Abstract
ObjectivesIt is a matter of debate whether impaired insulin action originates from a defect at the neural level or impaired transport of the hormone into the brain. In this study, we aimed to investigate the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity.MethodsInsulin, glucose and albumin concentrations were determined in 160 paired human serum and cerebrospinal fluid (CSF) samples. Additionally, insulin was applied in young and aged mice by subcutaneous injection or intracerebroventricularly to circumvent the blood-brain barrier. Insulin action and cortical activity were assessed by Western blotting and electrocorticography radiotelemetric measurements.ResultsIn humans, CSF glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Western blot analysis in murine whole brain lysates revealed impaired phosphorylation of AKT (P-AKT) in aged mice following peripheral insulin stimulation whereas P-AKT was comparable to levels in young mice after intracerebroventricular insulin application. As readout for insulin action in the brain, insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. When insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved.ConclusionsThis study discloses age-dependent changes in insulin CSF/serum ratios in humans. In the elderly, cerebral insulin resistance might be partially attributed to an impaired transport of insulin into the central nervous system.
Highlights
Insulin resistance is one hallmark of type 2 diabetes mellitus (T2DM)
cerebrospinal fluid (CSF) glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations
The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins
Summary
While impaired insulin action in peripheral tissues like skeletal muscle, liver and fat is well documented in a large number of studies and thought to be a predictor of alterations in glucose homeostasis, the causes and consequences of insulin resistance in the brain are far less understood [1;2]. The underlying mechanisms include mediators that are present in obesity, such as elevated levels of saturated free fatty acids [6,7,8]. Aging is one of the main risk factors for the development of T2DM, and age-related modifications in central insulin action, including changes in the insulin concentration itself or its intracellular signaling pathways seem to be pronounced in neurodegenerative diseases such as Alzheimer’s disease (AD) [14]. Defective brain insulin signaling is considered as an important feature of AD pathology, the underlying mechanisms of reduced insulin signaling in AD remain unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
