The Brain-insulin Connection, Metabolic Diseases and Related Pathologies

Abstract

By its action in the brain, insulin controls neuronal survival, energy balance, glucose and lipid metabolism, cognition and additional vital functions. Metabolic, endocrine and neural signals interact with the hormone in the central nervous system, in particular in the hypothalamus and the hippocampus, and regulate its efficiency. Insulin, leptin and serotonin share common signaling routes involved in food intake, energy and glucose homeostasis, such as phosphatidylinositol-3-kinase (PI3K), STAT-3 and MAP kinase pathways. Alterations of brain levels and brain signaling of either insulin or its partners, associated with deficient beta-cell secretion and/or peripheral insulin resistance, contribute to the initiation and progress of metabolic and related pathologies, Alzheimer's disease and depressive syndromes. Despite the availability of numerous therapeutic options for diabetes, current approaches are not adequately effective. Most of them do not take into account either the complex interactions among the various sites of insulin action or the importance of central insulin resistance or its interplay with neurotransmitters and peptides. Most antidiabetic therapies induce many adverse effects, in particular obesity, and thus may initiate a vicious cycle of problems. Furthermore, inefficient diabetic therapy is a high risk for the development of mood and neurodegenerative diseases. At present, new compounds and novel routes of drug administration targeting insulin and its partners in the CNS, resulting in increased central efficiency of the hormone, and studies aiming to further elucidate central mechanisms of insulin action offer hope for novel ways of prevention and intervention in metabolic pathologies and complications.