Abstract
Diabetic-like sequalae are hallmarks of Duchenne muscular dystrophy (DMD). Here, we present a mechanistic framework that identified decoupling of the endocrine-metabolic system in the mdx mouse model of DMD that explains systemic glucose intolerance and metabolic inflexibility. Leveraging behavioural stress hypersensitivity to stimulate transient hepatic-induced hyperglycaemia and exacerbate glucose intolerance, we show that the mdx mouse cannot synthesise appropriate levels of insulin to accommodate fluctuations in systemic glucose. Insulin synthesis and down-stream glucose clearance are impaired due to hyperactivation of the hypothalamic-pituitary-adrenal axis, which were completely overcome with the bilateral removal of the adrenal glands. Ex vivo, isolated pancreatic islets from mdx mice fail to mount a glucose-dependent increase in insulin production, indicating glucose-sensing dysfunction. Despite this pancreatic-intrinsic dysfunction with dystrophin-deficiency, skeletal muscle of mdx mice presented with wildtype-like sensitivity to insulin when it was exogenously administered, which overcame glucose intolerance. These data indicate that a peripheral manipulation of the pancreatic system drives a stress-endocrine bottleneck to disturb metabolic flexibility in DMD.