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Diabetes 54:1452-1458, 2005
© 2005 by the American Diabetes Association, Inc.

Pyruvate Administered After Severe Hypoglycemia Reduces Neuronal Death and Cognitive Impairment

Sang Won Suh1,2, Koji Aoyama1,2, Yasuhiko Matsumori2,3, Jialing Liu2,3, and Raymond A. Swanson1,2

1 Department of Neurology, University of California, San Francisco, San Francisco, California
2 Veterans Affairs Medical Center, San Francisco, California
3 Department of Neurosurgery, University of California, San Francisco, San Francisco, California

Hypoglycemia-induced brain injury is a significant obstacle to optimal blood glucose control in diabetic patients. Severe hypoglycemia triggers a cascade of events in vulnerable neurons that may culminate in cell death even after glucose normalization. A key event in this cascade is the activation of poly(ADP-ribose) polymerase-1 (PARP-1). Activated PARP-1 consumes cytosolic NAD, and because NAD is required for glycolysis, hypoglycemia-induced PARP-1 activation may render cells unable to use glucose even when glucose availability is restored. Pyruvate, however, can be metabolized in the absence of cytosolic NAD. Here we tested whether pyruvate could improve the outcome in rats subjected to insulin-induced hypoglycemia by terminating hypoglycemia with either glucose alone or glucose plus pyruvate. In the four brain regions studied—CA1, subiculum, dentate gyrus of the hippocampus, and piriform cortex—the addition of pyruvate reduced neuron death by 70–90%. Improved neuron survival was also observed when pyruvate delivery was delayed for up to 3 h. The improved neuron survival was accompanied by a sustained improvement in cognitive function as assessed by the Morris water maze. These results suggest that pyruvate may significantly improve the outcome after severe hypoglycemia by circumventing a sustained impairment in neuronal glucose utilization resulting from PARP-1 activation.

Address correspondence and reprint requests to Raymond A. Swanson, MD, (127) Neurology, VAMC, 4150 Clement St., San Francisco, CA 94121. E-mail: ray{at}itsa.ucsf.edu

Abbreviations: EEG, electroencephalogram; H&E, hematoxylin and eosin; PARP-1, poly(ADP-ribose) polymerase-1


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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.