Metformin regulates glycemic homeostasis in patients with type 2 diabetes mellitus as an NO donor

Abstract

Aim. To evaluate the influence of metformin on nitric oxide bioavailability in patients with type 2 diabetes mellitus (T2DM) regarding glycemic homeostasis, and to investigate a correlation between metformin dosage and NO levels in vivo. Materials and Methods. Two groups ? primary and control ? were assembled for the clinical section of this study. Patients with newly diagnosed T2DM on metformin therapy were included to the primary group, while drug-naive T2DM patients were enrolled as control subjects. Glycemic parameters and NO bioavailability was tested in both groups prior to and after the follow-up period. Experimental section was dedicated to the elucidation of potential dose-dependent effects of metformin on NO bioavailability. Mice were intraperitoneally infused with metformin at 0.5; 1.1; 5.6 mg per subject. Tissue detection of NO was performed with diethyldithiocarbamate (DETC) iron complexes to form mononitrosyl iron compounds (MIC) with paramagnetic properties. Control rodents were intraperitoneally infused with metformin without spin trapping. Results. We found nitrite and methaemoglobin (a marker for NO bioavailability) to increase in parallel along with glycemic compensation in the primary but not control group. In vivo rodent models showed linear correlation between accumulation of DETC/MIC and dose of metformin, as well as formation of dinitrosyl iron complexes, known as endogenous NO transporters. Conclusion. Our data suggests that metformin benefits glycemic homeostasis in T2DM as an NO donor via formation of dinitrosyl iron complexes.