Abstract
Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ). Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.
Highlights
Insulin is a peptide hormone composed of 51 aminoacids and has a molecular weight of about 6,000Da
Insulin signaling is crucial for growth and survival [3] and despite studies in lower metazoans showing that reduced insulin signaling extends life span [4,5], in mammals things are not so linear because insulin/its receptor (IR) exert opposite effects whether they are located in the central nervous system (CNS) or the periphery [6]
When evaluating the effects of fat mass reduction and alterations in insulin/insulin growth factor 1 (IGF-1) pathway in longevity using a fat-specific insulin receptor knockout (FIRKO) mice it was observed that a reduction in adipose tissue is associated with an increase in longevity probably through a reduction in insulin signaling [175]
Summary
Insulin is a peptide hormone composed of 51 aminoacids and has a molecular weight of about 6,000. Recent studies show that insulin/IR are involved in brain functions such as learning and memory [8,9], whereas their impairment has been linked to the development of age-related neurodegenerative disorders [10,11,12]. The alteration of mitochondrial energy metabolism leads to reduced ATP production, impaired calcium buffering, and generation of reactive oxygen species (ROS). PPAR-γ is the best characterized isoform mainly because it regulates serum glucose levels and insulin sensitivity, being widely used in the treatment of diabetes [22,23]. Several studies demonstrated that PPAR-γ agonists improve disease-related symptomology and pathology in several animal models [24] by directly improving mitochondrial function and, ATP production [25,26]. The potential protective role of insulin and insulin-sensitizing agents in AD, HD and PD and ALS will be discussed
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