Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate ‘ketogenic’ diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl-(R)-1,3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium βHB. Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 g or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations (D-βHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3-4 h. KS drinks were found to contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-βHB and L-βHB was < 1.5 % of the total βHB ingested and was in proportion to the blood AUC. D-βHB, but not L-βHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-βHB concentrations was determined in 16 participants. Food lowered blood D-βHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-βHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-βHB AUC of 1.3-1.4 moles.min. Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.

Background: To study the pathogenesis of diabetic cardiomyopathy, reliable animal models of type 2 diabetes are required. Physiologically relevant rodent models are needed, which not only replicate the human pathology but also mimic the disease process. Here we characterised cardiac metabolic abnormalities, and investigated the optimal experimental approach for inducing disease, in a new model of type 2 diabetes. Methods and results: Male Wistar rats were fed a high-fat diet for three weeks, with a single intraperitoneal injection of low dose streptozotocin (STZ) after fourteen days at 15, 20, 25 or 30 mg/kg body weight. Compared with chow-fed or high-fat diet fed control rats, a high-fat diet in combination with doses of 15–25 mg/kg STZ did not change insulin concentrations and rats maintained body weight. In contrast, 30 mg/kg STZ induced hypoinsulinaemia, hyperketonaemia and weight loss. There was a dose-dependent increase in blood glucose and plasma lipids with increasing concentrations of STZ. Cardiac and hepatic triglycerides were increased by all doses of STZ, in contrast, cardiac glycogen concentrations increased in a dose-dependent manner with increasing STZ concentrations. Cardiac glucose transporter 4 protein levels were decreased, whereas fatty acid metabolism-regulated proteins, including uncoupling protein 3 and pyruvate dehydrogenase (PDH) kinase 4, were increased with increasing doses of STZ. Cardiac PDH activity displayed a dose-dependent relationship between enzyme activity and STZ concentration. Cardiac insulin-stimulated glycolytic rates were decreased by 17% in 15 mg/kg STZ high-fat fed diabetic rats compared with control rats, with no effect on cardiac contractile function. Conclusions: High-fat feeding in combination with a low dose of STZ induced cardiac metabolic changes that mirror the decrease in glucose metabolism and increase in fat metabolism in diabetic patients. While low doses of 15–25 mg/kg STZ induced a type 2 diabetic phenotype, higher doses more closely recapitulated type 1 diabetes, demonstrating that the severity of diabetes can be modified according to the requirements of the study.

Obesity is linked to increased left ventricular mass, an independent predictor of mortality. As a result of this, understanding the determinants of left ventricular mass in the setting of obesity has both therapeutic and prognostic implications. Using cardiovascular magnetic resonance our goal was to elucidate the main predictors of left ventricular mass in severely obese subjects free of additional cardiovascular risk factors.

Ketone bodies acetoacetate (AcAc) and D-β-hydroxybutyrate (βHB) may provide an alternative carbon source to fuel exercise when delivered acutely in nutritional form. The metabolic actions of ketone bodies are based on sound evolutionary principles to prolong survival during caloric deprivation. By harnessing the potential of these metabolic actions during exercise, athletic performance could be influenced, providing a useful model for the application of ketosis in therapeutic conditions. This article examines the energetic implications of ketone body utilisation with particular reference to exercise metabolism and substrate energetics.