Mini-review: impact of recurrent hypoglycemia on cognitive and brain function

Abstract

Recurrent hypoglycemia (RH), the most common side-effect of intensive insulin therapy for diabetes, is well established to diminish counter-regulatory responses to further hypoglycemia. However, despite significant patient concern, the impact of RH on cognitive and neural function remains controversial. Here we review the data from both human studies and recent animal studies regarding the impact of RH on cognitive, metabolic, and neural processes. Overall, RH appears to cause brain adaptations which may enhance cognitive performance and fuel supply when euglycemic but which pose significant threats during future hypoglycemic episodes.

Figure 1

This schematic illustrates some of the sites at which known alterations in hippocampal fuel supply and function occur in response to recurrent hypoglycemia. In particular, glucose transporter (2, 4) expression increases at both the blood-brain barrier (1) and neuronal cell-surface; the dominant GluT forms will be GluT1 at the BBB, and GluTs 3 and perhaps 4 on neurons. This upregulation of transport capacity means that glucose (3a, 3b) metabolism increases, following RH, at euglycemia; the reason for decreased glucose metabolism when acutely hypoglycemic subsequent to RH remains to be determined.. Monocarboxylate transporter (MCT, 5) expression may also increase, permitting increased use of lactate exported from astrocytes. Finally, RH has been shown to alter several aspects of neural transmission across synapses (8), with the impact of RH depending on glycemic state.