Anti-diabetic effects of mildronate alone or in combination with metformin in obese Zucker rats

Mildronate is a cardioprotective drug, the mechanism of action of which is based on the regulation of l-carnitine concentration. We studied the metabolic effects of treatment with mildronate, metformin and a combination of the two in the Zucker rat model of obesity and impaired glucose tolerance. Zucker rats were p.o. treated daily with mildronate (200 mg/kg), metformin (300 mg/kg), and a combination of both drugs for 4 weeks. Weight gain and plasma metabolites reflecting glucose metabolism were measured. The expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ and target genes was measured in rat heart and liver tissues. Each treatment decreased the blood glucose concentration during the fed and fasted states by 1 to 2 mmol/l. Treatment with mildronate and metformin decreased the plasma insulin concentration by 31 and 29%, respectively, while the combination of both drugs significantly reduced fed insulin concentration by about 47%. Mildronate treatment increased the expression of PPAR-α in the heart tissue and PPAR-γ in the heart and liver tissues. In addition, treatment increased the expression of PPAR target genes in the heart, but not in the liver tissue. In contrast to monotherapy, treatment with the combination of mildronate and metformin significantly decreased weight gain by 19% and did not affect food intake. In conclusion, our results demonstrate that mildronate, an inhibitor of l-carnitine biosynthesis, improves adaptation to hyperglycemia- and hyperlipidemia-induced metabolic disturbances and increases PPAR-α activity.