Coadministration of Intranasally Delivered Insulin and Proinsulin C-Peptide to Rats with Types 1 and 2 Diabetes Mellitus Restores Their Metabolic Parameters

C-peptide is the product of proinsulin proteolysis, which is not only a signal molecule but is also able to modulate insulin signaling functions by forming a complex with it. The insulin-sensitive signaling systems in the hypothalamus and other brain areas are among the insulin targets. We hypothesized that, in the systemic deficiency of insulin and C-peptide in type-1 diabetes mellitus (DM) and in severe forms of type-2 DM, an increase in the C-peptide level in the central nervous system (CNS) will improve the central effects of insulin, including its influence on the peripheral metabolism. To verify this, the influence of separate and coadministration of intranasal insulin (II) and C-peptide (IP) on their metabolic parameters and insulin sensitivity in rats with acute and mild type-1 DM induced by streptozotocin at doses of 60 and 35 mg/kg and in rats with neonatal type-2 DM corresponding to severe long-term form of type-2 DM in humans was studied. The treatment of animals with II and IP was carried out for 7 days in daily doses of 20 and 10 µg/rat, respectively. The coadministration of II and IP leading to increased insulin and C-peptide levels in the brain showed the highest effect. In rats with type-1 DM treated with a combination of II and IP, hyperglycemia was decreased and weight loss was prevented. In rats with type-2 DM, coadministration of II and IP led to normalization of glucose homeostasis and increased insulin sensitivity, as shown by the glucose-tolerance and insulin-glucose tolerance tests, as well as to improved lipid metabolism, as demonstrated by a decrease in the atherogenic index. The effectiveness of monotherapy with II was lower than in case of a combination of II and IP, while monotherapy with C-peptide had little effect on the studied indicators. Thus, a simultaneous increase in the insulin and C-peptide levels in the brain upon their deficiency due to diabetic pathology can be considered a promising approach to the restoration of central insulin–dependent regulation of peripheral metabolism and improved glucose utilization in different DM forms.