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.

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>

NLRP3 Inflammasome Blocking as a Potential Treatment of Central Insulin Resistance in Early-Stage Alzheimer’s Disease

Background: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder. In recent years, attention of researchers has increasingly been focused on studying the role of brain insulin resistance (BIR) in the AD pathogenesis. Neuroinflammation makes a significant contribution to the BIR due to the activation of NLRP3 inflammasome. This study was devoted to the understanding of the potential therapeutic roles of the NLRP3 inflammasome in neurodegeneration occurring concomitant with BIR and its contribution to the progression of emotional disorders. Methods: To test the impact of innate immune signaling on the changes induced by Aβ1-42 injection, we analyzed animals carrying a genetic deletion of the Nlrp3 gene. Thus, we studied the role of NLRP3 inflammasomes in health and neurodegeneration in maintaining brain insulin signaling using behavioral, electrophysiological approaches, immunohistochemistry, ELISA and real-time PCR. Results: We revealed that NLRP3 inflammasomes are required for insulin-dependent glucose transport in the brain and memory consolidation. Conclusions NLRP3 knockout protects mice against the development of BIR: Taken together, our data reveal the protective role of Nlrp3 deletion in the regulation of fear memory and the development of Aβ-induced insulin resistance, providing a novel target for the clinical treatment of this disorder.