Can insulin resistance and chronic hyperglycemia impair endothelial function and brain insulin signaling?

At age 77, this pathway is clinically relevant because vascular and metabolic exposures can coexist with age-related vulnerability to cognitive decline. The claim is strongest for endothelial effects; the proposed brain-signaling-to-resilience sequence is biologically coherent but not yet directly proven in living humans.

Vascular and clinical evidence

• Insulin resistance and chronic hyperglycemia are strongly linked to endothelial dysfunction. In a pooled analysis of 12 studies (n=3,190), insulin resistance was significantly associated with impaired endothelial function. In older adults (mean age 74), metabolic syndrome/higher HOMA-IR correlated with lower flow-mediated dilation (FMD).
• Across 193 studies (n=26,570), each 1 mmol/L higher fasting glucose was associated with a 0.52% lower FMD; type 2 diabetes was associated with a 4.26-percentage-point lower FMD than healthy status. Endothelial dysfunction is also observed in prediabetes.
• Higher HbA1c predicts faster decline in global cognition, memory, and executive function in longitudinal ELSA data.

Brain metabolism and mechanisms

• A 2024 meta-analysis of 31 FDG-PET studies linked peripheral insulin-resistance measures with lower fasting cerebral glucose metabolism; metabolic-state effects were heterogeneous. A systematic review found reduced cerebral FDG uptake in 22 of 23 studies of diabetes, hyperglycemia, or insulin resistance.
• Mechanistically, endothelial insulin resistance reduces PI3K–Akt–eNOS signaling and nitric-oxide availability. Hyperglycemia increases oxidative stress and AGE–RAGE inflammatory injury. These processes may damage blood–brain-barrier insulin transport and reduce brain insulin receptor–IRS-1–PI3K–Akt signaling.
• Downstream effects may include altered mitochondrial function, glycolytic/TCA-cycle activity, oxidative phosphorylation, and ATP availability. However, neuronal glucose uptake is predominantly insulin-independent.

Interpretation

• Lower FDG-PET metabolism has been associated with poorer memory in cognitively healthy late-middle-aged adults, but it is not specific to insulin signaling and may also reflect vascular injury, inflammation, or neurodegenerative processes.

Bottom line

• Insulin resistance and chronic hyperglycemia can credibly impair endothelial function and are associated with cerebral hypometabolism and faster cognitive decline. Their direct causal progression through impaired brain insulin signaling and reduced neuronal energy efficiency to diminished cognitive resilience remains plausible, moderately supported, rather than conclusively demonstrated.