Abstract
AIMS/HYPOTHESIS: The physiological basis of the well-described neurocognitive decrements and structural brain changes in type 1 diabetes is unclear. We aimed to assess differences in cerebral blood flow (CBF) and neural activity before, during and after induced hypoglycaemia and hyperglycaemia in adolescents with type 1 diabetes. METHODS: An observational hyperinsulinaemic clamp and functional MRI study was conducted. Parallel study arms assessed participants during three consecutive glycaemic phases: baseline euglycaemia (5.0±0.5 mmol/l), either hypoglycaemia (2.6±0.5 mmol/l) or hyperglycaemia (18-20 mmol/l), and euglycaemic recovery (5.0±0.5 mmol/l). During each glycaemic phase, CBF/brain perfusion was measured with arterial spin labelling and brain neural activity was measured with fractional amplitude of low frequency fluctuations. Comparative analyses were based on the seven regional functional parcellation areas (networks) of the cerebral cortex. A Bayesian multi-level regression model was employed to test regional differences in CBF and brain neural activity between the various glycaemic conditions. RESULTS: Twenty adolescents with type 1 diabetes participated: ten in each of the hypoglycaemic and hyperglycaemic study arms. Relative to baseline, acute hypoglycaemia was associated with substantially reduced brain neural activity (six of seven functional networks); no significant differences in CBF were evident. By contrast, acute hyperglycaemia was associated with widespread increases in brain activity (five of seven functional networks) and decreased perfusion (six of seven functional networks). Hypoglycaemia and hyperglycaemia had symmetrically opposite effects on brain neural activity in the visual, ventral attention, dorsal attention, frontoparietal and default networks. Recovery from both hypoglycaemia and hyperglycaemia was associated with persistent alterations in both brain perfusion and neural activity, relative to baseline, despite >45 min of sustained euglycaemia. CONCLUSIONS/INTERPRETATION: Across widespread areas of the brain, both brain perfusion and neural metabolic activity are altered by acute hypoglycaemia and hyperglycaemia in adolescents with type 1 diabetes. Recovery from glycaemic extremes is delayed. These findings offer important further insights into the acute cerebral responses to abnormal blood glucose levels.