Central nervous system insulin signaling can influence the rate of insulin influx into brain

Abstract

Background Insulin transport across the blood-brain barrier (BBB) is a highly regulated, saturable process, known to be affected by many peripheral substrates including insulin itself and triglycerides. This is in contrast to insulin leakage into peripheral tissues. Whether the central nervous system (CNS) can control the rate of insulin uptake by brain remains to be determined. Insulin BBB interactions are impaired in Alzheimer’s disease (AD) and CNS insulin resistance is widely prevalent in AD. Therefore, if CNS insulin controls the rate of insulin transport across the BBB, then the defective transport of insulin seen in AD could be one manifestation of the resistance to CNS insulin observed in AD. Methods We investigated whether enhancing CNS insulin levels or induction of CNS insulin resistance using an inhibitor of the insulin receptor altered the blood-to-brain transport of radioactively labeled insulin in young, healthy mice. Results We found that insulin injected directly into the brain decreased insulin transport across the BBB for whole brain and the olfactory bulb in male mice, whereas insulin receptor blockade decreased transport in female mice for whole brain and hypothalamus. Intranasal insulin, currently being investigated as a treatment in AD patients, decreased transport across the BBB of the hypothalamus. Conclusions These results suggest CNS insulin can control the rate of insulin brain uptake, connecting CNS insulin resistance to the rate of insulin transport across the BBB.

Dietary restriction alters insulin signaling pathway in the brain

“…It is also very likely that what we observe in the hippocampus does not reflect what is going on in other insulin‐rich brain regions. Although insulin is present throughout the brain, there are significant differences in insulin levels between different brain regions, particularly the olfactory bulb and hypothalamus (which are characterized by the highest insulin levels), and the amygdala and midbrain, which contain much less insulin 75,80 . Regional specificities in the response to DR are worthy of further investigation, particularly in the context of the possible specific role that insulin plays in these regions, but unfortunately, this type of analysis significantly exceeds the experimental design presented in this article.…”

“…Accordingly, it has been shown that an increase in serum insulin under normal, physiological conditions may cause only a small increase in the insulin in the cerebrospinal and interstitial fluids 74 . However, insulin transport across the blood–brain barrier could be affected by other serum parameters like triglycerides, 75 while the ratio of serum to brain and CSF insulin could be changed due to various factors, including the age of the subject 72–74 or in certain pathologic conditions such as inflammation, when markedly increased insulin transport to the brain has been noted 76 . Interestingly, a high‐fat diet is associated with a significantly decreased insulin transport rate to the brain, 77 while the deregulation of insulin transport to the brain caused by obesity could be restored by caloric restriction 78 …”

“…A limitation of this study is that we do not have data on receptor‐mediated transcytosis of insulin through the BBB. CNS insulin resistance negatively affects transport across the BBB and the overall insulin transport system of the brain, suggesting that the brain may affect the rate of insulin transport across the BBB toward the blood–brain direction 75 . On the other hand, systemic insulin resistance or high circulating levels of insulin also affects BBB by downregulating endothelial IR and thus decreasing the permeability of the BBB to insulin 79 …”

Cerebrospinal fluid soluble insulin receptor levels in Alzheimer's disease

“…49 and we have shown loss of brain IR signaling slows insulin transport into the brain in mice. 50 Therefore, it is possible the dysregulated processing of the sIR by insulin could perpetuate a vicious cycle, leading ultimately to brain insulin resistance and deficiency.…”

Epigenetic modifications of DNA and RNA in Alzheimer’s disease

“…Insulin is essential for glutamatergic signaling, BBB integrity, vasodilation, neuronal proliferation, differentiation, cognition, and memory ( Åberg et al, 2003 ; Hallschmid et al, 2007 ; Sawallisch et al, 2009 ; Heni et al, 2011 ; Irvine et al, 2011 ; Kuwabara et al, 2011 ; Chirivella et al, 2017 ; Pomytkin et al, 2019 ; Fetterly et al, 2021 ; Wang et al, 2022 ; Nguyen et al, 2023 ). Changes to insulin signaling, particularly desensitization to insulin, result in chronic inflammation and are a known risk factor for AD across human and rodent in vitro and in vivo models ( Baker et al, 2011 ; Blázquez et al, 2014 ; Craft et al, 2017 ).…”