Background
Brain insulin resistance is an important hallmark of age-related conditions, such as type 2 diabetes and dementia. Brain insulin sensitivity can be assessed by quantifying effects of intranasal insulin on cerebral blood flow (CBF), which is a well-validated marker for cerebrovascular function. The aim of this systematic review is to summarize effects of intranasal insulin on (regional) CBF in adults, and to explore potential relationships between changes in brain insulin sensitivity and cognitive performance.

Methods
A systemic literature search was performed that identified a total of 58 randomized, placebo-controlled intervention trials (RCTs) involving adults. These studies investigated the effects of intranasal insulin on CBF and different domains of cognitive performance.

Results
Acute intranasal insulin administration did not affect whole-brain CBF. However, insulin spray significantly affected regional CBF in healthy adults. An increased CBF was observed in the inferior frontal gyrus, dorsal striatum and insular cortex, while CBF decreased around the middle frontal gyrus and hypothalamus. Also, intranasal insulin improved working memory and spatial memory acutely and declarative memory over longer-term application. However, no clear associations were found between insulin-induced changes in regional CBF and cognitive performance. CBF responses to insulin were different in obese and aged adults for multiple brain regions, including the prefrontal, occipital and insular cortex, fusiform gyrus, hippocampus, striatum, and the hypothalamus.

Conclusions
We identified insulin-induced changes in CBF that indicates regional brain insulin-sensitivity. These responses were dependent on risk factors for the development of peripheral insulin resistance, which may indicate a close relation between peripheral and brain insulin sensitivity. Future studies should investigate if these brain regions are sensitive targets for interventions aimed to prevent cognitive decline.