Recurrent Antecedent Hypoglycemia Alters Neuronal Oxidative Metabolism In Vivo
- Lihong Jiang1,
- Raimund I. Herzog2,
- Graeme F. Mason1,3,
- Robin A. de Graaf1,
- Douglas L. Rothman1,
- Robert S. Sherwin2 and
- Kevin L. Behar3
- 1Department of Diagnostic Radiology, Yale University School of Medicine, The Anlyan Center, New Haven, Connecticut;
- 2Department of Internal Medicine, Yale University School of Medicine, The Anlyan Center, New Haven, Connecticut;
- 3Department of Psychiatry, Magnetic Resonance Research Center, Yale University School of Medicine, The Anlyan Center, New Haven, Connecticut.
- Corresponding author: Lihong Jiang, lihong.jiang{at}yale.edu.
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L.J. and R.I.H. contributed equally to this article.
Abstract
OBJECTIVE The objective of this study was to characterize the changes in brain metabolism caused by antecedent recurrent hypoglycemia under euglycemic and hypoglycemic conditions in a rat model and to test the hypothesis that recurrent hypoglycemia changes the brain's capacity to utilize different energy substrates.
RESEARCH DESIGN AND METHODS Rats exposed to recurrent insulin-induced hypoglycemia for 3 days (3dRH rats) and untreated controls were subject to the following protocols: [2-13C]acetate infusion under euglycemic conditions (n = 8), [1-13C]glucose and unlabeled acetate coinfusion under euglycemic conditions (n = 8), and [2-13C]acetate infusion during a hyperinsulinemic-hypoglycemic clamp (n = 8). In vivo nuclear magnetic resonance spectroscopy was used to monitor the rise of13C-labeling in brain metabolites for the calculation of brain metabolic fluxes using a neuron-astrocyte model.
RESULTS At euglycemia, antecedent recurrent hypoglycemia increased whole-brain glucose metabolism by 43 ± 4% (P < 0.01 vs. controls), largely due to higher glucose utilization in neurons. Although acetate metabolism remained the same, control and 3dRH animals showed a distinctly different response to acute hypoglycemia: controls decreased pyruvate dehydrogenase (PDH) flux in astrocytes by 64 ± 20% (P = 0.01), whereas it increased by 37 ± 3% in neurons (P = 0.01). The 3dRH animals decreased PDH flux in both compartments (−75 ± 20% in astrocytes, P < 0.001, and −36 ± 4% in neurons, P = 0.005). Thus, acute hypoglycemia reduced total brain tricarboxylic acid cycle activity in 3dRH animals (−37 ± 4%, P = 0.001), but not in controls.
CONCLUSIONS Our findings suggest that after antecedent hypoglycemia, glucose utilization is increased at euglycemia and decreased after acute hypoglycemia, which was not the case in controls. These findings may help to identify better methods of preserving brain function and reducing injury during acute hypoglycemia.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received December 2, 2008.
- Accepted March 2, 2009.
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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
- © 2009 by the American Diabetes Association.
