# Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia

## TL;DR

Alpha-ketoglutarate helps reduce insulin resistance and brain cell degeneration in a mouse model of Ataxia-Telangiectasia.

## Contribution

The study reveals a novel metabolic strategy using alpha-ketoglutarate to mitigate neurodegeneration in Ataxia-Telangiectasia.

## Key findings

- Insulin-activated ATM regulates glucose metabolism and its disruption causes insulin resistance and glutamine dependence.
- Supplementing with alpha-ketoglutarate alleviates glutamine dependence and reduces Purkinje cell degeneration in Ataxia-Telangiectasia.
- Metabolic disruptions in Ataxia-Telangiectasia contribute to sustained neurodegeneration, highlighting the need for metabolic monitoring in patients.

## Abstract

The maintenance of metabolic homeostasis relies on the ability to flexibly transit between catabolic and anabolic states in response to insulin signaling. Here we show insulin-activated ATM is a critical mediator of this process, facilitating the swift transition between catabolic-and-anabolic fates of glucose by regulating the functional status of PKM2 and HIF1α. In Ataxia-Telangiectasia (A-T), these mechanisms are disrupted, resulting in intrinsic insulin resistance and glucose intolerance. Consequently, cells exhibit a compensatory dependence on glutamine as an alternative metabolite for energy metabolism. Cerebellar degeneration, a hallmark of A-T, is characterized by the pronounced vulnerability of Purkinje cells, attributed to their unexpected sensitivity to insulin. Supplementation with α-ketoglutarate, the α-keto acid backbone of glutamine, has demonstrated potentials in alleviating glutamine dependence and attenuating Purkinje cell degeneration. These findings suggest that peripheral metabolic deficiencies may contribute to sustained neurodegenerative changes in A-T, underscoring the importance of screening, monitoring and addressing these metabolic disruptions in patients.

Insulin-activated ataxia-telangiectasia mutated (ATM) regulates glucose metabolism. Here the authors report that its disruption in a mouse model of ataxia-telangiectasia leads to insulin resistance, glutamine dependence, and selective Purkinje cell degeneration, while α-Ketoglutarate supplementation shows promise in mitigating neurodegeneration.