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

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