title: Recurrent antecedent hypoglycemia alters neuronal oxidative metabolism in vivo.
abstract: OBJECTIVE
  The objective of this study was to characterize the changes in brain metabolism caused by antecedent recurrent hypoglycemia under euglycemic and hypoglycemic conditions in a rat model and to test the hypothesis that recurrent hypoglycemia changes the brain's capacity to utilize different energy substrates.
  
  
  METHODS
  Rats exposed to recurrent insulin-induced hypoglycemia for 3 days (3dRH rats) and untreated controls were subject to the following protocols: [2-(13)C]acetate infusion under euglycemic conditions (n = 8), [1-(13)C]glucose and unlabeled acetate coinfusion under euglycemic conditions (n = 8), and [2-(13)C]acetate infusion during a hyperinsulinemic-hypoglycemic clamp (n = 8). In vivo nuclear magnetic resonance spectroscopy was used to monitor the rise of(13)C-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. Although acetate metabolism remained the same, control and 3dRH animals showed a distinctly different response to acute hypoglycemia: controls decreased pyruvate dehydrogenase (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 tricarboxylic acid cycle activity in 3dRH animals (-37 +/- 4%, P = 0.001), but not in controls.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Diagnostic Radiology, Yale University School of Medicine, The Anlyan Center, New Haven, Connecticut, USA. lihong.jiang@yale.edu
authors.forename: Lihong
authors.initials: L
authors.lastname: Jiang
authors.forename: Raimund I
authors.initials: RI
authors.lastname: Herzog
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Mason
authors.forename: Robin A
authors.initials: RA
authors.lastname: de Graaf
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Rothman
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sherwin
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Behar
mesh_terms: D000085:Acetates / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006946:Hyperinsulinism / Q000378:metabolism; D007003:Hypoglycemia / Q000139:chemically induced / Q000503:physiopathology*; D007328:Insulin / Q000009:adverse effects* / Q000494:pharmacology; D007700:Kinetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D012008:Recurrence
chemical_list: D000085:Acetates; D001786:Blood Glucose; D007328:Insulin; D011768:Pyruvate Dehydrogenase Complex; D005947:Glucose