Intranasal Administration of Proinsulin C-Peptide Enhances the Stimulating Effect of Insulin on Insulin System Activity in the Hypothalamus of Diabetic Rats

摘要

In type 1 diabetes mellitus, the levels of insulin and C-peptide decrease at the periphery and in CNS. C-peptide potentiates the regulatory effects of insulin. We studied the effects of single and repeated (over 7 days) individual and combined nasal administration of C-peptide (10 mu g/day) and insulin (20 mu g/day) on activity of Akt kinase and kinase-3 beta-glycogen synthase (GSK3 beta), the components of 3-phosphoinositide pathway, in the hypothalamus of intact rats and rats with mild streptozotocin-induced type 1 diabetes mellitus. Phosphorylation of Akt kinase at Thr(308) and Ser(473) (stimulation) and GSK3 beta at Ser(9) (inhibition) was evaluated. In diabetes, phosphorylation of Akt kinase and, to a lesser extent, GSK3 beta, is reduced. A single injection of insulin or C-peptide and insulin increased this process. Long-term combined treatment with C-peptide and insulin normalized activity of Akt kinase and GSK3 beta in diabetic rats, treatment with insulin alone produced less pronounced effect; monotherapy with C-peptide was ineffective. Intranasal co-administration of C-peptide and insulin effectively stimulates the insulin system in the hypothalamus that is weakened at diabetes mellitus type 1, which can be used in the treatment of this disease.