Ketones: Metabolism's Ugly Duckling

Abstract

Ketones were first discovered in the urine of diabetic patients in the mid-19th century; for almost 50 years thereafter, they were thought to be abnormal and undesirable by-products of incomplete fat oxidation. In the early 20th century, however, they were recognized as normal circulating metabolites produced by liver and readily utilized by extrahepatic tissues. In the 1920s, a drastic "hyperketogenic" diet was found remarkably effective for treatment of drug-resistant epilepsy in children. In 1967, circulating ketones were discovered to replace glucose as the brain's major fuel during the marked hyperketonemia of prolonged fasting. Until then, the adult human brain was thought to be entirely dependent upon glucose. During the 1990s, diet-induced hyperketonemia was found therapeutically effective for treatment of several rare genetic disorders involving impaired neuronal utilization of glucose or its metabolic products. Finally, growing evidence suggests that mitochondrial dysfunction and reduced bioenergetic efficiency occur in brains of patients with Parkinson's disease (PD) and Alzheimer's disease (AD). Because ketones are efficiently used by mitochondria for ATP generation and may also help protect vulnerable neurons from free radical damage, hyperketogenic diets should be evaluated for ability to benefit patients with PD, AD, and certain other neurodegenerative disorders.

Should animal fats be back on the table? A critical review of the human health effects of animal fat

“…Moreover, trials of ketogenic diets in the treatment of final stage cancer patients and in experimental systems (Tisdale et al 1987;Breitkreutz et al 2005;Zuccoli et al 2010;Ho et al 2011;Klement and Kaemmerer 2011;Schmidt et al 2011;Chang et al 2013) have occurred, with some interesting results of reduction in tumour size, reduction of cachexia, or delay of initiation of cancer. Ketogenic diets continue to be used to treat some classes of epilepsy (Freeman et al 1998;Kossoff et al 2006;Neal et al 2008), and have been suggested for other mental disorders or dementias including Alzheimer's disease and Parkinson's disease (VanItallie and Nufert 2003;Kim et al 2007;Kossoff and Hartman 2012). A random controlled trial of an additive to the normal diet, AC-1202, consisting of short-and medium-chain TAG derived from coconut oil and that are metabolised to ketone bodies, has shown some improvement in Alzheimer's disease sufferers from ketone body production (Henderson et al 2009).…”

Hypercarnivory and the brain: protein requirements of cats reconsidered

“…Ketone bodies are utilised by brain proportional to their arterial concentrations (Hawkins et al 1971;Robinson and Williamson 1980;Blomqvist et al 2002) and in humans, can provide as much as 60% of brain substrate requirements during prolonged starvation (Cahill 1983). This partial substitution of glucose by ketones not only helps to maintain fuel supply to the brain, but also reduces the need for protein catabolism to provide gluconeogenic precursors (Cahill 1983;VanItallie and Nufert 2003) and thus greatly prolongs survival time, as mammals tend to have a greater capacity for catabolism of body fat than body protein. However, brain tissue cannot run on ketone bodies as an exclusive substrate and continues to use glucose at all times (Sokoloff et al 1977;Hertz and Dienel 2002).…”

The Ketogenic Diet Approach as Metabolic Treatment for a Variety of Diseases

“…However, before analyzing how benefits from therapeutic ketosis could be exploited, let us mention some pivotal concepts about metabolism. Under normal conditions and mostly in western societies, a healthy brain utilizes glucose as primary energy source, which unbalance can lead to a number of neurodegenerative disorders often associated with mitochondrial impairment and glucose transport-related dysfunctions, such as in epilepsy, Traumatic Brain Injury (TBI), Parkinson's and Alzheimer's diseases [6,7]. Ketone bodies and Krebs cycle intermediates represent the best fuels for brain and other organs.…”

“…Thus, ketone esters may represent the future "ketogenic diet in a pill" [42] paving the road to further testing. Through the past decades, confusion on physiological state of nutritional ketosis has generated some misunderstanding within the medical community [7], such as the wrong association of "therapeutic ketosis" (blood ketones comprised between 0.5 and 8 mM) with "diabetic ketoacidosis" (>10 mM). In addition, another frequent observation is that initial stages of ketosis induce a transient blood pH drop [43] due to ketone bodies accumulation in the bloodstream.…”