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

Aim 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. Dobutamine‐induced stimulation of myocardial glycolysis was more enhanced in KD‐fed diabetic rats than 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 increased 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.