Supplementary Material for: 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.

引言。脑胰岛素抵抗是包括2型糖尿病（T2D）与痴呆在内的年龄相关疾病的重要标志性特征。本系统综述总结了鼻内胰岛素干预后的脑血流量（CBF）响应情况，以评估健康人群与患病人群的脑胰岛素敏感性；同时探讨了脑胰岛素敏感性变化与认知表现之间的关联。方法。通过系统性文献检索（PROSPERO注册号：CRD42022309770），共纳入58项随机对照安慰剂试验（RCTs），这些试验针对成人群体，探究了鼻内胰岛素对（区域）脑血流量、认知表现以及全身溢出效应的影响。结果。急性鼻内胰岛素干预未对健康成人的全脑血流量产生影响，但可提升额下回、背侧纹状体与岛叶皮层的区域脑血流量，同时降低额中回与下丘脑周围的脑血流量。肥胖成人在接受鼻内胰岛素干预后，额中回的脑血流量响应增强，但下丘脑与皮质边缘区域的脑血流量出现下降。此外，2型糖尿病患者的岛叶皮层脑血流量响应有所提升，老年群体的枕叶与丘脑区域脑血流量亦出现升高。鼻内胰岛素还可改善记忆与执行功能，但目前仍需明确其与区域脑血流量变化的因果关系。最后，鼻内胰岛素仅产生微量的全身溢出效应，该效应不太可能对观测结果造成影响。结论。鼻内胰岛素给药后出现的区域特异性脑血流量变化，会受到肥胖、T2D以及正常衰老的影响，这提示脑胰岛素敏感性发生了改变。未来的随机对照安慰剂试验应探究鼻内胰岛素的长期干预效果，并探讨脑血流量响应变化与认知表现之间的潜在关联。