Journal
DIABETES
Volume 58, Issue 6, Pages 1266-1274Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db08-1664
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Funding
- National Institutes of Health (NIH)
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK027121, R37 DK20495, F32 DK077461]
- National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS037527, NS051854-01]
- Juvenile Diabetes Research Foundation [4-2004-807]
- NIH NINDS [1 P30 NS052519]
- Quantitative Neuroscience with Magnetic Resonance Program for NMR spectrometer
- Yale Diabetes Endocrinology Research Center [P30 DK45735]
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OBJECTIVE-The objective of this study was to characterize the changes in brain metabolism caused by antecedent recurrent, hypoglycemia tinder 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-(13)C]acetate infusion under euglycemic conditions (n = 8), [1-(13)C]glucose and unlabeled acetate coinfusion under euglycemic conditions (n = 8), and [2-(13)C]acetate infusion during a hyperinsulinemic-hypoglycemic clamp (n = 8). In vivo nuclear magnetic resonance spectroscopy was used to monitor the rise of (13)C-labeling in brain metabolites for the calculation of brain metabolic fluxes rising 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 (-7.5 +/- 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. Diabetes 58:1266-1274, 2009
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