Endocrine-metabolic decoupling drives stress vulnerability in dystrophin deficiency

Skeletal muscle orchestrates systemic metabolism, dynamically coordinating glucose uptake and fuel use to match energy demand. In Duchenne muscular dystrophy, loss of dystrophin derails this control, exposing a hidden metabolic weakness. In the mdx mouse, we show that physiological stress exposes a primary failure in insulin-stress axis integration: unchecked glucocorticoid signalling outpaces insulin secretion, driving systemic hyperglycaemia despite preserved muscle insulin sensitivity. These data support multi-tissue dystrophinopathy driving endocrine-metabolic decoupling. Skeletal muscle glycogen accumulates excessively and resists mobilisation under stress. The heart maintains high glucose uptake, whereas the brain remains glucose-limited, defining tissue-specific vulnerabilities. Acute insulin supplementation normalises systemic glucose uptake and rescues stress-induced behavioural deficits. Likewise, empagliflozin-mediated glucose offloading stabilises blood glucose and enhances muscle function to levels comparable with standard care prednisolone. These findings identify endocrine-metabolic decoupling as a central driver of metabolic fragility in DMD, correctable though insulin restoration or targeted glucose redirection.