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

• Published in: Diabetologia Vol. 49; no. 9; pp. 2153 - 2161
• Main Authors: GALEA, E, FEINSTEIN, D. L, LACOMBE, P
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.09.2006; Springer Nature B.V
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Analysis of Variance; Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Carbon Radioisotopes; Clinical trials; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Deoxyglucose - metabolism; Diabetes; Diabetes. Impaired glucose tolerance; Disease; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glucose; Glucose - metabolism; Growth factors; Heterozygote; Humans; Hypoglycemic Agents - pharmacology; Hypotheses; Inflammation; Insulin resistance; Male; Medical sciences; Metabolism; Mice; Mice, Inbred C57BL; Neurology; Pathogenesis; Thiazolidinediones - pharmacology; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Endocrinopathy; Transforming growth factor beta-1; Peroxisome proliferator-activated receptor gamma; Nervous system diseases; Neurodegenerative diseases; Alzheimer disease; Diabetes mellitus; Transforming growth factor; Pioglitazone; Rodentia; Central nervous system; Thiazolidinedione derivatives; Glucose; Cerebral disorder; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Degenerative disease; Models; Alzheimer's disease; Peroxisome proliferator activated receptor; Cerebral glucose utilisation Murine model
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-006-0326-0

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. The regional pattern of CGU was measured with the 2-deoxy [(14)C] glucose autoradiographic technique in adult awake mice overexpressing transforming growth factor beta1 (TGFbeta1), and in wild-type littermates. Mice were treated with pioglitazone for 2 months. Measurement of CGU in 27 brain regions confirmed that TGFbeta1 overexpression induced hypometabolism across the brain. Pioglitazone did not reverse the effect of TGFbeta1 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 TGFbeta1, correlated strongly with basal CGU, suggesting that the higher the local metabolic rate the greater the reduction of CGU effected by pioglitazone. 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.