Effects of Intranasal Insulin Administration on Cerebral Blood Flow and Cognitive Performance in Adults: A Systematic Review of Randomized, Placebo-Controlled Intervention Studies

Introduction. Brain insulin resistance is an important hallmark of age-related conditions, including type 2 diabetes (T2D) and dementia. This systematic review summarized effects of cerebral blood flow (CBF) responses to intranasal insulin to assess brain insulin sensitivity in healthy and diseased populations. We also explored relationships between changes in brain insulin sensitivity and cognitive performance. Methods. A systemic literature search (PROSPERO: CRD42022309770) identified 58 randomized, placebo-controlled trials (RCTs) that investigated effects of intranasal insulin on (regional) CBF, cognitive performance, and systemic spill-over in adults. Results. Acute intranasal insulin did not affect whole-brain CBF in healthy adults, but increased regional CBF of the inferior frontal gyrus, dorsal striatum and insular cortex, and reduced CBF around the middle frontal gyrus and hypothalamus. Obese adults showed increased CBF responses following internasal insulin for the middle frontal gyrus, but decreased CBF for hypothalamic and cortico-limbic regions. Furthermore, increased CBF responses were reported for the insular cortex in T2D patients, and for occipital and thalamic regions in older adults. The spray also improved memory and executive function, but a causal relation with regional CBF still needs to be established. Finally, intranasal insulin resulted in only a small amount of systemic spill-over, which is unlikely to have an impact on the observed findings. Conclusions. Region-specific changes in CBF after intranasal insulin administration were affected by obesity, T2D, and normal aging, indicating altered brain insulin sensitivity. Future RCTs should investigate longer-term effects of intranasal insulin and explore potential associations between effects on CBF and cognitive performance.