The Role of Insulin Resistance and Glucose Metabolism Dysregulation in the Development of Alzheimer´s Disease

Abstract

Alzheimer´s disease is a chronic neurodegenerative disorder affecting millions of people worldwide, characterized by a progressive decline in cognitive functions. Factors involved in the pathogenesis of Alzheimer´s disease include metabolic alterations such as insulin resistance and hyperglycemia, both of which are also hallmarks of type-2 diabetes mellitus. The accumulation of β-amyloid peptides in the brain of Alzheimer´s patients is responsible in part for the neurotoxicity underlying the loss of synaptic plasticity that triggers a cascade of events leading to cell death. A large number of studies revealed the key role of the hippocampus and cerebral cortex in the memory and learning deficits of Alzheimer´s disease. Although ample evidence suggests a link between altered insulin action, the dysregulation of glucose metabolism, and β-amyloid accumulation in animal models and humans with Alzheimer´s, no supporting evidence was available. In this article, we review the potential toxic effects of β-amyloid in the hypothalamus, a brain center involved in the control of insulin action and glucose metabolism. Furthermore, we discuss our recent studies unraveling a novel neurotoxic action of β-amyloid that perturbs hypothalamic glucoregulation, leading to increased hepatic glucose production and hyperglycemia. These findings provide evidence for a link between β-amyloid toxicity and altered glucose metabolism.