Amino Acids

, Volume 49, Issue 7, pp 1147–1157 | Cite as

Glucose transportation in the brain and its impairment in Huntington disease: one more shade of the energetic metabolism failure?

  • Veronica Morea
  • Eris Bidollari
  • Gianni Colotti
  • Annarita Fiorillo
  • Jessica Rosati
  • Lidia De Filippis
  • Ferdinando SquitieriEmail author
  • Andrea IlariEmail author
Review Article


Huntington’s disease (HD) or Huntington’s chorea is the most common inherited, dominantly transmitted, neurodegenerative disorder. It is caused by increased CAG repeats number in the gene coding for huntingtin (Htt) and characterized by motor, behaviour and psychiatric symptoms, ultimately leading to death. HD patients also exhibit alterations in glucose and energetic metabolism, which result in pronounced weight loss despite sustained calorie intake. Glucose metabolism decreases in the striatum of all the subjects with mutated Htt, but affects symptom presentation only when it drops below a specific threshold. Recent evidence points at defects in glucose uptake by the brain, and especially by neurons, as a relevant component of central glucose hypometabolism in HD patients. Here we review the main features of glucose metabolism and transport in the brain in physiological conditions and how these processes are impaired in HD, and discuss the potential ability of strategies aimed at increasing intracellular energy levels to counteract neurological and motor degeneration in HD patients.


Huntington disease Energetic metabolism Glucose transport GLUT1 GLUT3 



We thank the Foundation “Lega Italiana Ricerca Huntington e malattie correlate” ( for supporting research on HD (FS) and taking care of families.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics statement

This research did not involve human participants and/or animals.


