Introduction: Diabetic cardiomyopathy (DCM) is an asymptomatic condition responsible for almost 80% of diabetic deaths via interconnected pathways. There is currently no specific effective pharmacological or lifestyle modification regimen prescribed to mitigate its development, although many monotherapies have been suggested. Treatment with metformin (MET) and consumption of ketogenic diets (KD) have individually demonstrated anti-hyperglycaemic effects however, whether they can synergistically exert ameliorative effects against DCM remains largely unknown.

Objective: This study was designed to evaluate the ameliorative potentials of co-exposure to metformin and ketogenic diet on experimental DCM using male Wistar rats.

Methods: Experimental DCM was induced using 10% fructose drinking water and streptozotocin (40 mg/kg i.p.). Forty-nine male Wistar rats (100-150g) were divided into seven groups (n=7). Groups I-IV had experimental DCM and were exposed to Normal Diet (ND), ND+MET (300mg/kg/day, p.o.), KD, and MET+KD, while Groups V-VII were non-diabetic and exposed to KD, ND+MET, and ND, respectively, for 4 weeks. Thereafter, blood samples were obtained and analysed for glucose regulatory indices (glucose, HbA1c, insulin), lipid profile and BNP.  Cardiac samples were also evaluated for metabolic indices (AMPK, GLUT-4), oxidative stress (Nrf2, MDA, MPO), and cell apoptosis (Bax, Bcl-2, and Caspase-3). Insulin resistance was estimated mathematically, while cardiac histology was evaluated using standard H&E. Data obtained evaluated using ANOVA and descriptive statistics at p<0.05.

Results: DCM was characterised by significantly reduced body weight, left ventricular hypertrophy hyperglycaemia, hyperinsulinaemia, and dyslipidaemia compared to control. Body weight increased, while impaired glucose regulatory indices and dyslipidaemia was improved (p<0.05) in the DCM animals exposed to MET+KD compared to DCM exposed to normal diet. Impaired cardiac cell metabolism and oxidative stress observed in the experimental DCM only group was somewhat reversed following exposure to MET+KD. Compared to DCM exposed to normal diet, cardiomyopathy and apoptosis markers in the DCM exposed to MET+KD were also significantly reduced and was accompanied by improved left ventricular histoarchitecture. The DCM animals exposed to either ND+MET or KD alone individually showed similar, though not so potent responses, as that obtained in the DCM animals exposed to MET+KD.

Discussion and Conclusion: This study suggests that consumption of ketogenic diet and treatment with metformin may exert a synergistic effect in mitigating diabetic cardiomyopathic symptoms as against using either treatment regimen individually.

Keywords: Diabetic cardiomyopathy, metformin, ketogenic diet, hyperglycemia, cardiac inflammation, cardiac apoptosis