Characterizing longitudinal patterns of central and peripheral insulin resistance

Area of Science:

• Neuroscience
• Metabolic Health
• Aging

Background:

• Insulin resistance (IR) can impair brain function years before clinical diagnosis.
• Understanding peripheral and central IR's distinct roles is crucial for early intervention.

Purpose of the Study:

• To assess peripheral and central IR biomarkers over three years in cognitively healthy adults.
• To clarify their differential contributions to metabolic and cognitive changes.

Main Methods:

• Assessed peripheral IR using steady-state plasma glucose (SSPG) and ancillary metabolic indices.
• Indexed central IR via phosphorylated insulin-receptor-substrate-1 (p-IRS1) in neuron-derived extracellular vesicles (NDEs).
• Utilized mixed-effects models in 125 cognitively intact adults (aged 23-61).

Main Results:

• Higher baseline SSPG predicted increased HOMA-IR and fasting insulin, but not cognitive decline.
• Higher baseline NDE p-IRS1 predicted better global cognition (MMSE) over time, especially in younger individuals.
• NDE p-IRS1 showed inverse correlation with SSPG, BMI, and leptin, suggesting brain-periphery coupling.

Conclusions:

• Central IR markers (NDE p-IRS1) capture a distinct aspect of brain metabolic vulnerability separate from peripheral measures.
• Peripheral IR measures do not predict cognitive trajectories in non-diabetic, non-depressed adults.
• NDE p-IRS1 may serve as a potential biomarker for brain metabolic health and cognitive resilience.