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A research team from the School of Life Sciences and the Gerald Choa Neuroscience Institute at The Chinese University of Hong Kong (CUHK) has published a new study revealing for the first time the critical role of metabolic flexibility in the progression of ataxia-telangiectasia (A-T). Metabolic flexibility refers to the ability of cells to dynamically switch between energy breakdown (catabolism) and energy storage or building (anabolism). Good metabolic flexibility plays an important role in maintaining metabolic stability, regulating blood sugar and managing body weight. The findings have been published in the renowned international journal Nature Communications.

In A-T patients, the loss of the ATM (ataxia-telangiectasia mutated) gene results in inherent insulin resistance, causing impaired anabolism (or excessive catabolism). After weaning in infancy, patients’ bodies struggle to obtain sufficient energy from food and remain in a predominantly catabolic state, continuously depleting body fat and then protein reserves (especially glutamine, released in large quantities from muscle breakdown; glutamine is also a metabolic substrate for neurotransmitters) to maintain basic life functions rather than for normal development and growth. Consequently, patients develop cachexia-like symptoms from early childhood, including growth retardation, muscle loss and cerebellar degeneration.

Key findings: vulnerability of cerebellar neurons and a potential intervention

This research provides the first evidence that Purkinje neurons in the human cerebellum are highly sensitive to insulin. These neurons depend on insulin signalling during early development to promote neurite growth. However, A-T patients’ loss of the ATM gene causes abnormal insulin signal transduction, making Purkinje neurons extremely vulnerable and ultimately triggering progressive neurodegeneration. This discovery explains why A-T patients experience motor disorders from childhood and are forced to depend on wheelchairs.

The research team conducted experiments using mice, confirming that supplementation with alpha-ketoglutarate (the alpha-keto acid of glutamine) can reduce demand for glutamine and alleviate the metabolic bottleneck caused by ATM deficiency. Meanwhile, improved muscle maintenance also helps enhance the body’s insulin sensitivity, relieve metabolic disorders, protect Purkinje neurons and delay cerebellar degeneration and motor function deterioration.

The study also found that ATM activity requires precise regulation. Continuous ATM activation triggers excessive anabolic metabolism, creating conditions similar to hyperinsulinemia (a common symptom of diabetes), which instead leads to weight gain and metabolic imbalance.

The corresponding author Professor Kim Chow Hei-man, Associate Professor in CUHK’s School of Life Sciences, noted: “In nutritional science, we always adopt a life-stage approach that emphasises age- and sex-specific needs, as these change significantly throughout the lifespan. During early childhood to early puberty, hyperinsulinemia can be considered part of the body’s physiological response to reduced insulin sensitivity caused by growth hormones, which are essential to accelerate overall growth and brain maturation. However, outside these contexts, hyperinsulinemia is pathological. It is a hallmark of prediabetes and is strongly correlated in the general population with an increased risk of being overweight or obese. This also indicates that the control of ATM must be precisely balanced.”

Balancing catabolism and anabolism for health

This research highlights that metabolic health is not simply about maintaining consistently high or low levels of insulin but rather the body’s ability to dynamically respond to insulin signals. A well-functioning metabolism must balance periods of catabolism (breaking down energy stores) and anabolism (building and storing energy) to meet the body’s demands during different life stages and physiological conditions:

• During growth and development: Anabolism is critical to build tissues, support brain development and sustain overall growth. Insulin signalling plays a key role in triggering these anabolic processes.
• During stress or energy demands: Catabolism is essential to break down stored energy and fuel immediate needs. A healthy metabolism can seamlessly switch to catabolic pathways when required.
• When metabolic flexibility breaks down: In A-T, impaired insulin signalling locks the body into a catabolic state, leading to energy depletion and neurodegeneration. Conversely, in obesity and insulin resistance, excessive anabolic signalling drives fat storage and metabolic stress.

Impact on community metabolic health in an ageing society

Professor Chow further highlighted the broader implications of metabolic flexibility for health and ageing. “Our team’s earlier research on the blood profiles of supercentenarians revealed that being insulin-sensitive – an indicator of metabolic flexibility – is a major factor contributing to their extended health span, meaning the absence of chronic disease. Conversely, we also found that hyperinsulinemia and insulin resistance are significant risk factors for developing dementia in later stages of life.”

This research represents a significant step forward in understanding the intricate relationship between metabolism and brain health. It underscores the importance of maintaining metabolic flexibility – the ability to adapt between anabolic and catabolic states – as a cornerstone of health. It also supports the need for tailored nutritional and metabolic interventions at different life stages to optimise growth, prevent metabolic disorders and promote healthy ageing.

For the full research, please visit: https://doi.org/10.1038/s41467-025-64360-8