Insulin Resistance in Neurodegenerative Disorders

Insulin resistance, a state in which cells fail to respond adequately to insulin, extends beyond peripheral tissues and has emerged as a salient feature of many neurodegenerative disorders. In the central nervous system, impaired insulin signalling disturbs neuronal energy supply, synaptic plasticity and proteostasis, thereby fostering hallmark pathologies such as amyloid-beta accumulation and tau hyperphosphorylation. This metabolic dysfunction often coexists with mitochondrial deficits, oxidative stress and inflammatory activation of glial cells, creating a vicious cycle that amplifies neuronal vulnerability. Clinically, brain insulin resistance associates with cognitive decline and may precede overt neurodegeneration by years, offering a potential window for early intervention. Intranasal insulin and insulin-sensitising agents are under investigation for their capacity to restore cerebral insulin action, improve glucose utilisation and ameliorate memory deficits. Understanding the mechanistic interplay between systemic metabolic health and brain integrity is therefore critical for devising strategies that target both metabolic and neurodegenerative pathways, with implications for ageing populations worldwide.

Research from Nature Portfolio

Recent studies have revealed that even brief exposure to a calorie-dense diet can induce lasting alterations in brain insulin responsiveness. In healthy men, a short-term high-caloric intake led to accumulation of liver fat and blunted insulin signalling in key brain regions long after the dietary challenge ceased. This persistence of central insulin resistance occurred without significant weight gain, suggesting that dietary composition alone can reprogramme insulin sensitivity within the brain. Such findings underscore the dynamic nature of cerebral insulin action and implicate dietary excess as a modifiable risk factor for both metabolic and neurodegenerative diseases.

Insulin Resistance in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in insulin resistance in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Insulin resistance: A pathological condition in which cells fail to respond effectively to insulin, leading to impaired glucose uptake and signalling.

Amyloid-beta (Aβ): A peptide derived from amyloid precursor protein that aggregates into plaques and is implicated in synaptic toxicity and neuronal loss in Alzheimer’s disease.

Tau pathology: Abnormal hyperphosphorylation and aggregation of the microtubule-binding protein tau, forming neurofibrillary tangles characteristic of several neurodegenerative disorders.

Mitochondrial unfolded protein response (UPRmt): A stress-activated signalling pathway that restores mitochondrial proteostasis by upregulating chaperones and proteases in response to misfolded proteins.

Biliverdin reductase-A (BVR-A): An enzyme that converts biliverdin to bilirubin and also participates in insulin-signal transduction and mitochondrial regulation in the brain.

References

1. A short-term, high-caloric diet has prolonged effects on brain insulin action in men. Nature Metabolism (2025).
2. Biliverdin Reductase-A integrates insulin signaling with mitochondrial metabolism through phosphorylation of GSK3β. Redox Biology (2024).
3. The insulin resistant brain: impact on whole-body metabolism and body fat distribution. Diabetologia (2024).
4. A multi‐layered network model identifies Akt1 as a common modulator of neurodegeneration. Molecular Systems Biology (2023).