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Comparative Study
. 2019 Oct 1;11(10):2330.
doi: 10.3390/nu11102330.

Exogenous Ketones Lower Blood Glucose Level in Rested and Exercised Rodent Models

Csilla Ari  1   2 , Cem Murdun  3 , Andrew P Koutnik  3 , Craig R Goldhagen  3 , Christopher Rogers  3 , Collin Park  4 , Sahil Bharwani  4 , David M Diamond  4   3 , Mark S Kindy  5   6   7 , Dominic P D'Agostino  3   8 , Zsolt Kovács  9
Affiliations
Comparative Study

Exogenous Ketones Lower Blood Glucose Level in Rested and Exercised Rodent Models

Csilla Ari et al. Nutrients. .

Abstract

Diseases involving inflammation and oxidative stress can be exacerbated by high blood glucose levels. Due to tight metabolic regulation, safely reducing blood glucose can prove difficult. The ketogenic diet (KD) reduces absolute glucose and insulin, while increasing fatty acid oxidation, ketogenesis, and circulating levels of β-hydroxybutyrate (βHB), acetoacetate (AcAc), and acetone. Compliance to KD can be difficult, so alternative therapies that help reduce glucose levels are needed. Exogenous ketones provide an alternative method to elevate blood ketone levels without strict dietary requirements. In this study, we tested the changes in blood glucose and ketone (βHB) levels in response to acute, sub-chronic, and chronic administration of various ketogenic compounds in either a post-exercise or rested state. WAG/Rij (WR) rats, a rodent model of human absence epilepsy, GLUT1 deficiency syndrome mice (GLUT1D), and wild type Sprague Dawley rats (SPD) were assessed. Non-pathological animals were also assessed across different age ranges. Experimental groups included KD, standard diet (SD) supplemented with water (Control, C) or with exogenous ketones: 1, 3-butanediol (BD), βHB mineral salt (KS), KS with medium chain triglyceride/MCT (KSMCT), BD acetoacetate diester (KE), KE with MCT (KEMCT), and KE with KS (KEKS). In rested WR rats, the KE, KS, KSMCT groups had lower blood glucose level after 1 h of treatment, and in KE and KSMCT groups after 24 h. After exercise, the KE, KSMCT, KEKS, and KEMCT groups had lowered glucose levels after 1 h, and in the KEKS and KEMCT groups after 7 days, compared to control. In GLUT1D mice without exercise, only KE resulted in significantly lower glucose levels at week 2 and week 6 during a 10 weeks long chronic feeding study. In 4-month and 1-year-old SPD rats in the post-exercise trials, blood glucose was significantly lower in KD and KE, and in KEMCT groups, respectively. After seven days, the KSMCT group had the most significantly reduced blood glucose levels, compared to control. These results indicate that exogenous ketones were efficacious in reducing blood glucose levels within and outside the context of exercise in various rodent models of different ages, with and without pathology.

Keywords: blood glucose; blood ketone; exercise; exogenous ketone supplements; ketogenic diet.

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Conflict of interest statement

International Patent # PCT/US2014/031237, University of South Florida for DPD: Compositions and Methods for Producing Elevated and Sustained Ketosis. Patent pending: No. 11001-018-US1 for CA and DPD: Administration of Exogenous Ketone to Lower Blood Glucose”. D.P. D`Agostino and C. Ari are co-owners of the company Ketone Technologies LLC. DMD is a paid consultant and member of the science advisory board for Axcess Global Sciences and Real Ketones. These interests have been reviewed and managed by the University in accordance with its Institutional and Individual Conflict of Interest policies. All authors declare that there are no additional conflicts of interest.

