Broadening the definition of brain insulin resistance in aging and Alzheimer's disease

Abstract

It has been more than 20 years since studies first revealed that the brain is insulin sensitive, highlighted by the expression of insulin receptors in neurons and glia, the presence of circulating brain insulin, and even localized insulin production. Following these discoveries, evidence of decreased brain insulin receptor number and function was reported in both clinical samples and animal models of aging and Alzheimer's disease, setting the stage for the hypothesis that neuronal insulin resistance may underlie memory loss in these conditions. The development of therapeutic insulin delivery to the brain using intranasal insulin administration has been shown to improve aspects of memory or learning in both humans and animal models. However, whether this approach functions by compensating for poorly signaling insulin receptors, for reduced insulin levels in the brain, or for reduced trafficking of insulin into the brain remains unclear. Direct measures of insulin's impact on cellular physiology and metabolism in the brain have been sparse in models of Alzheimer's disease, and even fewer studies have analyzed these processes in the aged brain. Nevertheless, recent evidence supports the role of brain insulin as a mediator of glucose metabolism through several means, including altering glucose transporters. Here, we provide a review of contemporary literature on brain insulin resistance, highlight the rationale for improving memory function using intranasal insulin, and describe initial results from experiments using a molecular approach to more directly measure the impact of insulin receptor activation and signaling on glucose uptake in neurons.

Mindfulness, Education, and Exercise for age-related cognitive decline: Study protocol, pilot study results, and description of the baseline sample

“…In particular, we expect to demonstrate that exercise and mindfulness training impact physiological processes related to aging, 85 such as insulin sensitivity, inflammation, and stress hormone levels. [86][87][88] We will also test whether brain structural and functional changes mediate the cognitive benefits of the interventions on neuropsychological performance and behavioral measures of everyday functioning. This study has considerable clinical implications because of its potential to establish the use of behavioral interventions to preserve cognitive function and independence in older adults.…”

Neuronal transcriptome analyses reveal novel neuropeptide modulators of excitation and inhibition imbalance in C. elegans

“…In vitro analysis has also found, for example, that IGF signaling can be neuroprotective in response to injury, but can also promote epileptogenesis [42]. Insulin peptide signaling may also play a role in Alzheimer's Disease (AD) [6]. Although the role for insulin signaling in the brain is still unclear, levels of insulin and insulin receptors are markedly decreased in the brains of AD patients.…”

Intranasal Insulin for Alzheimer’s Disease

“…Insulin also potentiates NMDA receptor activity via delivery of NMDA receptors to the cell surface [ 97 ] and NMDA receptor phosphorylation [ 98 ], processes that may induce long-lasting meta-plastic changes. In addition to effects on synaptic plasticity [ 99 ], there is some evidence that insulin benefits regional brain glucose uptake by activating the neuronal glucose transporter type 4 and enhances glycogen uptake in regions such as the basal forebrain, hippocampus, amygdala, and cortex [ 100 , 101 ] (for reviews see [ 102 , 103 ]), in particular under conditions of high cognitive demand [ 104 , 105 ]. In experiments in healthy humans relying on 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements during intravenous insulin infusion while endogenous insulin production was suppressed by somatostatin, whole-brain glucose utilization was found to be stimulated by insulin [ 106 ], whereas experiments using 1 H-magnetic resonance spectroscopy yielded no effect of insulin infusion on brain glucose [ 14 ].…”