Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals

Henk M De Feyter, Graeme F Mason, Gerald I Shulman, Douglas L Rothman, Kitt Falk Petersen, Henk M De Feyter, Graeme F Mason, Gerald I Shulman, Douglas L Rothman, Kitt Falk Petersen

Abstract

Previous studies have reported that brain metabolism of acetate is increased more than twofold during hypoglycemia in type 1 diabetic (T1D) subjects with hypoglycemia unawareness. These data support the hypothesis that upregulation of blood-brain barrier monocarboxylic acid (MCA) transport may contribute to the maintenance of brain energetics during hypoglycemia in subjects with hypoglycemia unawareness. Plasma lactate concentrations are ∼10-fold higher than acetate concentrations, making lactate the most likely alternative MCA as brain fuel. We therefore examined transport of [3-(13)C]lactate across the blood-brain barrier and its metabolism in the brains of T1D patients and nondiabetic control subjects during a hypoglycemic clamp using (13)C magnetic resonance spectroscopy. Brain lactate concentrations were more than fivefold higher (P < 0.05) during hypoglycemia in the T1D subjects compared with the control subjects. Surprisingly, we observed no increase in the oxidation of blood-borne lactate in the T1D subjects, as reflected by similar (13)C fractional enrichments in brain glutamate and glutamine. Taken together, these data suggest that in addition to increased MCA transport at the blood-brain barrier, there may be additional metabolic adaptations that contribute to hypoglycemia unawareness in patients with T1D.

Figures

FIG. 1.
FIG. 1.
Schematic illustrating the time line of the hyperinsulinemic-hypoglycemic clamp, [3-13C]lactate infusion, and 13C MRS acquisition.
FIG. 2.
FIG. 2.
One-compartment model describing incorporation of 13C label from [3-13C]lactate into the brain glutamate and glutamine pools. This figure illustrates the fluxes Vin (lactate influx), Vout (lactate efflux), CMRglc (glucose consumption), and VTCA (TCA cycle rate), which were considered to derive Eq. 2. BBB, blood-brain barrier; α-KG, α-ketoglutarate; MCT1, MCA transporter 1. , 13C-labeled carbon position. Lactate in the neuronal and glial compartments was treated as a single pool due to the rapid transfer of lactate between these cells (24).
FIG. 3.
FIG. 3.
13C MR spectra of a T1D subject (top) and control subject (bottom) averaged over the last 30 min of [3-13C]lactate infusion.
FIG. 4.
FIG. 4.
Total calculated lactate concentrations in brain.

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