Mitochondria-targeting compounds for management of metabolic and hemostatic abnormalities associated with heart dysfunctions in experimental type 2 diabetes

Objective. Cardiovascular complications are highly prevalent in type 2 diabetes mellitus (T2DM) driven by obesity, dyslipidemia, hypertension, and hypercoagulability associated with insulin resistance. The purpose of this study was to elucidate the effects of combined treatment with acetyl-L-carnitine (ALC), alpha-lipoic acid (ALA), and nicotinamide (NAm) on diabetes-induced metabolic, hemostatic, and heart abnormalities. Methods. Male non-linear Wistar rats were fed with a high-calorie diet for 2 months followed by a single low-dose streptozotocin injection to induce T2DM. Two weeks later, the diabetic rats received ALC (100 mg/kg), ALA (50 mg/kg), and NAm (100 mg/kg) for 2 weeks in separate daily injections. Fasting blood glucose, glycated hemoglobin (HbA1c), and hemostatic parameters: fibrinogen, protein C, factor X, plasminogen activator inhibitor-1 (PAI-1), were measured. The NAD+ content and NAD + /NADH ratio were assessed in the heart tissue. Results. After 12 weeks, blood glucose and HbA1c levels in diabetic rats were 1.8-fold and 2-fold higher, respectively. Diabetes increased fibrinogen (1.5-fold) and PAI-1 (1.7-fold) levels, caused the appearance of soluble fibrin monomers complexes, while protein C and factor X levels were decreased by 18% and 19%, respectively, indicating hypercoagulability and impaired fibrinolysis. In diabetic rats, the cardiac NAD+ level was reduced by 48%. The NAD+/NADH ratio decreased by 2-fold. Combined treatment lowered the glucose levels by 1.3-fold and HbA1c by 1.7-fold and improved the NAD+ metabolism and partially corrected the hemostatic abnormalities. Conclusion. Co-treatment with ALC, ALA, and NAm improved the glycemic control, partially restored the cardiac NAD + metabolism and reduced the hemostatic abnormalities in T2DM suggesting their potential as a safe adjunct therapy for diabetes-associated cardiovascular complications.