Insulin in Central Nervous System: More than Just a Peripheral Hormone

Insulin signaling in central nervous system (CNS) has emerged as a novel field of research since decreased brain insulin levels and/or signaling were associated to impaired learning, memory, and age-related neurodegenerative diseases. Thus, besides its well-known role in longevity, insulin may constitute a promising therapy against diabetes- and age-related neurodegenerative disorders. More interestingly, insulin has been also faced as the potential missing link between diabetes and aging in CNS, with Alzheimer's disease (AD) considered as the “brain-type diabetes.” In fact, brain insulin has been shown to regulate both peripheral and central glucose metabolism, neurotransmission, learning, and memory and to be neuroprotective. And a future challenge will be to unravel the complex interactions between aging and diabetes, which, we believe, will allow the development of efficient preventive and therapeutic strategies to overcome age-related diseases and to prolong human “healthy” longevity. Herewith, we aim to integrate the metabolic, neuromodulatory, and neuroprotective roles of insulin in two age-related pathologies: diabetes and AD, both in terms of intracellular signaling and potential therapeutic approach. 1. Introduction Almost all cell types are responsive to insulin. However, liver, muscle, and adipose tissue are the most sensitive to the hormone [1], rendering it the most important anabolic hormone identified to date. In vertebrates, this peptide belongs to a superfamily of structurally related proteins, the insulin-related family of substances, that includes insulin-like growth factors-1 (IGF-1) and -2 (IGF-2) and relaxin [2]. Until three decades ago, insulin was considered only as a peripheral hormone, unable to cross the blood-brain barrier (BBB) and to affect the central nervous system (CNS) [3–5]. However, this idea was challenged after the detection of immunoreactive insulin in dog cerebrospinal fluid (CSF) [6]. Further studies provided clear evidence that insulin occurs in brain, where it may reach high levels [7, 8], exerting long-term trophic effects on CNS neurons [2]. Although the in vivo brain insulin levels remain controversial, they appear to be 10- to 100-fold higher than in plasma and to change during brain development, with the highest values in late fetal and early neonatal rabbit brain (about 80–90 and 195？ng/g, respectively), that decrease in the adult brain (about 32？ng/g) [7]. Insulin present in adult CNS is primarily derived from pancreatic β-cells and is transported by CSF into the brain [3–5, 9, 10]. This insulin crosses