Increased brain transport and metabolism of acetate in hypoglycemia unawareness

Context: Intensive insulin therapy reduces the risk for long-Term complications in patients with type 1 diabetes mellitus (T1DM) but increases the risk for hypoglycemia-Associated autonomic failure (HAAF), a syndrome that includes hypoglycemia unawareness and defective glucose counterregulation (reduced epinephrine and glucagon responses to hypoglycemia). Objective: The objective of the studywasto address mechanisms underlying HAAF,weinvestigated whether nonglucose fuels such as acetate, a monocarboxylic acid (MCA), can support cerebral energetics during hypoglycemia in T1DM individuals with hypoglycemia unawareness. Design: Magnetic resonance spectroscopy was used to measure brain transport and metabolism of [2-13C]acetate under hypoglycemic conditions. Setting: The study was conducted at the Yale Center for Clinical Investigation Hospital Research Unit, Yale Magnetic Resonance Research Center. Patients and Other Participants: T1DM participants with moderate to severe hypoglycemia unawareness (n = 7), T1DM controls without hypoglycemia unawareness (n = 5), and healthy nondiabetic controls (n = 10) participated in the study. MainOutcomeMeasure(s): Brain acetate concentrations, 13Cpercent enrichment of glutamineand glutamate, and absolute rates of acetate metabolism were measured. Results: Absolute rates of acetate metabolism in the cerebral cortex were 1.5-fold higher amongT1DM/unaware participants compared with both control groups during hypoglycemia (P = .001). Epinephrine levels of T1DM/unaware subjects were significantly lower than both control groups (P=.05). Epinephrine levels were inversely correlated with levels of cerebral acetate use across the entire study population (P = .01), suggesting a relationship between up-regulated brain MCA use and HAAF. Conclusion: IncreasedMCAtransportandmetabolismamongT1DMindividuals with hypoglycemia unawareness may be a mechanism to supply the brain with nonglucose fuels during episodes of acute hypoglycemia and may contribute to the syndrome of hypoglycemia unawareness, independent of diabetes.