Cognitive and Neural Hippocampal Effects of Long-Term Moderate Recurrent Hypoglycemia

  1. Ewan C. McNay1,
  2. Anne Williamson2,
  3. Rory J. McCrimmon1 and
  4. Robert S. Sherwin1
  1. 1Section of Endocrinology, Yale School of Medicine, New Haven, Connecticut
  2. 2Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut
  1. Address correspondence and reprint requests to Ewan C. McNay, Section of Endocrinology, Yale School of Medicine, One Gilbert Street, TAC S147, P.O. Box 208020, New Haven, CT 06519. E-mail: ewan.mcnay{at}yale.edu

Abstract

Recurrent hypoglycemia is the most feared complication of intensive insulin therapy for type 1 diabetes. Study of the cognitive impact of recurrent hypoglycemia in humans has been hampered by difficulty in controlling for prior glycemic history and diabetes status; there have been no prospective studies. We used a rat model of recurrent hypoglycemia with hypoglycemia for 3 h, once weekly, from 1 month of age. At 4, 8, and 12 months of age, cohorts were tested on a hippocampally dependent spatial memory task, during which hippocampal extracellular fluid (ECF) glucose and lactate were measured using microdialysis. At 4 months, recurrent hypoglycemia improved euglycemic task performance (76 ± 4 vs. 64 ± 3% for controls) and reversed the task-associated dip in ECF glucose seen in controls. However, recurrent hypoglycemia impaired performance in animals tested when hypoglycemic (45 ± 4 vs. 55 ± 2%). Recurrent hypoglycemia preserved euglycemic task performance across age: at 12 months, both task performance (62%) and ECF glucose changes in euglycemic recurrently hypoglycemic animals resembled those of 4-month-old control animals, whereas control animals’ performance deteriorated to chance (44%) by 8 months. At 12 months, hippocampal slice physiology was assessed, with results paralleling the cognitive findings: slices from recurrently hypoglycemic rats showed improved γ-aminobutyric acid (GABA)ergic inhibition at euglycemia but much greater loss of this tone at low bath glucose. Our data show that moderate weekly hypoglycemia prevented age-related decline in hippocampally cognitive function and cognitive metabolism, at least when euglycemic. The impact of recurrent hypoglycemia on cognition is multifaceted and includes both metabolic and electrophysiological components.

Footnotes

    • Accepted January 5, 2006.
    • Received October 9, 2005.
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