Limits...
Recurrent antecedent hypoglycemia alters neuronal oxidative metabolism in vivo.

Jiang L, Herzog RI, Mason GF, de Graaf RA, Rothman DL, Sherwin RS, Behar KL - Diabetes (2009)

Bottom Line: 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.The 3dRH animals decreased PDH flux in both compartments (-75 +/- 20% in astrocytes, P < 0.001, and -36 +/- 4% in neurons, P = 0.005).These findings may help to identify better methods of preserving brain function and reducing injury during acute hypoglycemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Diagnostic Radiology, Yale University School of Medicine, The Anlyan Center, New Haven, Connecticut, USA. lihong.jiang@yale.edu

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.

Research design and 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.

Show MeSH

Related in: MedlinePlus

Time courses of Glu4 and Gln4 labeling during labeled substrate infusions. A: [2-13C]acetate at euglycemia. B: [1-13C]glucose and unlabeled acetate at euglycemia. C: [2-13C]acetate at hypoglycemia. Group-averaged data are depicted in the upper panels, whereas representative individual animals with best fits of the two-compartment metabolic model appear in lower panels. ♦, Gln4 control; ◇, Gln4 3dRH; ■, Glu4 control; □, Glu4 3dRH. Error bars = SE.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2682668&req=5

Figure 4: Time courses of Glu4 and Gln4 labeling during labeled substrate infusions. A: [2-13C]acetate at euglycemia. B: [1-13C]glucose and unlabeled acetate at euglycemia. C: [2-13C]acetate at hypoglycemia. Group-averaged data are depicted in the upper panels, whereas representative individual animals with best fits of the two-compartment metabolic model appear in lower panels. ♦, Gln4 control; ◇, Gln4 3dRH; ■, Glu4 control; □, Glu4 3dRH. Error bars = SE.

Mentions: The Vcyc/VtcaN ratio, representing the coupling between glutamate/glutamine cycling and the neuronal TCA cycle, had no significant change after exposure to recurrent hypoglycemia (0.58 ± 0.05) in comparison to controls (0.51 ± 0.03, P = 0.15).Figure 4 (top panels) shows the group averages for 13C time courses of Glu4 and Gln4 during [2-13C]acetate infusion in control and 3dRH animals under euglycemia. Individual time courses served as the input for the metabolic model.


Recurrent antecedent hypoglycemia alters neuronal oxidative metabolism in vivo.

Jiang L, Herzog RI, Mason GF, de Graaf RA, Rothman DL, Sherwin RS, Behar KL - Diabetes (2009)

Time courses of Glu4 and Gln4 labeling during labeled substrate infusions. A: [2-13C]acetate at euglycemia. B: [1-13C]glucose and unlabeled acetate at euglycemia. C: [2-13C]acetate at hypoglycemia. Group-averaged data are depicted in the upper panels, whereas representative individual animals with best fits of the two-compartment metabolic model appear in lower panels. ♦, Gln4 control; ◇, Gln4 3dRH; ■, Glu4 control; □, Glu4 3dRH. Error bars = SE.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682668&req=5

Figure 4: Time courses of Glu4 and Gln4 labeling during labeled substrate infusions. A: [2-13C]acetate at euglycemia. B: [1-13C]glucose and unlabeled acetate at euglycemia. C: [2-13C]acetate at hypoglycemia. Group-averaged data are depicted in the upper panels, whereas representative individual animals with best fits of the two-compartment metabolic model appear in lower panels. ♦, Gln4 control; ◇, Gln4 3dRH; ■, Glu4 control; □, Glu4 3dRH. Error bars = SE.
Mentions: The Vcyc/VtcaN ratio, representing the coupling between glutamate/glutamine cycling and the neuronal TCA cycle, had no significant change after exposure to recurrent hypoglycemia (0.58 ± 0.05) in comparison to controls (0.51 ± 0.03, P = 0.15).Figure 4 (top panels) shows the group averages for 13C time courses of Glu4 and Gln4 during [2-13C]acetate infusion in control and 3dRH animals under euglycemia. Individual time courses served as the input for the metabolic model.

Bottom Line: 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.The 3dRH animals decreased PDH flux in both compartments (-75 +/- 20% in astrocytes, P < 0.001, and -36 +/- 4% in neurons, P = 0.005).These findings may help to identify better methods of preserving brain function and reducing injury during acute hypoglycemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Diagnostic Radiology, Yale University School of Medicine, The Anlyan Center, New Haven, Connecticut, USA. lihong.jiang@yale.edu

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.

Research design and 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.

Show MeSH
Related in: MedlinePlus