April 2018, Dr Chee L Khoo
Ketogenesis is the production of ketone bodies (KB) when glucose levels decline and the glucagon:insulin ratio is high. When the body is deprived of glucose, KB act as an alternative fuel source for brain, heart, kidneys and skeletal muscles. KB have also been shown to have other physiological functions including lower glucose levels.
To understand the potential therapeutic implications of KB, we need to revise our knowledge about KB metabolism. Acetoacetate (AcAc), acetone, and β-hydroxybutyrate are produced in the liver from free fatty acids (FFA) liberated from adipose stores in lipolysis. In times of prolonged starvation, prolonged exercises or very low carbohydrate intake, KB replace glucose as the primary fuel for peripheral tissues such as the brain, heart and skeletal muscles.
Because glucose remains an important fuel for the brain and heart, under those conditions, KB reduce glucose utilisation in the peripheral tissues including muscles. KB also reduce further circulating FFA by reducing lipolysis. The muscle capacity to utilise KB increases in exercise especially in trained athletes. With training, there is evidence that KB act as signalling molecules to regulate gene expression and adaptation including suppression of endogenous glucose production.
You may ponder whether the physiological effects of ketosis stem from fat loss from lipolysis or the effect of exercises in improving insulin sensitivity. Instead of prolonged exercises or prolonged starvation, acute nutritional ketosis can also be achieved by ingestion of oral ketone supplements. This will address the issue of whether the metabolic effects are from KB or from exercise or starvation.
In a most recent randomised cross-over trial, following a 10 h overnight fast, participants consumed either ketone or placebo supplement followed 30 min later by a 75 g glucose drink for a standard 2 h oral glucose tolerance tests (OGTT). At least 48 h later, participants returned to the lab following a similar overnight fast and performed the alternate experimental condition. No exercises were performed and no alcohol was consumed.
In individuals with fasting glucose levels within the normal range, a single dose of ketone ester supplement (KES) resulted in a reduction in 2 h total and incremental glucose compared to a placebo. This reduction in glycaemic response was accompanied by a decrease in circulating FFA levels and an improvement in the oral glucose insulin sensitivity (OGIS) index, a marker of insulin sensitivity. C-peptide levels were decreased with KES, supporting the notion that exogenous ketone supplementation may lower glucose via improved insulin sensitivity.
The authors admitted that the study was performed on healthy subjects and the results may not apply to real patients with metabolic derangement especially in patients with insulin resistance and beta cell dysfunction and patients on medications. They also acknowledged they are unable to rule out that KES affect gastric emptying and glucose absorption.
The physiological actions of KB may explain the early glycaemic response in patients with T2D on a low carbohydrate diet or following bariatric surgery. With the fairly recent development of oral ketone esters, there have been a surge in interest in KB supplements in the exercise world as an aid to improving exercise performance, endurance and recovery from exercises. Because KB serve as a substrate for the brain, KB may be useful for cognitive enhancement and neuro-degenerative pathologies (Veech, 2004).
These acute effects of reduced glycaemic response and insulin sensitivity suggest that ketone ester supplements could have therapeutic potential in the management and prevention of metabolic disease.
By the way, the KES in this study had an absolutely foul taste!
Access abstract here.
Reference
- Veech RL (2004). The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids 70, 309–319.
- Mark Evans, Karl E. Cogan1 and Brendan Egan. Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J Physiol 595.9 (2017) pp 2857–2871
- Myette-Cote, E et al. Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals. J Physiol 2 March 2018 pp 1–11