A positive effect of intranasal insulin on spatial memory in rats with neonatal diabetes mellitus

Type 2 diabetes mellitus (T2DM) is associated with cognitive impairments. However, their causal factors and the approaches to be used in their treatment have not been fully clarified and further study is needed. The aim of this work was to study the effect of intranasal insulin (I-I) on cognitive functions in rats with experimental T2DM. Neonatal rats (5 days old) were treated with an intraperitoneal (i.p.) administration of a single dose of streptozotocin (STZ) (80 mg/kg i.p.) which in adult animals leads to impairment of glucose tolerance and mild hyperglycemia, typical of T2DM. The insulin receptor binding in the synaptosomal and liver membranes was evaluated with [125I]-insulin, and the IRS2 expression in the brain was estimated by RT-PCR. Daily I-I (0.48 IU/day) or placebo were delivered to diabetic and non-diabetic rats during a week before and the 39 days of cognition experiments. Spatial memory and learning were studied in a Morris water-maze (MWM) test. The MWM test showed that, in the case of diabetic rats, the latent period for finding the platform (escape latency) and the swimming path length were increased, and the number of annulus crossings decreased compared with control (P<0.05). I-I normalized cognitive functions in diabetic rats but had no effect on those of non-diabetic animals. Specific insulin binding in the liver of diabetic rats was decreased, indicating peripheral insulin resistance, but changed very little in the brain. In the hypothalamus of diabetic rats, but not in the cortex and the olfactory bulbs, the expression of IRS2 was reduced by 68% compared with control and was restored after I-I delivery. Rats with neonatal T2DM had cognitive deficit likely associated with impaired IRS2-mediated signaling pathways in the diabetic brain and eliminated by I-I treatment.