Reduced gluconeogenesis and lactate clearance in Huntington's disease Knud Josefsen a, ⁎, Signe M.B. Nielsen a,b , André Campos a , Thomas Seifert d , Lis Hasholt b , Jørgen E. Nielsen b,c , Anne Nørremølle b , Niels H. Skotte b , Niels H. Secher d , Bjørn Quistorff e a The Bartholin Institute, Rigshospitalet, Copenhagen, Denmark b Section of Neurogenetics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark c Neurogenetics Clinic, Memory Disorders Research Group, Rigshospitalet, Copenhagen, Denmark d Copenhagen Muscle Research Centre, Department of Anaesthesia, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark e Nuclear Magnetic Resonance Centre, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark abstract article info Article history: Received 16 April 2010 Revised 23 July 2010 Accepted 11 August 2010 Available online xxxx Keywords: Glucose Exercise Liver perfusion Gluconeogenesis Brain metabolism 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 ± 0.2 mM, P b 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. © 2010 Elsevier Inc. All rights reserved. Introduction HD is a dominantly inherited, neurodegenerative disease caused by a CAG repeat expansion mutation in the huntingtin gene. This creates an elongated polyglutamine stretch in the expressed protein, that causes cellular dysfunction and, in some instances, cell death (The Huntington's Disease Collaborative Research Group, 1993). Although the symptomatology of HD is primarily neurological, most tissues express mutant huntingtin (Li et al., 1993; Van Raamsdonk et al., 2007), which is also the case in the murine HD model R6/2 (Sathasivam et al., 1999). In HD patients, an elevated lactate concentration has been found in the frontal cortex of 17 patients and 4 asymptomatic carriers (Harms et al., 1997) and in the basal ganglia from 18 HD patients or carriers (Jenkins et al., 1993). Also, the lactate/creatine and lactate/N-acetyl aspartate ratios were increased in parieto-occipital and cerebellar regions in 23 patients (Martin et al., 2007). Increased lactate concentration was also seen in several brain areas of R6/2 mice (Tsang et al., 2006) and in a transgenic primate model for HD (Dautry et al., 1999). In contrast, no lactate increase was found in the brain of 15 HD patients (Hoang et al., 1998) or in serum from 11 HD patients (Nicoli et al., 1993). In order to determine, whether this increase in brain lactate was related to a change in brain lactate metabolism and/or peripheral lactate handling, we investigated systemic and cerebral glucose and lactate metabolism in HD patients. This was achieved by performing an ergometer exercise test during which repeated blood sampling was performed. During intense exercise, accumulation of lactate takes place when the rate of production by glycolysis exceeds the capacity for removal. More specifically, this happens as the delivery of glycolysis substrate from breakdown of glycogen in the working muscles will occur at a higher rate than pyruvate dehydrogenase and mitochondrial oxidation can cope with (Putman et al., 1995; News- holme and Leech, 1983), and blood lactate may reach 30 mM (Nielsen, 1999). If not consumed by the muscle itself (Secher et al., 1977), this lactate is released to the blood to be transformed to glucose, primarily by liver but with contribution from kidney (Lauritsen et al., 2002) or oxidized in other organs like the brain (Ide et al., 2000) and the heart (Gertz et al., 1988). Lactate accumulation may also occur when the cytosolic redox state (NADH/NAD) is increased for reasons other than glycolytic flux. Thus, net lactate accumulation may be initiated by tissue hypoxia and reduced mitochondrial respiration. Methods Patient studies HD patients (51.7 ± 10 years, 9 males, 2 females) participated in the study after providing informed written consent. The patients’ BMI Neurobiology of Disease xxx (2010) xxx–xxx ⁎ Corresponding author. Bartholin Instituttet, Rigshospitalet, Copenhagen Biocenter, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark. E-mail address: knud@eln.dk (K. Josefsen). Available online on ScienceDirect (www.sciencedirect.com). YNBDI-02223; No. of pages: 7; 4C: 0969-9961/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2010.08.009 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi Please cite this article as: Josefsen, K., et al., Reduced gluconeogenesis and lactate clearance in Huntington's disease, Neurobiol. Dis. (2010), doi:10.1016/j.nbd.2010.08.009