Cerebrovascular insulin receptors are defective in Alzheimerˈs disease

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.

Current and Near-Future Treatment of Alzheimer's Disease

: Recent findings have improved our understanding of the multifactorial nature of AD. While in early, asymptomatic stages of AD, increased amyloid-β synthesis and tau hyperphosphorylation play a key role, in the later stages of the disease, numerous dysfunctions of homeostatic mechanisms in neurons, glial cells and cerebrovascular endothelium determine the rate of progression of clinical symptoms. The main driving forces of advanced neurodegeneration include: increased inflammatory reactions in neurons and glial cells, oxidative stress, deficiencies in neurotrophic growth and regenerative capacity of neurons, brain insulin resistance with disturbed metabolism in neurons, or reduction of the activity of the Wnt-β catenin pathway which should integrate the homeostatic mechanisms of brain tissue. In order to more effectively inhibit the progress of neurodegeneration, one should use combination therapies consisting of drugs that rectify several of the above-mentioned dysfunctions. It should be noted that many of widely-used drugs from various pharmacological groups, "in addition" to the main therapeutic indications, also have a beneficial effect on neurodegeneration and may be introduced into clinical practice in combination therapy of AD. There is a real hope that complex treatment will effectively inhibit the progression of AD and turn it into a slowly progressing chronic disease. Moreover as the mechanisms of bidirectional communication between the brain and microbiota are better understood, it is expected that these pathways will be harnessed to provide novel method to enhance health and treat AD.

Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial

<b>Objective:</b> Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its’ distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since SGLT2 inhibitors lowers glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance. <p><b>Research Design and Methods:</b> In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age: 60 ± 9 years; BMI: 31.5 ± 3.8 kg/m²) with prediabetes were randomized to receive 25 mg empagliflozin qd or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain.</p> <p><b>Results:</b> We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated empagliflozin-induced decrease in fasting glucose and liver fat.</p> <p><b>Conclusions:</b> Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity; a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.</p>

Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial

<b>Objective:</b> Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its’ distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since SGLT2 inhibitors lowers glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance. <p><b>Research Design and Methods:</b> In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age: 60 ± 9 years; BMI: 31.5 ± 3.8 kg/m²) with prediabetes were randomized to receive 25 mg empagliflozin qd or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain.</p> <p><b>Results:</b> We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated empagliflozin-induced decrease in fasting glucose and liver fat.</p> <p><b>Conclusions:</b> Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity; a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.</p>