Recurrent Antecedent Hypoglycemia Alters Neuronal Oxidative Metabolism in Vivo

Abstract

Objective- To characterize the changes in brain metabolism caused by antecedent recurrent hypoglycemia under euglycemic and hypoglycemic conditions in a rat model, and test the hypothesis that recurrent hypoglycemia changes the brain's capacity to utilize different energy substrates.

Research design and methods- Rats exposed to recurrent insulin-induced hypoglycemia for 3 days (3dRH) and untreated controls were subject to the following protocols: [2-¹³C]-acetate infusion under euglycemic conditions (n=8), [1-¹³C]-glucose and unlabeled acetate co-infusion under euglycemic conditions (n=8), and [2-¹³C]-acetate infusion during a hyperinsulinemic-hypoglycemic clamp (n=8). In vivo nuclear magnetic resonance spectro scopy was employed to monitor the rise of ¹³C-labeling in brain metabolites for the calculation of brain metabolic fluxes using a neuron-astrocyte model.

Results- At euglycemia, antecedent recurrent hypoglycemia increased whole brain glucose metabolism by 43±4% (p<0.01 vs controls), largely due to higher glucose utilization in neurons. While acetate metabolism remained the same, control and 3dRH animals showed a distinctly different response to acute hypoglycemia: Controls decreased pyruvatedehydrogenase-(PDH)-flux in astrocytes by 64±20% (p=0.01), whereas it increased by 37±3% in neurons (p=0.01). The 3dRH animals decreased PDH-flux in both compartments (−75±20% in astrocytes, p<0.001 and −36±4% in neurons, p=0.005). Thus, acute hypoglycemia reduced total brain TCA cycle activity in 3dRH animals (−37±4% p=0.001), but not in controls.

Conclusion- Our findings suggest that after antecedent hypoglycemia glucose utilization is increased at euglycemia and decreased after acute hypoglycemia, which was not the case in controls. These findings may help to identify better methods of preserving brain function and reducing injury during acute hypoglycemia.