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

Bull Exp Biol Med. 2019 Jul;167(3):351-355. doi: 10.1007/s10517-019-04525-w. Epub 2019 Jul 26.


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 μg/day) and insulin (20 μg/day) on activity of Akt kinase and kinase-3β-glycogen synthase (GSK3β), 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 Thr308 and Ser473 (stimulation) and GSK3β at Ser9 (inhibition) was evaluated. In diabetes, phosphorylation of Akt kinase and, to a lesser extent, GSK3β, 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 GSK3β 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.

Keywords: 3-phosphoinositide turnover; hypothalamus; insulin; intranasal administration; proinsulin C-peptide.

MeSH terms

  • Administration, Intranasal
  • Animals
  • C-Peptide / administration & dosage
  • C-Peptide / pharmacology*
  • Diabetes Mellitus, Experimental / drug therapy*
  • Drug Synergism
  • Glycemic Index / drug effects
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Hypothalamus / metabolism*
  • Insulin / pharmacology*
  • Male
  • Phosphatidylinositols / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Wistar
  • Streptozocin
  • Weight Loss / drug effects


  • C-Peptide
  • Insulin
  • Phosphatidylinositols
  • Streptozocin
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Proto-Oncogene Proteins c-akt