Preventing the neurotoxic effects of hypoglycaemia in adolescents with Type 1 diabetes- a randomised placebo-controlled trial

The aim of this study is to assess whether medium chain triglycerides (MCT) can protect the brains of adolescents with type1 diabetes mellitus (T1D) during hypoglycaemia. Glucose is the dominant metabolic substrate for brain function. Hypoglycaemia is an inevitable consequence of insulin therapy in type 1 diabetes mellitus (T1D). Even with good control, children and adolescents with T1D spend up to one hour per day with blood glucose levels in the hypoglycaemic range. If untreated, hypoglycaemia can lead to impaired cognition, loss of consciousness and potentially death. Fear of the neurologic consequences of hypoglycaemia is one of the main impediments to optimal metabolic control in children with T1D. Thus there is an imperative for neuroprotective therapies that mitigate or prevent the effects of hypoglycaemia. Using hyperinsulinaemic glucose clamp techniques and simultaneous neuroimaging we have previously investigated the effects of hypo- and hyperglycaemia on brain metabolism, neural networks and cognition in adolescents with T1D. Our studies found clinically important, novel, consistent and robust changes in regional brain perfusion, activation and metabolism during passage from euglycaemia to hypoglycaemia. These abnormalities in neuronal activity persist over hours despite return to euglycaemia. We now plan to exploit these novel findings and to study whether the observed changes can be mitigated or prevented by the prophylactic administration of MCT prior to hypoglycaemic challenge. We will test the efficacy of MCT during clamp-induced hypoglycaemia in a randomised, cross-over placebo-controlled trial. The study population will be 10 adolescents aged 12-18years with Type 1 diabetes, recruited from the Diabetes Clinic at the Royal Children’s Hospital, Melbourne. Our primary outcome will be difference in cerebral perfusion as measured by arterial spin labelling – ASL) during hypoglycaemia induced following MCT as compared with placebo.. Our secondary outcomes will be differences between groups in, functional connectivity /activation in the default mode network (measured using blood oxygen level dependent [BOLD] signalling), brain metabolism (measured using BOLD signalling), frontal lobe biochemistry (measured spectroscopically) and cognitive function (measured on a working memory task). We hypothesize that the changes in all of these outcome measures during hypoglycaemia will be mitigated or prevented by prior oral MCT administration. Our ultimate aim is to devise a simple oral therapy that can be taken by all children with T1D to protect the brain from hypoglycaemia. This will lead to improved neurologic outcomes and facilitate better overall metabolic control of their diabetes.