Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes

Abstract

Objective: To determine acute effects of intranasal insulin on regional cerebral perfusion and cognition in older adults with type 2 diabetes mellitus (DM).

Research design and methods: This was a proof-of-concept, randomized, double-blind, placebo-controlled intervention evaluating the effects of a single 40-IU dose of insulin or saline on vasoreactivity and cognition in 15 DM and 14 control subjects. Measurements included regional perfusion, vasodilatation to hypercapnia with 3-Tesla MRI, and neuropsychological evaluation.

Results: Intranasal insulin administration was well tolerated and did not affect systemic glucose levels. No serious adverse events were reported. Across all subjects, intranasal insulin improved visuospatial memory (P ≤ 0.05). In the DM group, an increase of perfusion after insulin administration was greater in the insular cortex compared with the control group (P = 0.0003). Cognitive performance after insulin administration was related to regional vasoreactivity. Improvements of visuospatial memory after insulin administration in the DM group (R(2)adjusted = 0.44, P = 0.0098) and in the verbal fluency test in the control group (R(2)adjusted = 0.64, P = 0.0087) were correlated with vasodilatation in the middle cerebral artery territory.

Conclusions: Intranasal insulin administration appears safe, does not affect systemic glucose control, and may provide acute improvements of cognitive function in patients with type 2 DM, potentially through vasoreactivity mechanisms. Intranasal insulin-induced changes in cognitive function may be related to vasodilatation in the anterior brain regions, such as insular cortex that regulates attention-related task performance. Larger studies are warranted to identify long-term effects and predictors of positive cognitive response to intranasal insulin therapy.

Trial registration: ClinicalTrials.gov NCT01206322.

Figure 1

Brief visual memory scores for immediate recall trials 1–3 (T1–T3) and total recall for the DM and control groups. Overall, control subjects on insulin performed better than the DM group on insulin and on placebo; *P < 0.03 and **P < 0.01 control subjects on insulin vs. DM group on placebo (LS models adjusted for age). For the whole cohort, performance on insulin improved compared with placebo for † T2, P = 0.04, and was borderline for total recall, P = 0.052 (paired t test).

Figure 2

Voxel-based analysis demonstrates that within the DM group, intranasal administration of insulin induced more increased perfusion compared with placebo in the right insular cortex (independent Student t test applied to the subtraction result between conditions, voxel-level uncorrected P < 0.001) (A). In the DM group, the BVMT T score after insulin administration was related to vasodilatation in the MCA territory (R² = 0.58, R²_adjusted = 0.44, P = 0.0098) (B). This relationship was not observed after placebo administration (R² = 0.14, R²_adjusted = −0.14, P = 0.34, LS regression models adjusted for age and sex) (C). In control subjects, after insulin administration the verbal fluency category T score was also related to vasodilatation in the right MCA territory (R² = 0.75, R²_adjusted = 0.64, P = 0.0087, P = 0.024, LS regression models adjusted for age and sex) (D). (A high-quality color representation of this figure is available in the online issue.)