Brain functions and cognition on transient insulin deprivation in type 1 diabetes

Creo, Ana; Cortes, Tiffany; Jo, Hang Joon; Huebner, Andrea R.; Dasari, Surendra; Tillema, Jan Mendelt; Lteif, Aida; Klaus, Katherine A.; Ruegsegger, Gregory N.; Kudva, Yogish C.; Petersen, Ronald C.; Port, John D.; Nair, K. Sreekumaran

doi:10.1172/jci.insight.144014

Cited by 8 publications

(1 citation statement)

References 57 publications

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“…The human brain is sensitive to insulin, a hormone essential to life that is also at the heart of the pathophysiology and treatment of diabetes (Lewis and Brubaker, 2021;Polyzos and Mantzoros, 2021). The scientific literature is replete with studies in humans and other species reporting the effects of insulin on memory, cerebral blood flow, eating behavior and regulation of whole-body metabolism, supporting a therapeutic potential in brain-dependent metabolic disorders (Creo et al, 2021;Heni et al, 2015;Kleinridders et al, 2014). Although local synthesis has been detected, most insulin exercising an effect on the brain circulates in the blood after being produced by the pancreas (Banks, 2004;Csajbok and Tamas, 2016;Rhea and Banks, 2021).…”

Section: Introductionmentioning

confidence: 99%

Cerebrovascular insulin receptors are defective in Alzheimerˈs disease

Leclerc

Bourassa

Tremblay

et al. 2021

Preprint

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Central response to insulin is suspected to be defective in Alzheimer’s disease (AD), but its localization in the brain remains unknown. While most insulin is secreted in the bloodstream by the pancreas, how it interacts with the blood-brain barrier (BBB) to alter brain function remains poorly defined.Here, we show that human and murine cerebral insulin receptors (INSR), particularly the long isoform INSRα-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSRα-B were lower in the parietal cortex of subjects diagnosed with AD, positively correlating with cognitive scores, leading to a shift toward a higher INSRα-A/B ratio, consistent with cerebrovascular insulin resistance in the AD brain. Vascular INSRα was inversely correlated with β-amyloid (Aβ) plaques and β-site APP cleaving enzyme 1 (BACE1), but positively correlated with insulin-degrading enzyme (IDE), neprilysin and ABCB1. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the BBB remained very low (<0.03 µl.g-1.s-1) and was not inhibited by an INSR antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSRβ which was restricted to microvessels. Such an activation of vascular INSR was blunted in 3xTg-AD mice, suggesting that AD neuropathology induces insulin resistance at the level of the BBB.Overall, the present data in postmortem AD brains and an animal model of AD indicate that defects in the INSR localized at the BBB strongly contribute to brain insulin resistance in AD, in association with Aβ pathology.HighlightsCirculating insulin activates brain insulin receptors in microvessels.BBB INSR contribute to cerebral insulin resistance in AD.Cognitive impairment in AD is associated with a loss of cerebrovascular INSRα-B.Loss of isoform INSRα-B is associated with increased BACE1 activity.SummaryLeclerc et al. show that circulating insulin activates cerebral insulin receptor localized on the blood-brain-barrier level (BBB), not in the parenchyma. Experiments with human brain samples and animal models provide evidence that INSR at the BBB are impaired in Alzheimer’s disease, thereby contributing to brain insulin resistance.

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