Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Abstract

This article is available online at http://www.jlr.org family, its importance for purposes of this review is minimal.). KBs have been dubbed "metabolism's ugly duckling" because, in the mid-19th century, they were fi rst discovered in large quantities in the urine of patients succumbing to diabetic ketoacidosis. Thus, it is not surprising that physicians of the era considered KBs to be toxic byproducts of impaired carbohydrate metabolism. It took almost half a century for medical scientists to understand that KBs are normal metabolites manufactured by the liver in increasing amounts when dietary sources of carbohydrate and glucogenic amino acids are in short supply ( 1 ). Unfortunately, some physicians still fail to distinguish between the safe "physiological" hyperketonemia that occurs in healthy individuals during fasting or adherence to a ketogenic diet (KD), and the pathological, out-of-control hyperketonemia associated with insulin-defi cient diabetes.When Owen et al. ( 2 ) reported that during a prolonged fast KBs can provide 60% or more of the brain's daily energy requirement (thereby sparing ‫ف‬ 80 g/day of glucose that otherwise would have been derived largely from breakdown of the body's limited protein stores), it was finally acknowledged that, as in Hans Christian Andersen's 1843 fairy tale, the creature fi rst thought to be an ugly duckling was turning out to be an emerging swan. It became evident that the ketogenic response to starvation is an indispensable metabolic adaptation designed by nature to preserve strength and prolong life during times when food is unavailable ( 3 ) .It is now known that (in nondiabetic individuals), owing to the blood's effi cient buffering capacity, plasma KB Abstract Ketone bodies (KBs ), acetoacetate and ␤ -hydroxybutyrate ( ␤ HB), were considered harmful metabolic by-products when discovered in the mid-19th century in the urine of patients with diabetic ketoacidosis. It took physicians many years to realize that KBs are normal metabolites synthesized by the liver and exported into the systemic circulation to serve as an energy source for most extrahepatic tissues. Studies have shown that the brain (which normally uses glucose for energy) can readily utilize KBs as an alternative fuel. Even when there is diminished glucose utilization in cognition-critical brain areas, as may occur early in Alzheimer's disease (AD), there is preliminary evidence that these same areas remain capable of metabolizing KBs. Because the ketogenic diet (KD) is diffi cult to prepare and follow, and effectiveness of KB treatment in certain patients may be enhanced by raising plasma KB levels to у 2 mM, KB esters, such as 1,3-butanediol monoester of ␤ HB and glyceryl-tris-3-hydroxybutyrate, have been devised. When administered orally in controlled dosages, these esters can produce plasma KB levels comparable to those achieved by the most rigorous KD, thus providing a safe, convenient, and versatile new approach to the study and potential treatment of a variety of diseases, including epilepsy, ...

Scientific rationale for integrative and personalised strategies for pancreatic ductal adenocarcinoma management

“…284 In addition, keeping in view the significant role of inflammation and metabolic alteration, a ketogenic diet also provides an efficient therapeutic strategy, because lowering lactate production by ketogenic diet has been shown to decrease MDSC frequency leading to improved antitumour immune response.285 Remarkably, a ketogenic diet causes minimal side effects as previously demonstrated that a 2-7 mM ketone body concentration can be achieved without giving rise to clinical acidosis. 286 Recalling the fact that, at the time of diagnosis around 80% of patients with PDAC present cachexia, ketogenic diet might serve as an anti-cachectic agent as well as an anti-cancer agent. [284][285][286] …”

“…286 Recalling the fact that, at the time of diagnosis around 80% of patients with PDAC present cachexia, ketogenic diet might serve as an anti-cachectic agent as well as an anti-cancer agent. [284][285][286] …”

Foods as a Novel Treatment for Glioblastoma

“…[25] The other studies described that ketone bodies supplements, ketone monoester (KME), have protective effects in the brain by potentiating the KD and prevention of glucose consumption in brain cells. [41,42] The mechanism of bHB inhibiting oxidative stress has mentioned in some studies. The ketone body bHB increased the global histone acetylation in mouse model caused changes in transcription genes encoding oxidative stress resistance factors FOXO3A and MT2.…”

“…[45] Interesting data uncovered the role of bHB in reducing the growth of glioblastoma cells in the presence of glucose in some cancer cell lines and increasing the radio-sensitivity in vitro studies. [41] Moreover, the efficacy of chemotherapy drugs has been increased by ketone bodies in vitro.…”

Using positron emission tomography to study human ketone body metabolism: A review

“…It is unclear to what extent such differences affect the variables measured, but it is not unlikely that the amount of carbohydrate in the diets can considerably affect the degree of ketonemia and/or glycemia and thereby the experimental results. A strict hyperketogenic diet as prescribed for control of refractory epilepsy in humans can result in blood ketone levels of up to 12 mmol/L [51], whereas more moderate ketogenic diets with higher protein and/or carbohydrate content typically result in ketonemia around 4-6 mmol/L (reviewed in [52]). …”