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

Intranasal insulin (II) administration is widely used in the last years to treat Alzheimer’s disease and other cognitive disorders. Meanwhile, it is almost not used to treat type 2 diabetes mellitus (DM2), mainly due to insufficiently studied molecular mechanisms of its effect on the hormonal and metabolic status of the organism. The effect of II on activity of the hypothalamic signaling systems playing a key role in central regulation of energy metabolism is also poorly studied. The aim of this work was to study the effect of 5-week II treatment of male rats with the neonatal model of DM2 (0.48 ME/rat) both on the metabolic parameters and functional activity of the hypothalamic signaling systems. II treatment of diabetic rats (DI group) was shown to normalize the blood glucose level and restore glucose tolerance and utilization. In the hypothalamus of the DI group, the regulatory effects of agonists of the type 4 melanocortin receptor (MC4R), type 2 dopamine receptor (D2-DAR) and serotonin 1B receptor (S1BR) on adenylyl cyclase (AC) activity, reduced under DM2, were found to be restored; moreover, the inhibitory effect of S1BR agonists became even stronger as compared to control. In the DI group, the restoration of AC hormonal regulation was associated with a considerable increase in expression of the genes encoding S1BR and MC4R. Besides, the attenuation of the AC-stimulating effect of D2-DAR agonists against the background of decreasing expression of the Drd1 gene was found to promote the enhancement of the negative effect of dopamine on AC activity. II treatment did not have a considerable effect on expression of the genes encoding the insulin receptor and insulin receptor substrate-2, which was slightly reduced in the hypothalamus of diabetic rats. Thus, II treatment of rats with the neonatal model of DM2 partially restores the hypothalamic AC signaling pathways regulated by melanocortin, serotonin and dopamine, demonstrating thereby one of the mechanisms of the positive influence of II on energy metabolism and insulin sensitivity in peripheral tissues.