Heart ketone metabolism under acute ketone supplementation in ZDF rats, a type 2 diabetes heart failure model

In non-insulin-dependent, type 2, diabetes mellitus (T2D), glucose metabolism is compromised, and the heart loses its metabolic flexibility. The Zucker Diabetic Fatty rat (ZDF) model, which replicates the pathophysiology of T2D in patients, shows that as T2D progresses so does heart failure. Heart ketone metabolism seems to play a role in mitigating the heart failure process. This study assesses ketone metabolism in a ZDF heart failure model using cardiac PET imaging.

Six lean ZDF rats (CTRL) and six diabetic obese ZDF rats (T2D) were evaluated for coronary flow reserve (CFR) using [¹³N]ammonia ([¹³N]NH₃) cardiac PET. In addition, rats were evaluated with [¹¹C]acetoacetate ([¹¹C]AcAc) PET during rest and stress conditions to assess ketone metabolism, both at baseline and under an acute exogenous ketone ester oral supplementation. Blood chemistry, cardiac function and hemodynamic parameters were also evaluated under these conditions.

CFR was impaired in the T2D model (CTRL: 1.8 ± 0.5; T2D: 1.4 ± 0.2, p < 0.05) suggesting the development of heart failure in the T2D model. Blood ketones increased more than 2-fold after supplementation. The [¹¹C]AcAc heart ketone uptake values with and without ketone supplementation were similar for the CTRL group, and these values were higher than for T2D rats. For the T2D group, the uptake decreased by 20% at rest under ketone supplementation vs. no supplementation (p < 0.05) and remained unchanged under stress with and without supplementation. Because of this decrease at rest, the stress/rest ratio after supplementation increases to the level observed in CTRL. [¹¹C]AcAc heart ketone metabolism showed a slight decrease under stress for the CTRL group, but not for the T2D. Under ketone supplementation, the metabolism stress/rest ratio increased only in T2D (1.25 ± 0.29, p = 0.03 compared to baseline).

In a rat model of T2D and CFR impairment, we were able to measure changes in ketone metabolism using [¹¹C]AcAc PET at rest and under stress with and without acute ketone supplementation. Our findings suggest that the heart ketone metabolism of T2D rats is impaired during the heart failure process. Ketone supplementation may have the potential to restore this cardiac reserve.