Ketone monoester ingestion improves cardiac function in adults with type 2 diabetes: a double-blind, placebo-controlled, randomized, crossover trial

Type 2 diabetes (T2D) is a metabolic disease associated with cardiovascular dysfunction. The myocardium preferentially uses ketones over free fatty acids as a more energy-efficient substrate. The primary aim was to assess the effects of ketone monoester (Kme) ingestion on cardiac output index (Q(center dot)i). The secondary aims were to assess the effects of Kme ingestion on markers of cardiac hemodynamics, muscle oxygenation, and vascular function at rest, during and following step-incremental cycling. We undertook a double-blind, randomized, crossover design study in 13 adults [age, 66 +/- 10 yr; body mass index (BMI), 31.3 +/- 7.0 kg<middle dot>m(-2)] with T2D. Participants completed two conditions, where they ingested a Kme (0.115 g<middle dot>kg(-1)) or a placebo taste-matched drink. Cardiac function was measured using thoracic impedance cardiography, and muscle oxygenation of the calf was determined via near-infrared spectroscopy. Macrovascular endothelial function was measured by flow-mediated dilation (FMD), and microvascular endothelial function was measured via transdermal delivery of acetylcholine (ACh) and insulin. Circulating beta-hydroxybutyrate [beta-Hb] was measured throughout. Kme ingestion raised circulating beta-Hb throughout the protocol (peak 1.9 mM; P = 0.001 vs. placebo). Kme ingestion increased Q(center dot)i by 0.75 +/- 0.5 L<middle dot>min(-1)<middle dot>m(-2) (P = 0.003), stroke volume index by 7.2 +/- 4.5 mL<middle dot>m(-2) (P = 0.001), and peripheral muscle oxygenation by 9.9 +/- 7.1% (P = 0.001) and reduced systemic vascular resistance index by -420 +/- -225 dyn<middle dot>s(-1)<middle dot>cm(-5)<middle dot>m(-2) (P = 0.031) compared with the placebo condition. There were no differences between Kme and placebo in heart rate (P = 0.995), FMD (P = 0.542), ACh max (P = 0.800), and insulin max (P = 0.242). Ingestion of Kme improved Q(center dot)i, stroke volume index, and peripheral muscle oxygenation but did not alter macro- or microvascular endothelial function in people with T2D. NEW & NOTEWORTHY For the first time, we show that acute ketone monoester ingestion (Kme) can increase cardiac output and stroke volume and reduce systemic vascular resistance at rest and during exercise in sodium glucose transporter inhibitors na & iuml;ve (i.e. no drug-induced ketosis) people with type 2 diabetes. Acute Kme ingestion improves peripheral skeletal muscle oxygenation during moderate intensity and maximal exercise. Kme has no effect on macro- or microvascular endothelial function in people with type 2 diabetes.