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

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.

Exogenous Ketone Supplements Improved Motor Performance in Preclinical Rodent Models

“…While our previous study showed that ketone supplementation lowered blood glucose levels [ 27 ] in the nonexercised state, we found that in the postexercise state it was elevated at 1 h ( Figure 2 D), possibly due to exercise augmenting glycogenolysis induced glucose elevation which may offset the blood glucose lowering effect. However, in some cases in SPD and WR rats after 1 h and 7 days the blood glucose levels were lower than control and baseline ( Figure 2 D, Figure 3 D and Figure 4 D) and in G1D mice after 6 weeks it was lower than baseline ( Figure 5 D), suggesting that exogenous ketones may be able to offset the glycogenolysis induced glucose elevation in postexercised state.…”

“…Supplementation with ketone (ketogenic) supplements, such as ketone ester (KE), has proven effective in achieving a state of nutritional ketosis independent of carbohydrate restriction [ 14 , 17 , 18 , 27 , 28 ]. Ketone supplementation that contains either KE, ketone salt (KS), medium chain triglycerides (MCTs), or their combinations (e.g., KEKS, KEMCT, and KSMCT) has been studied in both animal models and humans.…”

“…However, it is unknown whether different exogenous ketone supplements and their combinations would increase motor performance in animal models under different conditions associated with motor function impairment. Our previous study also demonstrated that exogenous ketones have a blood glucose lowering effect [ 27 ]; however, the hormonal response to exercise can cause stored glucose to be released from the liver and skeletal muscle while temporarily raising blood glucose levels. Thus, the main goal of the present study was to determine if specific ketogenic supplements and/or combinations would improve motor performance in rodents with pathology (Wistar Albino Glaxo/Rijswijk, WAG/Rij/WR rats and Glut1 Deficiency Syndrome/G1D mice) and without pathology (Sprague-Dawley/SPD rats) [ 36 , 37 ] and to test whether they are able to offset the postexercise induced blood glucose elevation.…”

Age- and Sex-Dependent Modulation of Exogenous Ketone Supplement-Evoked Effects on Blood Glucose and Ketone Body Levels in Wistar Albino Glaxo Rijswijk Rats

“…It has been demonstrated that metabolism and utilization of ketone bodies on CNS processes may be regionally different ( Hawkins and Biebuyck, 1979 ; Hawkins et al, 1986 ; Bilger and Nehlig, 1992 ). Moreover, KD- and EKS-generated changes in blood level of ketone bodies and glucose and, as a consequence, their effects on physiological and pathophysiological processes of different organs may be modulated by gender and age ( Page et al, 1971 ; Buc et al, 1986 ; Nehlig and Pereira de Vasconcelos, 1993 ; Vannucci, 1994 ; Cao et al, 2017 ; Ari et al, 2019 , 2020 ). These results suggest that the alleviating effects (e.g., neuroprotective influences) of KD- and EKS-evoked increase in ketone body levels may be age- and gender-dependent in the treatment of different diseases, such as ischemia, traumatic brain injury, and epilepsy ( Freeman et al, 1998a ; Rho et al, 1999 ; Appelberg et al, 2009 ).…”

Why a d-β-hydroxybutyrate monoester?

“…However, it is unclear if the benefit arose from a reduced glucose load or a ketone specific mechanism. It is an undisputed fact that, regardless of the animal model and regardless of the ketogenic intervention, acute ketosis lowers blood glucose within a few minutes [20,50,51]. There is evidence suggesting ketosis acutely reduces the glycaemic response to a glucose challenge [52], and improves insulin secretion [50] however, ketone infusions lower blood glucose concentration even in the absence of insulin [53] and there is current research looking into the effect of acute ketosis substrate availability for gluconeogenesis [54].…”