Figures

Figure 1
Figure 1
Schematic drawing of the experimental design. Abbreviations: BL: Baseline measurement; RR: rotarod.
Figure 2
Figure 2
Changes in blood glucose and R-βHB levels of 1-year-old SPD rats after 1 h of treatment, in post-exercise state. (A) In KEMCT group the blood glucose level was not significantly elevated, compared to baseline. (B) The corresponding percent change in glucose levels. (C) The resulting blood R-βHB levels. (D) The percent change in the blood R-βHB levels. Abbreviations: SPD: Sprague-Dawley rat; BD: 1, 3-butanediol; KE: ketone ester; KEMCT: ketone ester and medium chain triglyceride, 1:1 ratio; KSMCT: ketone salt and medium chain triglyceride, 1:1 ratio; KEKS: ketone ester and ketone salt, 1:1 ratio. *: p < 0.05, **: p < 0.01, ***: p < 0.001 and ****: p < 0.0001 level of significance.
Figure 3
Figure 3
Changes in blood glucose and R-βHB levels of 4-months-old SPD rats after 24 h and seven days of treatment, in post-exercise state. (A) The change in glucose levels in SPD rats, with exercise, for the baseline, 24 h, and seven days post-intervention. (B) The corresponding percent change in glucose levels. (C) The resulting blood R-βHB levels. (D) The percent change in the blood R-βHB levels. Abbreviations: SPD: Sprague-Dawley rat; SD: standard diet (control); KD: ketogenic diet; KE: ketone ester; KS: ketone salt; KSMCT: ketone salt and medium chain triglyceride, 1:1 ratio. *: p < 0.05, **: p < 0.01, and ****: p < 0.0001 level of significance.
Figure 4
Figure 4
Changes in blood glucose and R-βHB levels of 6-months-old WR rats after 1 h of treatment, in rested state. (A) The change in glucose levels in WR rats, with no exercise, for the baseline and 1 h post-treatment. (B) The corresponding percent change in glucose levels. (C) The resulting blood R-βHB levels. (D) The percent change in the blood R-βHB levels. Abbreviations: WR: WAG/Rij rat; SD: standard diet (Control); KE: ketone ester; KS: ketone salt; KSMCT: ketone salt and medium chain triglyceride, 1:1 ratio. *: p<0.05, **: p < 0.01, ***: p < 0.001 and ****: p < 0.0001 level of significance.
Figure 5
Figure 5
Changes in blood glucose and R-βHB levels of 6-month-old WR rats after 24 h and seven days of treatment, in rested state. (A) The change in glucose levels in WR rats, with no exercise, for the baseline, after 24 h and after seven days of daily treatment. (B) The corresponding percent change in glucose levels. (C) The resulting blood R-βHB levels. (D) The percent change in the blood R-βHB levels. Abbreviations: WR: WAG/Rij rat; SD: standard diet (Control); KE: ketone ester; KS: ketone salt; KSMCT: ketone salt and medium chain triglyceride, 1:1 ratio. *: p < 0.05, **: p < 0.01, ***: p < 0.001 and ****: p < 0.0001 level of significance.
Figure 6
Figure 6
Changes in blood glucose and R-βHB levels of 6-month-old WR rats after 1 h and seven days of treatment, in post-exercise state. (A) The change in glucose levels in WR rats, with exercise, for the baseline, 1 h and seven days of the treatment. (B) The corresponding percent change in glucose levels. (C) The resulting blood R-βHB levels. (D) The percent change in the blood R-βHB levels. Abbreviations: WR: WAG/Rij rat; SD: standard diet (Control); KE: ketone ester; KS: ketone salt; KSMCT: ketone salt and medium chain triglyceride, 1:1 ratio; KEKS: ketone ester and ketone salt, 1:1 ratio; KEMCT: ketone ester and medium chain triglyceride, 1:1 ratio. *: p <0.05, **: p <0.01, ***: p <0.001 and ****: p < 0.0001 level of significance.
Figure 7
Figure 7
The effect of chronic feeding of ketogenic compounds on blood glucose and R-βHB level was assessed in glucose transporter type 1 (G1D)-deficiency syndrome mice during 10 weeks long experiment, in rested state. (A) The change in blood glucose levels in GLUT1D mice, without exercise, chronically exposed to various ketone supplements. (B) The corresponding percent change in blood glucose levels. (C) The resulting blood R-βHB levels. (D) The percent change in blood R-βHB levels. Abbreviations: SD: standard diet (Control); KD: ketogenic diet; KS: ketone salt; KE: ketone ester. *: p < 0.05, **: p < 0.01, ***: p < 0.001 and ****: p < 0.0001 level of significance.
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