OBJECTIVE: We examined whether ingestion of medium-chain triglycerides could improve cognition during hypoglycemia in subjects with intensively treated type 1 diabetes and assessed potential underlying mechanisms by testing the effect of beta-hydroxybutyrate and octanoate on rat hippocampal synaptic transmission during exposure to low glucose. RESEARCH DESIGN AND METHODS: A total of 11 intensively treated type 1 diabetic subjects participated in stepped hyperinsulinemic- (2 mU x kg(-1) x min(-1)) euglycemic- (glucose approximately 5.5 mmol/l) hypoglycemic (glucose approximately 2.8 mmol/l) clamp studies. During two separate sessions, they randomly received either medium-chain triglycerides or placebo drinks and performed a battery of cognitive tests. In vitro rat hippocampal slice preparations were used to assess the ability of beta-hydroxybutyrate and octanoate to support neuronal activity when glucose levels are reduced. RESULTS: Hypoglycemia impaired cognitive performance in tests of verbal memory, digit symbol coding, digit span backwards, and map searching. Ingestion of medium-chain triglycerides reversed these effects. Medium-chain triglycerides also produced higher free fatty acids and beta-hydroxybutyrate levels compared with placebo. However, the increase in catecholamines and symptoms during hypoglycemia was not altered. In hippocampal slices beta-hydroxybutyrate supported synaptic transmission under low-glucose conditions, whereas octanoate could not. Nevertheless, octanoate improved the rate of recovery of synaptic function upon restoration of control glucose concentrations. CONCLUSIONS: Medium-chain triglyceride ingestion improves cognition without adversely affecting adrenergic or symptomatic responses to hypoglycemia in intensively treated type 1 diabetic subjects. Medium-chain triglycerides offer the therapeutic advantage of preserving brain function under hypoglycemic conditions without causing deleterious hyperglycemia.