Moderate Recurrent Hypoglycemia Markedly Impairs Set-Shifting Ability in a Rodent Model: Cognitive and Neurochemical Effects

Recurrent hypoglycemia (RH) is the major complication of intensive insulin treatment for diabetes mellitus. Of particular concern is the perceived potential for long-term impact of RH on cognition. Because diabetic patients have been reported to have deficits in mental flexibility and judgment, both generally considered to be mediated predominantly by the prefrontal cortex, the purpose of the present study was to determine whether RH would affect prefrontal cortex function. Medial prefrontal cortex (mPFC)-mediated set-shifting ability was tested in male Sprague-Dawley rats using a maze-based, food-reward Set-Shift task analogous to the Wisconsin card-sorting task. The performance measure was the number of trials to criterion on both day 1 (initial rule-learning) and day 2 (set-shifting in response to a changed contingency). In vivo microdialysis was used to measure mPFC extracellular glucose, lactate, pyruvate, glutamate, and dopamine. Post-mortem measures within the mPFC included glucose transporter 3 (GluT3) and c-Fos. RH animals had enhanced performance on day 1, consistent with previous work that showed RH to improve subsequent hippocampal function when euglycemic. The key finding of the present work is that RH led to impaired set-shifting performance on day 2, suggesting impairment in e.g. mental flexibility. Consistent with this finding, RH animals show decreased mPFC glycolysis on day 2 compared to controls. Our data show that RH can lead to subsequent impaired judgment, accompanied by reduced prefrontal cortex function. The findings suggest a potential underlying mechanism for the impaired judgment seen in diabetic patients.