What is the Origin of Cerebral Insulin Resistance?

The term integrates concepts from endocrinology, which defines insulin resistance in peripheral tissues, and neuroendocrinology, which recognizes insulin's significant role as a neuromodulator in the central nervous system. The clinical observation that brain glucose uptake and function can be impaired even with normal peripheral glucose control led to the conceptualization of a distinct cerebral form of insulin resistance.

What is the Mechanism of Cerebral Insulin Resistance?

Insulin resistance in the brain is characterized by a defect in the insulin signaling cascade within the CNS. The binding of insulin to its receptor on neuronal membranes typically activates the insulin receptor substrate (IRS) and the PI3K/Akt pathway, but this signaling is attenuated in resistant states. This impairment leads to reduced glucose transport across the blood-brain barrier and decreased neuronal glucose utilization, alongside compromised neurotransmitter regulation and increased oxidative stress, contributing to neurological dysfunction.

Cerebral Insulin Resistance

Meaning

A condition defined by the impaired responsiveness of brain cells, particularly neurons and glial cells, to the hormone insulin, independent of systemic insulin resistance. This hormonal insensitivity disrupts crucial brain functions regulated by insulin, including glucose metabolism, synaptic plasticity, and the regulation of appetite and energy balance. It is increasingly recognized as a key pathophysiological feature in neurodegenerative disorders and cognitive decline.