• brain metabolism
• cognitive function
• free fatty acids
• insulin-induced hypoglycemia
• medium-chain triglycerides
• type 1 diabetes mellitus
• β-hydroxybutyrate

The benefits of tight glycemic control in type 1 diabetes mellitus (T1DM) are limited by an increased risk of insulin-induced hypoglycemia, which leads to brain energy deficit and cognitive dysfunction. Medium-chain triglycerides (MCTs) may provide a source of non-glucose energy substrates for the brain, such as β-hydroxybutyrate (BHB) and free fatty acids (FFAs). Aim of this study was to examine whether a dietary supplementation with MCTs can support brain metabolism and function in T1DM patients under insulin-induced hypoglycemia by increasing BHB and FFA availability.
To study brain metabolism and function under hypoglycemia, functional MRI and cognitive testing were performed during a hyperinsulinemic-hypoglycemic clamp (target glucose 50 mg/dl [2.75 mmol/l]) in 16 T1DM patients with recurrent hypoglycemia after either a 4-week MCT-enriched diet (n=8) or a 4-week isocaloric control diet (n=8), and in 16 healthy controls without dietary intervention. To directly quantify the contribution of BHB to brain metabolism under hypoglycemia, magnetic resonance spectroscopy (MRS) of the brain cortex with the infusion of 13C-[2,4]-BHB was performed during a hyperinsulinemic-hypoglycemic clamp in 5 T1DM patients with recurrent hypoglycemia and 6 healthy controls.
T1DM patients on the MCT-enriched diet showed higher cognitive performance and regional brain activation under hypoglycemia than both T1DM and healthy controls. These effects directly correlated with plasma levels of BHB and FFA, which increased after the MCT-enriched diet. In MRS studies, BHB supported brain metabolism under hypoglycemia in all subjects. Remarkably, BHB contributed a larger share to whole brain oxidative capacity in intensively treated T1DM patients than in healthy subjects, suggesting the presence of adaptive changes to recurrent hypoglycemia that favor brain ketone utilization.
In conclusion, dietary supplementation with MCTs improved cognitive function and enhanced brain regional activation under hypoglycemia by increasing availability of BHB and FFAs in T1DM patients with recurrent hypoglycemia. MCT supplementation represents a novel prophylactic strategy to help implement tighter glycemic control in T1DM patients without increasing the risk of hypoglycemia-induced brain injury.