Reduced gluconeogenesis and lactate clearance in Huntington's disease

• Published in: Neurobiology of disease Vol. 40; no. 3; pp. 656 - 662
• Main Authors: Josefsen, Knud, Nielsen, Signe M.B., Campos, André, Seifert, Thomas, Hasholt, Lis, Nielsen, Jørgen E., Nørremølle, Anne, Skotte, Niels H., Secher, Niels H., Quistorff, Bjørn
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2010; Elsevier
• Subjects: Animals; Blood Glucose - analysis; Blotting, Western; Brain - metabolism; Exercise; Exercise - physiology; Exercise Test - methods; Female; Gluconeogenesis; Gluconeogenesis - physiology; Glucose; Humans; Huntington Disease - metabolism; Huntington Disease - physiopathology; Lactic Acid - metabolism; Liver - metabolism; Liver - physiopathology; Liver Function Tests - methods; Liver perfusion; Male; Mice; Mice, Transgenic; Middle Aged; Neurology; Reverse Transcriptase Polymerase Chain Reaction; Liver perfusion; Exercise; Glucose; Brain metabolism; Gluconeogenesis
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2010.08.009

We studied systemic and brain glucose and lactate metabolism in Huntington's disease (HD) patients in response to ergometer cycling. Following termination of exercise, blood glucose increased abruptly in control subjects, but no peak was seen in any of the HD patients (2.0±0.5 vs. 0.0±0.2mM, P<2×10−6). No difference was seen in brain metabolism parameters. Reduced hepatic glucose output in the HD mouse model R6/2 following a lactate challenge, combined with reduced phosphoenolpyruvate carboxykinase and increased pyruvate kinase activity in the mouse liver suggest a reduced capacity for gluconeogenesis in HD, possibly contributing to the clinical symptoms of HD. We propose that blood glucose concentration in the recovery from exercise can be applied as a liver function test in HD patients. ►The rise in blood glucose normally seen after exercise was absent in Huntington's disease patients. ►Similar results were seen in R6/2 mice following intraperitoneal lactate injection. ►Hepatic gluconeogenesis and lactate clearance were reduced in this model. ►Brain oxygen, lactate and glucose metabolism did not differ between patients and controls. ►The exercise test could be applied as a liver function test in HD patients.