rats had signfiicantly reduced concentration of HDL blood levels compared to control (p < 0.001) (b). One-Way ANOVA with Tukey’s post hoc test, results considered significant if p < 0.05. Error bars represent mean (SD)
Fig. 2
Fig. 2
Effects of ketone supplementation on blood βHB. a, b Blood βHB levels at times 0, 0.5, 1, 4, 8, and 12 h post intragastric gavage for ketone supplements tested. a BMS + MCT and MCT supplementation rapidly elevated and sustained significant βHB elevation compared to controls for the duration of the 4-week dose escalation study. BMS did not significantly elevate βHB at any time point tested compared to controls. b BD and KE supplements, maintained at 5 g/kg, significantly elevated βHB levels for the duration of the 4-week study. Two-Way ANOVA with Tukey’s post hoc test, results considered significant if p < 0.05. Error bars represent mean (SD)
Fig. 3
Fig. 3
Effects of ketone supplementation on blood glucose. a, b Blood glucose levels at times 0, 0.5, 1, 4, 8, and 12 h (for 10 dose) post intragastric gavage for ketone supplements tested. a Ketone supplements BMS + MCT and MCT significantly reduced blood glucose levels compared to controls for the duration of the 4-week study. BMS significantly lowered blood glucose only at 8 h/week 1 and 12 h/week 3 (b) KE, maintained at 5 g/kg, significantly reduced blood glucose compared to controls from week 1–4. BD did not significantly affect blood glucose levels at any time point during the 4-week study. Two-Way ANOVA with Tukey’s post hoc test, results considered significant if p < 0.05. Error bars represent mean (SD)
Fig. 4
Fig. 4
Relationship between blood ketone and glucose levels: a BMS + MCT (5 g/kg) supplemented rats demonstrated a significant inverse relationship between elevated blood ketone levels and decreased blood ketone levels (r2 = 0.4314, p = 0.0203). b At week 4, BMS + MCT (10 g/kg) and MCT (10 g/kg) showed a significant correlation between blood ketone levels and blood glucose levels (r2 = 0.8619, p < 0.0001; r2 = 0.6365, p = 0.0057). Linear regression analysis, results considered significant if p < 0.05
Fig. 5
Fig. 5
Effects of ketone supplementation on organ weight: Data is represented as a percentage of organ weight to body weight. a, b, d, f Ketone supplements did not significantly affect the weight of the brain, lungs, kidneys or heart. c Liver weight was significantly increased as compared to body weight in response to administered MCT ketone supplement compared to control at the end of the study (day 29) (p < 0.001). e Rats supplemented with BMS + MCT, MCT, and BD had significantly smaller spleen percentage as compared to controls (p < 0.05, p < 0.001, p < 0.05). Two-Way ANOVA with Tukey’s post-hoc test; results considered significant if p < 0.05. Error bars represent mean (SD)
Fig. 6
Fig. 6
Effects of ketone supplementation on body weight: Rats administered ketone supplements gained less weight over the 4-week period; however, did not lose weight and maintained healthy range for age. KE supplemented rats gained significantly less weight during the entire 4-week study compared to controls. BMS + MCT, BMS, and BD supplemented rats gained significantly less weight than controls over weeks 2–4.MCT supplemented rats gained significantly less weight than controls over weeks 3–4, Two-Way ANOVA with Tukey’s post hoc test, results considered significant if p < 0.05. Error bars represent mean (SD)
Fig. 7
Fig. 7
Effects of ketone supplementation on basal blood ketone and basal blood glucose levels: Rats administered ketone supplements did not have a significant change in basal blood ketone levels (a) or basal blood glucose levels (b) for the four week study. Two-Way ANOVA with Tukey’s post-hoc test, results considered significant if p < 0.05. Error bars represent mean (SD)

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