C-Peptide and Insulin during Combined Intranasal Administration Improve the Metabolic Parameters and Activity of the Adenylate Cyclase System in the Hypothalamus, Myocardium, and Epididymal Fat of Rats with Type 2 Diabetes

Abstract

Abstract —C-peptide, a product of proinsulin proteolysis, regulates physiological and biochemical processes by increasing the bioavailability of insulin due to the formation of complexes and also by binding to C-peptide receptors. Under insulin deficiency in severe forms of type 2 diabetes mellitus (DM), the levels of C-peptide and insulin in the brain, the target of their action, are decreased. This deficit can be compensated by intranasally administered C-peptide (IACP) and insulin (IAI). It is assumed that the administration of IACP and IAI in type 2 diabetes will lead to the normalization of the activity of the adenylate cyclase signal system (ACSS) in the hypothalamus and on the periphery and will provide, thereby, a therapeutic effect of IACP and IAI. The aim of the work was to study the effect of a 9-day treatment of 4-month-old male rats with the neonatal model of type 2 diabetes with IACP (at a daily dose of 10 μg per animal) and IAI (at a daily dose of 20 μg per animal) under their combined and separate administration on metabolic and hormonal indicators and the activity of ACSS in the hypothalamus, myocardium and epididymal fat (EF). The treatment of diabetic rats with IAI and IACP + IAI weakened hyperglycemia and insulin resistance, improved lipid metabolism and decreased atherogenic index. In the hypothalamus, the regulation of adenylate cyclase (AC) activity by MC4-melanocortin and D2-dopamine receptor agonists weakened in type 2 diabetes was restored. In the myocardium and EF, the restoration of stimulating effects of β1/β2- and β3-adrenoreceptor agonists on the AC activity were noted, which indicates an improvement in hormonal regulation of the cardiovascular system and lipolytic processes in the adipose tissue. The combined use of IACP + IAI was more effective than the IAI monotherapy, which evidences an increase in the regulatory effects of insulin in the presence of C-peptide. The treatment of diabetic rats with IACP was not very effective. The obtained results suggest the prospects for the combined use of equimolar amounts of IACP and IAI for the correction of metabolic and functional disorders in severe forms of type 2 diabetes.