Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada. Electronic address: [Email]
Insulin signaling in the central nervous system is at the intersection of brain and body interactions, and represents a fundamental link between metabolic and cognitive disorders. Abnormalities in brain insulin action could underlie the development of comorbid schizophrenia and type 2 diabetes. Among its functions, central nervous system insulin is involved in regulation of striatal dopamine levels, peripheral glucose homeostasis, and feeding regulation. In this review, we discuss the role and importance of central nervous system insulin in schizophrenia and diabetes pathogenesis from a historical and mechanistic perspective. We describe central nervous system insulin sites and pathways of action, with special emphasis on glucose metabolism, cognitive functioning, inflammation, and food preferences. Finally, we suggest possible mechanisms that may explain the actions of central nervous system insulin in relation to schizophrenia and diabetes, focusing on glutamate and dopamine signaling, intracellular signal transduction pathways, and brain energetics. Understanding the interplay between central nervous system insulin and schizophrenia is essential to disentangling this comorbid relationship and may provide novel treatment approaches for both neuropsychiatric and metabolic dysfunction. This article is part of the issue entitled 'Special Issue on Antipsychotics'.