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

Abstract

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.

Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium

“…Among the factors that lead to the development of neurodegenerative processes and cognitive deficit in T2DM and MS, the most important are cerebrovascular dysfunctions [ 256 , 257 ], reduced glucose metabolism in brain structures [ 258 ], neuroinflammation [ 259 , 260 , 261 , 262 , 263 ], as well as central IR, which is also observed in patients with AD [ 258 , 262 , 264 ]. Impaired insulin signaling may affect only certain areas of the brain, which is due to region-specific changes in the expression, distribution, and activity of INSR and downstream components of the insulin signaling system [ 37 , 265 , 266 , 267 ].…”

“…One of these mechanisms may be the effect of brain insulin on the activity of the neurovascular unit, including endothelial, neuronal, and glial cells. The neurovascular unit is involved in functional interaction with vascular cells, causing a change in their tone in response to activation or inhibition of neuronal activity [ 257 , 286 ]. Administration of INI to healthy individuals resulted in an increase in CBF velocity in the inferior frontal gyrus, dorsal striatum, and insular cortex [ 287 ], as well as a decrease in CBF velocity in the hypothalamus and around the middle frontal gyrus [ 267 , 288 ].…”

“…The effect of INI on the CBF velocity in the brain of patients with T2DM differs significantly from that in healthy individuals [ 257 ]. In T2DM patients, a single treatment with INI (40 IU) affected the CBF velocity only in the insular cortex, causing its increase.…”

“…It has been shown that INI at a dose of 40 IU causes specific changes in certain brain regions responsible for feeding behavior, reward reactions, and visuospatial memory [ 287 ]. Thus, further studies are needed to clearly show in which areas of the brain and under what modes of INI use the CBF velocity changes and how these changes are associated with an improvement in cognitive functions and peripheral insulin sensitivity [ 257 ]. It is also important that INI doses of 160 IU and above can cause a number of side effects in patients with T2DM [ 295 ].…”

Brain insulin responsiveness is linked to age and peripheral insulin sensitivity

“…Hence, CBF measurements have been proposed to be ideally suited for pharmacological MRI studies. 27 Acute intranasal insulin results in regional specific CBF responses, [28][29][30][31] with no direct effect on the cerebral vasodilatory system. 29 This regional CBF responsiveness is affected by abdominal obesity, T2D and ageing, indicating alteration in brain insulin sensitivity.…”