Dataset Information

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.

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.

SUBMITTER: Jiang L

PROVIDER: S-EPMC2682668 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Publications

Recurrent antecedent hypoglycemia alters neuronal oxidative metabolism in vivo.

Jiang Lihong L Herzog Raimund I RI Mason Graeme F GF de Graaf Robin A RA Rothman Douglas L DL Sherwin Robert S RS Behar Kevin L KL

Diabetes 20090310 6

<h4>Objective</h4>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.<h4>Research design and methods</h4>Rats exposed to recurrent insulin-induced hypoglycemia for 3 days (3dRH rats) and untreated controls were subject to the following protocol ...[more]

PMID: 19276443

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Project description:Hypoglycemia-associated autonomic failure (HAAF) constitutes one of the main clinical obstacles to optimum treatment of type 1 diabetes. Neurons in the ventromedial hypothalamus are thought to mediate counterregulatory responses to hypoglycemia. We have previously hypothesized that hypoglycemia-induced hypothalamic angiotensin might contribute to HAAF, suggesting that the angiotensin blocker valsartan might prevent HAAF. On the other hand, clinical studies have demonstrated that the opioid receptor blocker naloxone ameliorates HAAF. The goal of this study was to generate novel hypothalamic markers of hypoglycemia and use them to assess mechanisms mediating HAAF and its reversal.Quantitative PCR was used to validate a novel panel of hypothalamic genes regulated by hypoglycemia. Mice were exposed to one or five episodes of insulin-induced hypoglycemia, with or without concurrent exposure to valsartan or naloxone. Corticosterone, glucagon, epinephrine, and hypothalamic gene expression were assessed after the final episode of hypoglycemia.A subset of hypothalamic genes regulated acutely by hypoglycemia failed to respond after repetitive hypoglycemia. Responsiveness of a subset of these genes was preserved by naloxone but not valsartan. Notably, hypothalamic expression of four genes, including pyruvate dehydrogenase kinase 4 and glycerol 3-phosphate dehydrogenase 1, was acutely induced by a single episode of hypoglycemia, but not after antecedent hypoglycemia; naloxone treatment prevented this failure. Similarly, carnitine palmitoyltransferase-1 was inhibited after repetitive hypoglycemia, and this inhibition was prevented by naloxone. Repetitive hypoglycemia also caused a loss of hypoglycemia-induced elevation of glucocorticoid secretion, a failure prevented by naloxone but not valsartan.Based on these observations we speculate that acute hypoglycemia induces reprogramming of hypothalamic metabolism away from glycolysis toward ?-oxidation, HAAF is associated with a reversal of this reprogramming, and naloxone preserves some responses to hypoglycemia by preventing this reversal.

Dataset Information

Recurrent antecedent hypoglycemia alters neuronal oxidative metabolism in vivo.

Objective

Research design and methods

Results

Conclusions

Publications

Recurrent antecedent hypoglycemia alters neuronal oxidative metabolism in vivo.

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