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Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
Ketone bodies acetoacetate and 3-hydroxybutyric acid are metabolites derived from fatty acids and ketogenic amino acids, such as leucine. They are mainly produced in the liver, via reactions catalysed by the ketogenic enzymes HMG CoA synthase and HMG CoA lyase. After prolonged starvation, ketone bodies can provide up to two-thirds of the brain’s energy requirements. The rate-limiting enzyme of ketone body utilisation (ketolysis) is succinylcoenzyme A: 3-oxoacid coenzyme A transferase. The subsequent step of ketolysis is catalysed by 2-methylactoacetyl-coenzyme A thiolase (beta-ketothiolase), which is also involved in isoleucine catabolism.
Effectiveness of Ketogenic Diets on the Survival of Adult Oncological Patients
Published in Nutrition and Cancer, 2021
The most described effect in the literature refers to the fact that the KD alters glucose metabolism of CaCe, generating a “selective fast” (8, 10). Because some tumor cells present a deficit of enzymes that participate in the process of ketolysis, it is difficult for them to adapt to the new energy source (7, 13). In addition, hypoxic areas have been described in solid tumors in which the lack of oxygen prevents the metabolization of KBs. This could cause an alteration in the growth of CaCe and promote greater susceptibility to cytotoxic treatments (17, 18). Moreover, the sustained reduction of glycemia is a contributing factor in the effectiveness of the KD against tumor growth (8). This decrease in glucose is also accompanied by a decrease in insulin and insulin-like growth factor 1 (IGF-1) levels, which normally promote cell growth and proliferation (5). It has also been described that KD could slow down tumor development by inhibiting intracellular metabolic signaling pathways of insulin and IGF-1, such as the enzyme phosphoinositol-3-kinase (PI3K), protein kinase b (Akt) and mTOR (5, 14). However, there are also studies in which, despite having reduced glucose and insulin levels, it is not possible to stop tumoral growth, showing that there are other factors that play a role in tumorigenesis (8).
Associations between ketone bodies and fasting plasma glucose in individuals with post-pancreatitis prediabetes
Published in Archives of Physiology and Biochemistry, 2020
Sakina H. Bharmal, Sayali A. Pendharkar, Ruma G. Singh, David Cameron-Smith, Maxim S. Petrov
Ketone body metabolism is determined by two processes - ketogenesis and ketolysis (Fukao et al.2004). While ketolysis is controlled by acetoacetyl succinyl-CoA transferase (enzyme) activity, ketogenesis is regulated by the availability of acetyl-CoA substrate, enzymatic activity of lipase, acetyl-CoA carboxylase, and hydroxymethyl glutaryl (HMG)-CoA synthase (Laffel 1999). Glucoregulatory hormones (in particular insulin) are crucial to maintaining the balance between ketogenesis and ketolysis. Insulin, while demonstrating an inhibitory effect on ketogenesis, has been shown to enhance ketolysis by increasing the peripheral utilisation of ketones (Keller et al.1988). Evidence from studies conducted in individuals with prediabetes and obesity have shown ketone bodies levels to be below the normal threshold, which has been attributed to high insulin concentrations (Nosadini et al.1985, Soeters et al.2009, Vega et al.2009, Mahendran et al.2013). The present study showed that BHB contributed to 26.2% of variance in fasting glucose levels in individuals with PPP, as opposed to 0.1% in individuals with NAP. Further, BHB was inversely associated with plasma levels of insulin. For every unit change in insulin, BHB levels significantly decreased by 15% in PPP compared to a 3% non-significant decrease in NAP. Given that individuals with PPP had higher levels of circulating insulin, in comparison with NAP, findings from the present study could be explained by the following mechanisms.
Urinary organic acids spectra in children with altered gut microbiota composition and autistic spectrum disorder
Published in Nordic Journal of Psychiatry, 2022
Zanda Daneberga, Miki Nakazawa-Miklasevica, Egija Berga-Svitina, Daiga Murmane, Dana Isarova, Liene Cupane, Madara Masinska, Inga Nartisa, Andzela Lazdane, Edvins Miklasevics
The urinary organic acid spectra for each individual were assessed using quantitative and semi-quantitative analysis. Twenty-seven analytes were identified and quantified, in addition fourteen analytes were identified based on mass spectra, but not quantified. Taking into the account the declining excretion of organic acids by urine trough the childhood and adolescence, acquired quantitative results from ASD group were compared to the laboratory developed reference values calculated from age matched individuals. Results of both ASD group and reference values are acquired by same standardized method using the same equipment. We did not find any significant deviation in any of quantified metabolites compared to the reference values of corresponding age group (Table 1). In the age group 3 to 5 years 3-OH-butiric acid along with adipic acid, suberic acid and 3-OH-3-methylglutaric acid showed large SD values. 3-OH-butiric acid (1.15-fold increase for mild ketosis and 10.53-fold increase in severe ketosis) and 3-OH-3-methylglutaric acid (4.5- and 3.99-fold increase) were altered due to physiological ketosis in two samples, in both samples also acetoacetic acid was identified but not quantified. Adipic acid and suberic acid, which are intermediate metabolites in fatty acids beta oxidation [23], showed 11-fold increase for adipic acid and 14-fold increase for suberic acid in one of samples with confirmed medium chain triglycerides (MCT) supplement in diet. 3-OH-3-methylglutaric acid is intermediate in leucin degradation and ketone body formation, both have increased urinary excretion in the case of ketosis [23]. The ketolysis defect and secondary reasons for ketosis were excluded in follow-up samples for both individuals. The rest of individual alterations in single metabolites, without corresponding changes of the linked metabolic pathway metabolites, were considered as not specific to ASD, environmental factor related secondary changes.