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Diabetologia
Published in: Diabetologia 9/2006

01-09-2006 | Article

Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer’s disease and decreases it in wild-type mice

Authors: E. Galea, D. L. Feinstein, P. Lacombe

Published in: Diabetologia | Issue 9/2006

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Abstract

Aims/hypothesis

Clinical trials are in progress to test thiazolidinediones in neurodegenerative diseases such as Alzheimer’s disease that involve deficiencies in brain glucose metabolism. While thiazolidinediones enhance glucose uptake in non-cerebral tissues, their impact on brain energy metabolism has not been investigated in vivo. We thus determined whether the thiazolidinedione pioglitazone reverses the decrease in cerebral glucose utilisation (CGU) in a model of brain metabolic deficiency related to Alzheimer’s disease. Results are relevant to diabetes because millions of diabetic patients take pioglitazone as an insulin-sensitising drug, and diabetes increases the risk of developing Alzheimer’s disease.

Materials and methods

The regional pattern of CGU was measured with the 2-deoxy [14C] glucose autoradiographic technique in adult awake mice overexpressing transforming growth factor β1 (TGFβ1), and in wild-type littermates. Mice were treated with pioglitazone for 2 months.

Results

Measurement of CGU in 27 brain regions confirmed that TGFβ1 overexpression induced hypometabolism across the brain. Pioglitazone did not reverse the effect of TGFβ1 overexpression and decreased regional CGU in control animals by up to 23%. The extent of the regional CGU decrease induced by pioglitazone, but not that induced by TGFβ1, correlated strongly with basal CGU, suggesting that the higher the local metabolic rate the greater the reduction of CGU effected by pioglitazone.

Conclusions/interpretation

In contrast to its stimulatory effect in non-cerebral tissues, chronic treatment with pioglitazone decreases CGU in vivo. This evidence does not support the hypothesis that pioglitazone could act as a metabolic enhancer in Alzheimer’s disease, and raises the question of how thiazolidinediones could be beneficial in neurodegenerative diseases.
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Metadata
Title
Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer’s disease and decreases it in wild-type mice
Authors
E. Galea
D. L. Feinstein
P. Lacombe
Publication date
01-09-2006
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 9/2006
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-006-0326-0

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