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.

Highlights

  • Glucose represents an important metabolic biomarker and is the primary fuel for most human cells

  • The effect of different combinations of exogenous ketone supplements on blood glucose levels following a single gavage administration in an exercised state was first tested in one-year-old Sprague Dawley rats (SPD) rats (Figure 2)

  • The blood drawn from the rats 1 h after administration of supplements, insignificant, showed either a trend of decreased (KE, KE with MCT (KEMCT), and KE with KS (KEKS) groups) and increased (BD and KS with medium chain triglyceride/MCT (KSMCT) groups) percent change in blood glucose levels when compared to the control group (Figure 2B)

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Summary

Introduction

Glucose represents an important metabolic biomarker and is the primary fuel for most human cells. This inhibition further activates the alternative glucose metabolic pathways, which leads to increased ROS production involved in glucotoxicity that is responsible for the exacerbation of diabetes and the development of diabetic complications [22,23,24,25] These and further studies support the concept that elevations in ROS and oxidative stress can be fomented by high blood glucose and NADH overproduction. To further investigate the effect of KD and exogenous ketones on blood glucose and ketone (R-βHB) levels, we tested non-pathological (SPD rats) and pathological (WR rats and GLUT1D mice) animal models in rested and in post-exercise state acute (1 h; SPD and WR rats), sub-chronic (7 days; SPD and WR rats), and chronic treatments (10 weeks; GLUT1D mice). Ex: exercised, R: Rested, SPD: Sprague-Dawley rats, WR: WAG/Rij rats, GLUT1D: GLUT1D deficiency syndrome mice, (R): Rested state in parenthesis indicates that data is already described in earlier literature

Animals
Diets and Ketogenic Compounds
Exercise with Accelerated Rotarod
Measurement of Blood R-βHB and Glucose
Statistics
Results
Changes
Sub-ChronicRats
Sub-Chronic of Ketone Supplements on Blood
Sub-Chronic of Ketone on level
Discussion
Full Text
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