Effect of recurrent hypoglycemia on spatial cognition and cognitive metabolism in normal and diabetic rats

The effects of recurrent hypoglycemia (RH) on cognition in human subjects remain controversial, perhaps in part due to difficulty in completely controlling previous hypoglycemic history. We used a model of RH in nondiabetic and diabetic rats to examine the effects of short-term (3 h daily for 3 days) RH on subsequent hippocampally dependent spatial memory, tested either at euglycemia or under acute hypoglycemia. Hippocampal metabolism was simultaneously measured using microdialysis. Antecedent RH improved task performance (79 +/- 2% alternation in nondiabetic RH animals vs. 63 +/- 3% in controls; P < 0.001) at euglycemia, accompanied by reversal of the task-associated dip (20 +/- 1% below baseline) in hippocampal extracellular fluid (ECF) glucose seen in control animals. RH rats also had a larger rise in hippocampal ECF glucose, after intraperitoneal glucose injection, than did controls. However, RH animals tested at acute hypoglycemia (similar to2.8 mmol/l) performed significantly worse than control animals. Results were similar in diabetic and nondiabetic rats. Our data suggest that RH causes improvement in subsequent cognitive performance at euglycemia, accompanied by alterations in cognitive metabolism. When glucose availability is limited, complex cognitive functioning seems to be adversely effected in RH animals, perhaps to better maintain and preserve basic brain functions. Diabetes 53:418-425, 2004.