The mechanisms of how recurrent hypoglycemia (HG) leads to impaired awareness of HG (IAH) remain elusive. Cortical glutamate (Glu) dynamics may be involved, as Glu levels were shown to decrease during HG in healthy controls and in patients with type 1 diabetes (T1D) and normal awareness of HG (T1D-NAH), but not in patients with IAH. While these data supported an association between blunted Glu response to HG and IAH, whether recurrent HG causes a blunting of the Glu response to HG remains unclear. We measured the neurochemical response to HG before and after induction of IAH in T1D-NAH patients undergoing four 2-hour HG clamps over 2 days. 1H-magnetic resonance spectroscopy at 7 tesla was used to measure Glu levels in the anterior cingulate cortex (ACC, 24x12x30 mm3) during the first (C1) and fourth clamps (C4), before and after induction of IAH, respectively. We focused on the ACC as differences in PET-measured glucose kinetics in ACC were associated with IAH. Epinephrine and symptom responses to HG during C1 and C4 confirmed induction of IAH. Glu levels significantly decreased in response to HG during C1, but not during C4. Glucose+Taurine (reported as sum due to cross-correlation) dropped by 40% with HG in C1, whereas it dropped by 32% in C4. We show that recurrent HG blunts the cortical Glu response to HG, which may be due to higher glucose or alternative fuel availability, eliminating the need to oxidize Glu.
Y. Park: None. D. Deelchand: None. A. Kumar: None. A. Moheet: None. Y. Zhang: None. L.E. Eberly: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company, Zucara Therapeutics Inc. Consultant; Self; 360 Consulting, MannKind Corporation. Research Support; Self; Eli Lilly and Company, JDRF, National Institutes of Health. Other Relationship; Self; American Diabetes Association, Sanofi, WebMD. G. Oz: None.
National Institutes of Health (R01NS035192, P41EB015894, P30NS076408)