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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.

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Hypoglycemic-hyperinsulinemic clamp. A: Plasma glucose concentration. B: Glucose infusion rate (GIR). The time point at t = 0 min indicates the beginning of the 13C-labeled acetate infusion and spectral acquisition. Error bars = SE. ♦, controls; ◇, 3dRH.
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Figure 2: Hypoglycemic-hyperinsulinemic clamp. A: Plasma glucose concentration. B: Glucose infusion rate (GIR). The time point at t = 0 min indicates the beginning of the 13C-labeled acetate infusion and spectral acquisition. Error bars = SE. ♦, controls; ◇, 3dRH.

Mentions: For this study, 2 mol/l [2-13C]acetate was infused into 3dRH (n = 8) and control (n = 8) animals during acute insulin-induced hypoglycemia. Animals were fasted overnight before a hyperinsulinemic-hypoglycemic clamp study (50 mU · kg−1 · min−1) in which a variable infusion of 20% dextrose (Hospira, Lakeforest, IL) was used to maintain plasma glucose at the target level of 2.1 ± 0.2 mmol/l (Fig. 2A). Plasma glucose concentrations (Fig. 2B) were measured every 10 min in between NMR scans using a Beckman glucose analyzer 2 (Beckman Coulter, Fullerton, CA). Infusion rates of labeled acetate were reduced by 20% compared with the euglycemic studies to optimize physiological parameters, such as blood pressure, blood pH, Po2, and Pco2. This dose, however, was sufficient for plasma acetate levels to saturate transport.


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)

Hypoglycemic-hyperinsulinemic clamp. A: Plasma glucose concentration. B: Glucose infusion rate (GIR). The time point at t = 0 min indicates the beginning of the 13C-labeled acetate infusion and spectral acquisition. Error bars = SE. ♦, controls; ◇, 3dRH.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Hypoglycemic-hyperinsulinemic clamp. A: Plasma glucose concentration. B: Glucose infusion rate (GIR). The time point at t = 0 min indicates the beginning of the 13C-labeled acetate infusion and spectral acquisition. Error bars = SE. ♦, controls; ◇, 3dRH.
Mentions: For this study, 2 mol/l [2-13C]acetate was infused into 3dRH (n = 8) and control (n = 8) animals during acute insulin-induced hypoglycemia. Animals were fasted overnight before a hyperinsulinemic-hypoglycemic clamp study (50 mU · kg−1 · min−1) in which a variable infusion of 20% dextrose (Hospira, Lakeforest, IL) was used to maintain plasma glucose at the target level of 2.1 ± 0.2 mmol/l (Fig. 2A). Plasma glucose concentrations (Fig. 2B) were measured every 10 min in between NMR scans using a Beckman glucose analyzer 2 (Beckman Coulter, Fullerton, CA). Infusion rates of labeled acetate were reduced by 20% compared with the euglycemic studies to optimize physiological parameters, such as blood pressure, blood pH, Po2, and Pco2. This dose, however, was sufficient for plasma acetate levels to saturate transport.

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