Heart ketone uptake reserve in diabetic ZDF rats with an acute ketone ester supplementation: a [11C]-acetoacetate rest-stress study

36 Objectives: In type II diabetes, glucose metabolism is compromised. This impairment is known to increase cardiac fatty acid consumption, but its effect on other substrates, such as ketones (acetoacetate and beta-hydroxybutyrate) is poorly understood. A recent study (EMPA-REG)[asterisk] evaluating the inhibition of glucose reabsorption by kidneys in type II diabetes has shown a reduction of sudden cardiac death and heart failure hospitalization. The treatment also led to a slight decrease in HbA1c and an increase in blood ketones. The aim of the present study is to use [11C]-acetoacetate as a direct index to characterize the in vivo heart ketone uptake reserve in the Zucker diabetic fatty (ZDF) rat model of type II diabetes. Methods: Dynamic PET scans using [11C]-acetoacetate, a ketone radiotracer, were performed to assess ketone myocardial uptake reserve in the Zucker lean rats (CTRL; N=6) and the type II diabetic ZDF rats (ZDF; N=6). Rest and stress (adenosine) conditions were studied using a one-tissue compartment kinetic model to extract the perfusion-uptake rate constant K1 (mL/g/min). The stress/rest ratio of K1 was used to assess the myocardial ketone uptake reserve. Cardiac imaging was performed at baseline and following ketone ester supplementation by an acute gavage (0.7 g/kg, 1 hour before the scanning session). Hemodynamic parameters were monitored throughout the imaging sessions and a blood sample before the imaging session was drawn to measure glucose, triglycerides and ketone levels. Note that ZDF rats did not receive insulin or antidiabetic drugs during this study. Results: In CTRL rats, blood glucose and triglycerides were stable throughout the study (19.8±1.6 and 0.5±0.2 mmol/L; p=0.25), whereas, after gavage, blood ketones doubled (0.7±0.3 to 1.4±0.7 mmol/L; p<0.01). In ZDF rats, blood glucose and triglycerides were elevated (40.7±2.8 and 4.2±1.1 mmol/L ) due to the lack of treatment, but blood ketones more than doubled after the gavage (1.2±0.6 to 3.3±1.2 mmol/L; p=0.01). Hemodynamic parameters were stable during imaging sessions. In CTRL rats, the K1 of [11C]-acetoacetate was equivalent under normal condition and light hyperketonaemia, for both rest and stress conditions (baseline: 2.6±0.2 rest / 3.6±0.6 stress vs. supplementation: 2.6±0.4 rest / 3.2±0.5 stress; p=0.4). On the other hand, ZDF rats had an impaired stress/rest reserve at baseline compared to the CTRL group and their K1 at rest decreased following ketone ester supplementation (baseline: 2.4±0.2 rest / 2.4±0.5 stress; p=0.9 vs. supplementation: 1.7±0.3 rest / 2.5±0.5 stress; p=0.01 ). Due to this decrease, the stress/rest reserve was apparently increased in the ZDF cohort following ketone ester gavage (1.0±0.1 vs 1.4±0.3; p=0.01 ). Conclusions: Ketone uptake reserve is impaired under stress in type II diabetes ZDF rats compared to CTRL rats. Interestingly, ketone ester supplementation decreases [11C]-acetoacetate uptake in the rest condition improving the uptake reserve in ZDF but not in CTRL rats. This is the first reported study of the in vivo heart ketone uptake reserve in an animal model of type II diabetes. [asterisk]Mudaliar S et al. Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis. Diabetes Care. 2016;39:1115-22.