Biguanide metformin, which is widely used for the treatment of
type 2 diabetes mellitus, improves
carbohydrate and lipid metabolism and shows a pronounced cardio- and
neuroprotective effects. It is assumed that an important role in these effects of
metformin plays its ability to positively influence the activity of
NO-synthase catalyzing the synthesis of NO, the most important
vasodilator, and the activity of
hormone-sensitive
adenylyl cyclase signaling system (ACSS. To prove this, we have carried out a study whose purpose was to study the effect of long-term
metformin treatment on the metabolic rates in obese rats, as well as on the activity of ACSS and
NO-synthase in the myocardium and the brain of these animals. The
metformin treatment of Wistar rats with
obesity induced by high-fat diet was carried out for 2 months (daily dose of 200 mg/kg). The treatment with
metformin led to a decrease in
body weight and body fat, reduced
glucose and
insulin levels as well as reduced
insulin resistance index HOMA-IR, improved
glucose tolerance, and decreased the level of atherogenic forms of
cholesterol. In the myocardium of obese rats, the attenuation of ACSS stimulation induced by the agonists of β1/β2-
adrenergic receptors (AR) and the strengthening of β3-AR signaling has been found. At the same time, in the myocardium of animals treated with
metformin, the regulation of ACSS by
adrenergic agonists was restored, and the ratio of β-AR-signaling pathways returned to normal. In the brain of rats treated with
metformin,
adenylyl cyclase stimulating effects of
serotonin and agonists of type 4
melanocortin receptors, which had been weakenend for
obesity, were restored.
Metformin treatment completely restored activity of total and endothelial
NO-synthase in the myocardium decreased in
obesity. It as also shown that
metformin treatment induced hyperactivation of
NO-synthase in the myocardium and brain of healthy animals. Thus, we conclude that the effects of
metformin identified by us in rats with long-term treatment of
obesity may explain cardio- and neuroprotective influence of this
drug.