In type 2 diabetes mellitus (DM2), the impaired functions of the brain insulin system are associated with the weakened insulin transport through the blood-brain barrier due to insulin resistance. Insulin deficiency in the brain can be corrected by intranasal administration of insulin (II), whose effect may be enhanced by intranasal administration of C-peptide (ICP). In this work, we study the effect of treating hyperinsulinemic and normoinsulinemic DM2 rats with ICP (36 µg/rat/day), II (20

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... t/day) and ICP+II on metabolic and hormonal parameters. In normoinsulinemic DM2, ICP attenuated thyroid hormone deficiency and enhanced the restorative effects of II on glucose, insulin, and leptin sensitivity. In hyperinsulinemic DM2, ICP was ineffective, and its combination with II weakened the restorative effects of II. Thus, ICP and its combination with II are effective in restoring metabolic and hormonal parameters in normoinsulinemic, but not hyperinsulinemic, DM2.