Abstract
Hyperinsulinemia as well as type II diabetes mellitus are among the risk factors for Alzheimers disease (AD). However, the molecular and cellular basis that link insulin resistance disorders and diabetes with AD are far from clear. Here, we discuss the potential molecular mechanisms that may explain the participation of these metabolic disorders in the pathogenesis of AD. The human brain uses glucose as a primary fuel; insulin secreted by the pancreas cross the bloodbrain barrier (BBB), reaching neurons and glial cells, and exerts a region-specific effect on glucose metabolism. Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia; this condition persists for several years before becoming fullblown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid (CSF) concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide (Aβ) and an increase of tau hyperphosphorylation as a result of augmented cdk5 and GSK3β activities. This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. Chronic peripheral hyperinsulinemia results in a reduction of insulin transport across the BBB and a reduced insulin signaling in brain, altering all of insulins actions, including its anti-apoptotic effect. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognitionenhancing effect in patient with AD. Some drugs utilized in type II diabetes mellitus reduce cognitive impairment associated with AD. The link between insulin resistance and neurodegeneration and AD, and the possible therapeutic targets in preventing the insulin-resistance disorders are analyzed.
Keywords: Insulin, insulin resistance, hyperinsulinemia, diabetes, cognition, neurodegeneration, Alzheimer's disease
Current Alzheimer Research
Title: Insulin Resistance and Alzheimers Disease: Molecular Links & Clinical Implications
Volume: 5 Issue: 5
Author(s): Karen F. Neumann, Leonel Rojo, Leonardo P. Navarrete, Gonzalo Farias, Paula Reyes and Ricardo B. Maccioni
Affiliation:
Keywords: Insulin, insulin resistance, hyperinsulinemia, diabetes, cognition, neurodegeneration, Alzheimer's disease
Abstract: Hyperinsulinemia as well as type II diabetes mellitus are among the risk factors for Alzheimers disease (AD). However, the molecular and cellular basis that link insulin resistance disorders and diabetes with AD are far from clear. Here, we discuss the potential molecular mechanisms that may explain the participation of these metabolic disorders in the pathogenesis of AD. The human brain uses glucose as a primary fuel; insulin secreted by the pancreas cross the bloodbrain barrier (BBB), reaching neurons and glial cells, and exerts a region-specific effect on glucose metabolism. Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia; this condition persists for several years before becoming fullblown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid (CSF) concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide (Aβ) and an increase of tau hyperphosphorylation as a result of augmented cdk5 and GSK3β activities. This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. Chronic peripheral hyperinsulinemia results in a reduction of insulin transport across the BBB and a reduced insulin signaling in brain, altering all of insulins actions, including its anti-apoptotic effect. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognitionenhancing effect in patient with AD. Some drugs utilized in type II diabetes mellitus reduce cognitive impairment associated with AD. The link between insulin resistance and neurodegeneration and AD, and the possible therapeutic targets in preventing the insulin-resistance disorders are analyzed.
Export Options
About this article
Cite this article as:
Neumann F. Karen, Rojo Leonel, Navarrete P. Leonardo, Farias Gonzalo, Reyes Paula and Maccioni B. Ricardo, Insulin Resistance and Alzheimers Disease: Molecular Links & Clinical Implications, Current Alzheimer Research 2008; 5 (5) . https://dx.doi.org/10.2174/156720508785908919
DOI https://dx.doi.org/10.2174/156720508785908919 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Alzheimer's Disease Drug Development
Alzheimer's disease is a progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no cure or disease-modifying treatment is available yet. Therefore, the need for developing effective therapies to treat Alzheimer's disease is an urgent matter. This special issue aims to provide a comprehensive overview of ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Novel Targets of Metformin in Cardioprotection: Beyond the Effects Mediated by AMPK
Current Pharmaceutical Design Vascular Endothelial Dysfunction and Nutritional Compounds in Early Type 1 Diabetes
Current Diabetes Reviews Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors
Current Neurovascular Research Epigenetic and Disease Targets by Polyphenols
Current Pharmaceutical Design Efficacy and Cardiovascular Safety of DPP-4 Inhibitors
Current Drug Safety Is There an Association between Periodontitis and Hypertension?
Current Cardiology Reviews Regulatory T Cells and Tolerogenic Dendritic Cells as Critical Immune Modulators in Atherogenesis
Current Pharmaceutical Design Potential Role of (-)-Epigallocatechin-3-Gallate (EGCG) in the Secondary Prevention of Alzheimer Disease
Current Drug Targets Olmesartan Reduces Pentosidine Production and Ameliorates Fragility of Bone in Ovariectomized Fructose-Fed Rats
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Relationship Between Non-Genomic Actions of Estrogens and Insulin Resistace
Infectious Disorders - Drug Targets Patent Selections:
Recent Patents on Anti-Cancer Drug Discovery Considerations in the Pharmacotherapy of Bipolar Disorder During and After Pregnancy
Current Drug Safety GuidAge Study: A 5-Year Double Blind, Randomised Trial of EGb 761 for the Prevention of Alzheimers Disease in Elderly Subjects with Memory Complaints. I. Rationale, Design and Baseline Data
Current Alzheimer Research Primary and Secondary Prevention Trials in Alzheimer Disease: Looking Back, Moving Forward
Current Alzheimer Research Anti-Inflammatory Role of Fetuin-A in Injury and Infection
Current Molecular Medicine Association Between Intra-Hospital Uncontrolled Glycemia and Health Outcomes in Patients with Diabetes: A Systematic Review of Observational Studies
Current Diabetes Reviews SGLT-2 Inhibitors and Cardiovascular Risk in Diabetes Mellitus: A Comprehensive and Critical Review of the Literature
Current Pharmaceutical Design Role of AGEs in Diabetic Nephropathy
Current Pharmaceutical Design Plasma Metabolite Profiling and Search for Biomarkers of Metabolic Dysfunction in Dogs Undergoing Rapid Weight Gain
Current Metabolomics Treatment Possibilities for Psychosis in Parkinson's Disease with An Emphasis on the Newly Approved Drug: Pimavanserin
CNS & Neurological Disorders - Drug Targets