Cardiac metabolic modulation upon low‐carbohydrate low‐protein ketogenic diet in diabetic rats studied in vivo using hyperpolarized 13 C pyruvate, butyrate, and acetoacetate probes

AIMS: To investigate the effects of long-term low-carbohydrate low-protein ketogenic diet (KD) on cardiac metabolism and diabetic cardiomyopathy status in lean diabetic Goto-Kakizaki (GK) rats. MATERIALS AND METHODS: Diabetic GK rats were fed with KD for 62 weeks. Cardiac function and metabolism were assessed using magnetic resonance imaging and 13 C magnetic resonance spectroscopy (13 C-MRS), at rest and under dobutamine stress. 13 C-MRS was performed following injection of hyperpolarized [3-13 C]acetoacetate, [1-13 C]butyrate, or [1-13 C]pyruvate to assess ketone body, short-chain fatty acid, or glucose utilization, respectively. Protein expression and cardiomyocyte structure were determined via Western blotting and histology, respectively. RESULTS: KD lowered blood glucose, triglyceride, and insulin levels, while increasing blood ketone body levels. In KD-fed diabetic rats, myocardial ketone body and glucose oxidation were lower than in chow-fed diabetic rats, while myocardial glycolysis and short-chain fatty acid oxidation were unaltered. Dobutamine stress revealed an increased cardiac preload and reduced cardiac compliance in KD-fed diabetic rats, together with an enhanced stimulation of glycolysis compared with that in chow-fed diabetic rats, which was potentially facilitated via an upregulation in basal expression of proteins involved in glucose transport and glycolysis in the hearts of KD-fed rats. The metabolic profile induced by KD was accompanied by cardiac hypertrophy, a trend for higher myocardial lipid and collagen content, and an increased marker of oxidative stress. CONCLUSION: KD seems to exacerbate diabetic cardiomyopathy in GK rats, which may be associated with maladaptive cardiac metabolic modulation and lipotoxicity. This article is protected by copyright. All rights reserved.