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Mildronate [3-(2, 2, 2-trimethylhydrazinium) propionate] is used in clinics as a cardioprotective drug that improves cardiac function during ischemia by modulating myocardial energy metabolism.As the long-term mildronate treatment induces significant changes in L-camitine homeostasis and L-camitine plays a pivotal role in the balanced metabolism of fatty acids and carbohydrates, we carried out studies to investigate whether long-term mildronate treatment could influence glucose levels and prevent diabetic complications in experimental models of diabetes mellitus and metabolic syndrome.In Goto-Kakizaki rats, mildronate decreased L-carnitine contents and exhibited cardioprotective effects, decreased blood glucose concentrations and prevented the loss of pain sensitivity.In Zucker rats, the 4 week mildronate treatment in combination with a known anti-diabetic drug, metformin, significantly decreased the rat weight gain while it did not affect food intake.Mildronate, metformin and combination prevented progression of metabolic syndrome and similarly decreased both the fed-and fasted-state blood glucose and fed-state insulin levels.In addition, the long-term mildronate treatment lead to increased glucose uptake and glucose metabolism-related gene expression, but it was not associated with cardiac impairment or disturbances in liver function.These findings indicate that mildronate treatment could be beneficial in diabetes patients with cardiovascular problems.