Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes

Abstract

Type 2 diabetes mellitus (T2DM) alters brain function and manifests as brain atrophy. Intranasal insulin has emerged as a promising intervention for treatment of cognitive impairment. We evaluated the acute effects of intranasal insulin on resting-state brain functional connectivity in older adults with T2DM. This proof-of-concept, randomized, double-blind, placebo-controlled study evaluated the effects of a single 40 IU dose of insulin or saline in 14 diabetic and 14 control subjects. Resting-state functional connectivity between the hippocampal region and default mode network (DMN) was quantified using functional MRI (fMRI) at 3Tesla. Following insulin administration, diabetic patients demonstrated increased resting-state connectivity between the hippocampal regions and the medial frontal cortex (MFC) as compared with placebo (cluster size: right, P = 0.03) and other DMN regions. On placebo, the diabetes group had lower connectivity between the hippocampal region and the MFC as compared with control subjects (cluster size: right, P = 0.02), but on insulin, MFC connectivity was similar to control subjects. Resting-state connectivity correlated with cognitive performance. A single dose of intranasal insulin increases resting-state functional connectivity between the hippocampal regions and multiple DMN regions in older adults with T2DM. Intranasal insulin administration may modify functional connectivity among brain regions regulating memory and complex cognitive behaviors.

Trial registration: ClinicalTrials.gov NCT01206322.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Figures

Figure 1

Resting-state functional network regions (MFC, PCC, IPC, and ACC) with significant connectivity (voxels with |t| ≥15.4, cluster size ≥270 mm3, and P < 1 × 10−9) to the right and left hippocampus in the diabetes and the control groups after intranasal insulin and placebo administration. A: Diabetes group, intranasal insulin administration. B: Diabetes group, placebo administration. C: Diabetes group, differences in functional connectivity between insulin and placebo administration. Intranasal insulin administration was associated with increased connectivity between hippocampal regions and MFC, R-IPC, and PCC, as compared with placebo (paired Student t test, voxel corrected within subject comparisons, cluster size ≥270 mm3, P < 0.05). D: Age-matched healthy control subjects, intranasal insulin administration. E: Control group, placebo administration. F: Control group, differences in functional connectivity between insulin and placebo administration.

Figure 2

Differences in connectivity between the diabetes and the control groups after insulin (A) and placebo administration (B). After insulin administration, diabetic subjects had lower functional connectivity only in MFC as compared with control subjects. B: After placebo administration, diabetic subjects had larger areas or lower functional connectivity in multiple regions; the threshold was set as P < 0.05, a minimum cluster extent = 270 mm3 (corrected).

Figure 3

The relationship between functional connectivity measures and cognitive performance in the diabetes group after insulin and placebo administration. After insulin administration (A), the average coefficient of connectivity between the right hippocampus and ACC was associated with better verbal fluency score, but not after placebo administration (B). Brief visuospatial memory learning T score showed a positive trend with coefficient connectivity between right hippocampus and R-IPC after insulin administration (C) and a strong negative association after placebo administration (D).