Functional state of hypothalamic signaling systems in rats with type 2 diabetes mellitus treated with intranasal insulin

Abstract

In the last years intranasally administered insulin (II) is widely used to treat Alzheimer's disease and other cognitive disorders. Meanwhile, it is little used to treat the type 2 diabetes mellitus (DM2); which is due to insufficient knowledge of molecular mechanisms of its action on hormonal and metabolic status of an organism. The effect of II on the activity of hypothalamic signaling systems, which plays a key role in the central regulation of energy metabolism, is still poorly understood. The aim of the present work was to study the effect of five-week treatment of male rats with neonatal model of DM2 using 11 (0.48 IU/rat) on metabolic parameters and on functional activity of the hypothalamic signaling systems. It was shown that treatment of diabetic rats with II'(Group DI) normalized plasma glucose level, restored glucose tolerance and its utilization. In the hypothalamus of rats of the Group DI the-regulatory effects of agonists of type 4 melanocortin receptors (MC4R), type 2 dopamine receptor (D2-DAR) and subtype 1B serotonin receptor (5-HTIBR) on adenylyl cyclase (AC) activity, which were reduced in DM2, restored. Moreover, the inhibitory effect of 5-HTIR agonists even was increased as compared to control. In the Group DI, the res- toration of AC regulation by hormones was accompanied by a significant increase in the expression of genes encoding 5-HTIBR and MC4R. Along with this, the attenuation of the AC stimulating effect of D1-DAR agonists and the decreased expression of Drdl gene were found, promoting the enhancement of the negative dopamine effect on AC activity. The II treatment did not significantly affect the expression of genes encoding insulin receptor and insulin receptor substrate 2, which was reduced, though to a small extent, in the hypothalamus of diabetic rats. Thus, the II treatment of rats with the neonatal model of DM2 partially restores the hypothalamic AC signaling pathways regulated by melanocortins, serotonin and do- pamine, which is one of the mechanisms of positive influence of II on energy metabolism and insulin sensitivity in the peripheral tissues.