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

IF 3.1 3区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING EJNMMI Research Pub Date : 2025-03-14 DOI:10.1186/s13550-025-01215-9

Etienne Croteau, Gabriel Richard, Patrick Prud'Homme, Etienne Rousseau, Stephen C Cunnane, Véronique Dumulon-Perreault, Otman Sarrhini, Serge Phoenix, Sébastien Tremblay, Brigitte Guérin, Roger Lecomte

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Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

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2型糖尿病心力衰竭模型ZDF大鼠急性补充酮对心脏酮代谢的影响

背景：在非胰岛素依赖型2型糖尿病（T2D）中，糖代谢受损，心脏失去代谢灵活性。Zucker糖尿病脂肪大鼠（ZDF）模型复制了患者T2D的病理生理，表明随着T2D的进展，心力衰竭也会发生。心酮代谢似乎在减轻心力衰竭过程中起作用。本研究利用心脏PET显像评估ZDF心衰模型中的酮代谢。方法：采用[13N]氨（[13N]NH3）心脏PET评价6只瘦ZDF大鼠（CTRL）和6只糖尿病肥胖ZDF大鼠（T2D）的冠状动脉血流储备（CFR）。此外，在休息和应激条件下，用[11C]乙酰乙酸酯（[11C]AcAc） PET评估大鼠在基线和急性外源性酮酯口服补充下的酮代谢。血液化学、心功能和血流动力学参数也在这些条件下进行了评估。结果：T2D模型CFR明显受损(CTRL: 1.8±0.5；T2D: 1.4±0.2，p 11C]添加和未添加酮的对照组AcAc心脏酮摄取值相似，且高于T2D大鼠。对于T2D组，补充酮组与不补充酮组相比，休息时摄取减少了20% （p 11C）。CTRL组在应激下AcAc心脏酮代谢略有下降，但T2D组没有。在补充酮的情况下，代谢应激/休息比仅在T2D时增加（1.25±0.29，与基线相比p = 0.03）。结论：在T2D和CFR损伤的大鼠模型中，我们能够使用[11C]AcAc PET测量在休息和应激下，有和没有急性补充酮的酮代谢的变化。我们的研究结果表明，在心力衰竭过程中，T2D大鼠的心酮代谢受到损害。补充酮可能有恢复这种心脏储备的潜力。

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来源期刊

EJNMMI Research RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING&nb-

CiteScore

5.90

自引率

3.10%

发文量

审稿时长

13 weeks

期刊介绍： EJNMMI Research publishes new basic, translational and clinical research in the field of nuclear medicine and molecular imaging. Regular features include original research articles, rapid communication of preliminary data on innovative research, interesting case reports, editorials, and letters to the editor. Educational articles on basic sciences, fundamental aspects and controversy related to pre-clinical and clinical research or ethical aspects of research are also welcome. Timely reviews provide updates on current applications, issues in imaging research and translational aspects of nuclear medicine and molecular imaging technologies. The main emphasis is placed on the development of targeted imaging with radiopharmaceuticals within the broader context of molecular probes to enhance understanding and characterisation of the complex biological processes underlying disease and to develop, test and guide new treatment modalities, including radionuclide therapy.