Increased brain transport and metabolism of acetate in hypoglycemia unawareness
BI Gulanski, HM De Feyter, KA Page… - The Journal of …, 2013 - academic.oup.com
The Journal of Clinical Endocrinology & Metabolism, 2013•academic.oup.com
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 study was to address mechanisms underlying
HAAF, we investigated whether nonglucose fuels such as acetate, a monocarboxylic acid …
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 study was to address mechanisms underlying
HAAF, we investigated whether nonglucose fuels such as acetate, a monocarboxylic acid …
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 study was to address mechanisms underlying HAAF, we investigated 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.
Main Outcome Measure(s)
Brain acetate concentrations, 13C percent enrichment of glutamine and glutamate, and absolute rates of acetate metabolism were measured.
Results
Absolute rates of acetate metabolism in the cerebral cortex were 1.5-fold higher among T1DM/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
Increased MCA transport and metabolism among T1DM individuals 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.
Oxford University Press