Intranasal Insulin Enhanced Resting-state Functional Connectivity of Hippocampal Regions in Type 2 Diabetes

Hui Zhang; Ying Hao; Bradley Manor; Peter Novak; William Milberg; Jue Zhang; Jing Fang; Vera Novak


Diabetes. 2015;64(3):1025-1034. 

In This Article


This study demonstrated that in diabetic and age-matched healthy subjects, intranasal administration of a single dose of insulin acutely increased resting-state functional connectivity between the hippocampal regions and multiple regions within the DMN (i.e., MFC, IPC, ACC, and PCC) that are linked to integrative higher cognitive functions. After placebo administration, connectivity between hippocampal regions and these DMN regions was lower in diabetic subjects as compared with healthy control subjects in several brain regions. After insulin administration, the cluster size differences between the diabetes and the control groups decreased by 44% in the MFC and by 95% in the ACC. After administration of intranasal insulin, the differences in functional connectivity between the diabetes and control groups were no longer significant.

These findings suggest that acute administration of insulin via intranasal delivery route may improve functional connections between brain regions involved in memory and cognitive processing in other domains.

The insulin resistance syndrome is associated with reduced brain insulin levels and sensitivity in age-related memory impairment and AD.[5,27–29] Brain insulin plays an important role as a neuromodulator in cognition,[4,5] energy homeostasis, food intake, sympathetic activity, neuron-astrocyte signaling, synapse formation, and neuronal survival.[7,30] Insulin has been shown to reinforce signaling in the dopamine-mediated brain reward system and modulate food intake and responses to reward stimuli.[31–33] Intranasal insulin increases rapidly in cerebrospinal fluid and binds to insulin receptors[34,35] in the olfactory bulb, several regions in the cerebral cortex including the autonomic network (e.g., insular cortex, dorsal root ganglia, nigro-striatal neurons), cerebellum,[36–38] hypothalamus, and hippocampus.[34,35,39]

T2DM is associated with impairment of hippocampus-dependent memory, and these effects are proportional to diabetes severity.[2] Resting-state functional connectivity is also altered in T2DM subjects, and the severity of impairment correlates with the degree of insulin resistance.[18,19] The effects of intranasal insulin on resting-state connectivity have not been studied. Diabetic subjects had worse baseline cognitive performance, especially in the memory and executive function domains. We have previously shown, in this cohort, that intranasal insulin may acutely improve visuospatial memory in older diabetic and healthy adults, and that this improvement of memory and verbal learning may be dependent upon vasodilation response in the middle cerebral artery territory and in particular insular cortex.[10] In diabetic subjects on insulin, better performance on the verbal fluency naming task was associated with stronger coefficient of connectivity between the right hippocampal region and ACC and lesser connectivity between the left hippocampal regions and the MFC for a more difficult category switching task. In control subjects on insulin, better performance on the visuospatial memory task (BVMT-R) tended to correlate with stronger connectivity between the left hippocampal region and PCC. Differences in relationships between cognition and connectivity between the right and left hippocampal regions are intriguing and reflect a complexity of the large-scale verbal fluency network that comprises of verbal fluency and orthographic discrimination subnetworks.[40] Set switching is a complex operation involving a number of different brain structures that usually include various parts of the dorsolateral and dorsomedial prefrontal cortex, as well as temporal regions where hippocampus is located.[41] Functional integration within the verbal fluency network declines with age and task difficulty. Low productive-difficult tasks are associated with significant decreases in connectivity. Therefore, the decreased connectivity between the left hippocampus and DMN regions may reflect inhibition of the left hippocampus as a result of the complex category switching process.[42] After placebo administration, we have observed a "deactivation pattern"[15,16] that is characterized by task-related decreases in activity and connectivity among several DMN regions. In other words, during a task, a better task-related performance is associated with a decrease in functional connectivity within DMN.

In diabetic subjects, the worse performance on BVMT-R task was associated with stronger functional connectivity between the hippocampal regions and the ACC and IPC. Similarly in the control groups, negative associations were found between the general cognitive score and verbal learning performance and connectivity between the hippocampal regions and the MFC, PCC, and IPC. It has been demonstrated using magnetoencephalography and a two-step hyperinsulimic clamp that resting-state activity correlates with insulin disposal.[43] Furthermore, intranasal insulin may improve peripheral insulin sensitivity; insulin sensitization was associated with increased hypothalamic blood flow and parasympathetic heart rate variability.[44,45] Intranasal insulin also diminished saliva cortisol and stress-induced responsiveness along the hypothalamus-pituitary axis.[46,47] These findings may suggest that intranasal insulin administration may enhance functional connectivity between DMN and other brain regions and may modulate central autonomic responses to stress.

This pilot study has several limitations. The small sample size may have limited the ability to observe the full extent of functional connectivity. Cognitive testing was performed after completion of fMRI scan, and therefore we could not assess acute responses in functional connectivity to different cognitive tasks that may involve different brain regions and range of difficulty. Eleven of 14 diabetic participants were treated with metformin, which may be associated with worse cognitive performance.[48] Women were required to be postmenopausal, and only one participant received hormone replacement therapy, which minimized potential effects of estrogen levels on functional connectivity.[49] Furthermore, the optimal dose of intranasal insulin to modulate brain function remains unknown, as no dose-response studies have been completed to date within this population. Larger and/or more frequent doses may thus optimize the effects of intranasal insulin on brain function. Longer-term studies are also warranted to evaluate the potential for intranasal insulin for neuroprotection and improvement of cortical connectivity.