Stop signs in hippocampal insulin signaling: the role of insulin resistance in structural, functional and behavioral deficits

- Insulin signaling in the central nervous system (CNS) facilitates cognition.
- CNS insulin resistance (IR) reduces cognition and neuroplasticity.
- Hippocampal IR impairs cognition and neuroplasticity independent of peripheral IR.
- Restoration of hippocampal insulin activity improves cognition and neuroplasticity.

In peripheral tissues insulin activates signaling cascades to facilitate glucose uptake from the blood into tissues like liver, muscle and fat. Although insulin appears to play a minor role in the regulation of glucose uptake in the central nervous system (CNS), insulin is known to play a major role in regulating synaptic plasticity in brain regions like the hippocampus. The concept that insulin regulates hippocampal neuroplasticity is further supported from animal models of type 2 diabetes (T2DM) and Alzheimer's disease (AD). The goal of this review is to provide an overview of these studies, as well as the studies that have examined whether deficits in hippocampal insulin signaling are amenable to intervention strategies.