  1. Adanyeguh IM, Rinaldi D, Henry P-G et al (2015) Triheptanoin improves brain energy metabolism in patients with Huntington disease. Neurology 84:490–495. doi: 10.1212/WNL.0000000000001214 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Badr GA, Zhang JZ, Tang J et al (1999) Glut1 and Glut3 expression, but not capillary density, is increased by cobalt chloride in rat cerebrum and retina. Mol Brain Res 64:24–33. doi: 10.1016/S0169-328X(98)00301-5 CrossRefPubMedGoogle Scholar
  3. Besson MT, Alegría K, Garrido-Gerter P et al (2015) Enhanced neuronal glucose transporter expression reveals metabolic choice in a HD Drosophila model. PLoS One 10:1–23. doi: 10.1371/journal.pone.0118765 CrossRefGoogle Scholar
  4. Bingham EM, Hopkins D, Smith D et al (2002) The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes 51:3384–3390. doi: 10.2337/diabetes.51.12.3384 CrossRefPubMedGoogle Scholar
  5. Browne SE, Ferrante RJ, Beal MF (1999) Oxidative stress in Huntington’s disease. Brain Pathol 9:147–163CrossRefPubMedGoogle Scholar
  6. Bruckner BA, Ammini CV, Otal MP et al (1999) Regulation of brain glucose transporters by glucose and oxygen deprivation. Metabolism 48:422–431. doi: 10.1016/S0026-0495(99)90098-7 CrossRefPubMedGoogle Scholar
  7. Burkhart RA, Pineda DM, Chand SN et al (2013) HuR is a post-transcriptional regulator of core metabolic enzymes in pancreatic cancer. RNA Biol 10:1312–1323. doi: 10.4161/rna.25274 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chaturvedi RK, Adhihetty P, Shukla S et al (2009) Impaired PGC-1α function in muscle in Huntington’s disease. Hum Mol Genet 18:3048–3065. doi: 10.1093/hmg/ddp243 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cherry J, Karschner V, Jones H, Pekala PH (2006) HuR, an RNA-binding protein, involved in the control of cellular differentiation. In Vivo 20:17–23PubMedGoogle Scholar
  10. Choeiri C, Staines W, Messier C (2002) Immunohistochemical localization and quantification of glucose transporters in the mouse brain. Neuroscience 111:19–34. doi: 10.1016/S0306-4522(01)00619-4 CrossRefPubMedGoogle Scholar
  11. Ciarmiello A, Cannella M, Lastoria S et al (2006) Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington’s disease. J Nucl Med 47:215–222PubMedGoogle Scholar
  12. Ciarmiello A, Giovacchini G, Orobello S et al (2012) 18F-FDG PET uptake in the pre-Huntington disease caudate affects the time-to-onset independently of CAG expansion size. Eur J Nucl Med Mol Imaging 39:1030–1036. doi: 10.1007/s00259-012-2114-z CrossRefPubMedGoogle Scholar
  13. Cifuentes M, García MA, Arrabal PM et al (2011) Insulin regulates GLUT1-mediated glucose transport in MG-63 human osteosarcoma cells. J Cell Physiol 226:1425–1432. doi: 10.1002/jcp.22668 CrossRefPubMedGoogle Scholar
  14. Clarke D, Sokoloff L (1999) Circulation and energy metabolism of the brain. In: Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD (eds) Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 6th edn. Lippincott-Raven, Philadelphia, pp 637–639Google Scholar
  15. Cui L, Jeong H, Borovecki F et al (2006) Transcriptional repression of PGC-1α by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127:59–69. doi: 10.1016/j.cell.2006.09.015 CrossRefPubMedGoogle Scholar
  16. Deng D, Xu C, Sun P et al (2014) Crystal structure of the human glucose transporter GLUT1. Nature 510:121–125. doi: 10.1038/nature13306 CrossRefPubMedGoogle Scholar
  17. Deng D, Sun P, Yan C et al (2015) Molecular basis of ligand recognition and transport by glucose transporters. Nature 526:391–396. doi: 10.1038/nature14655 CrossRefPubMedGoogle Scholar
  18. Dienel GA (2012) Fueling and imaging brain activation. ASN Neuro 4:267–321. doi: 10.1042/AN20120021 CrossRefGoogle Scholar
  19. Drouin-Ouellet J, Sawiak SJ, Cisbani G et al (2015) Cerebrovascular and blood-brain barrier impairments in Huntington’s disease: potential implications for its pathophysiology. Ann Neurol 78:160–177. doi: 10.1002/ana.24406 CrossRefPubMedGoogle Scholar
  20. Duarte AI, Moreira PI, Oliveira CR (2012) Insulin in central nervous system: more than just a peripheral hormone. J Aging Res. doi: 10.1155/2012/384017 PubMedPubMedCentralGoogle Scholar
  21. Feigin A, Tang C, Ma Y et al (2007) Thalamic metabolism and symptom onset in preclinical Huntington’s disease. Brain 130:2858–2867. doi: 10.1093/brain/awm217 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Finn RD, Coggill P, Eberhardt RY et al (2016) The Pfam protein families database: towards a more sustainable future. Nucl Acids Res 44:D279–D285. doi: 10.1093/nar/gkv1344 CrossRefPubMedGoogle Scholar
  23. Fladeby C, Skar R, Serck-Hanssen G (2003) Distinct regulation of glucose transport and GLUT1/GLUT3 transporters by glucose deprivation and IGF-I in chromaffin cells. Biochim Biophys Acta Mol Cell Res 1593:201–208. doi: 10.1016/S0167-4889(02)00390-7 CrossRefGoogle Scholar
  24. Formenti F, Constantin-teodosiu D, Emmanuel Y et al (2010) Regulation of human metabolism by hypoxia-inducible factor. Proc Natl Acad Sci USA 107:12722–12727. doi:10.1073/pnas.1002339107/-/ Scholar
  25. Gamberino WC, Brennan WA Jr (1994) Glucose transporter isoform expression in Huntington’s disease brain. J Neurochem 63:1392–1397CrossRefPubMedGoogle Scholar
  26. Gantt KR, Cherry J, Richardson M et al (2006) The regulation of glucose transporter (GLUT1) expression by the RNA binding protein HuR. J Cell Biochem 99:565–574. doi: 10.1002/jcb.20950 CrossRefPubMedGoogle Scholar
  27. Huang TJ, Verkhratsky A, Fernyhough P (2005) Insulin enhances mitochondrial inner membrane potential and increases ATP levels through phosphoinositide 3-kinase in adult sensory neurons. Mol Cell Neurosci 28:42–54. doi: 10.1016/j.mcn.2004.08.009 CrossRefPubMedGoogle Scholar
  28. Iancu CV, Zamoon J, Bum S et al (2013) Crystal structure of a glucose/H+ symporter and its mechanism of action. Proc Natl Acad Sci USA 110:17862–17867. doi: 10.1073/pnas.1311485110 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Jardetzky O (1966) Simple allosteric model for membrane pumps. Nature 211:969–970. doi: 10.1038/211969a0 CrossRefPubMedGoogle Scholar
  30. Joost HG, Thorens B (2001) The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members (review). Mol Membr Biol 18:247–256. doi: 10.1080/09687680110090 CrossRefPubMedGoogle Scholar
  31. Jurcovicova J (2014) Glucose transport in brain—effect of inflammation. Endocr Regul 48:35–48. doi: 10.4149/endo_2014_01_35 CrossRefPubMedGoogle Scholar
  32. Kapoor K, Finer-Moore JS, Pedersen BP et al (2016) Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides. Proc Natl Acad Sci 113:4711–4716. doi: 10.1073/pnas.1603735113 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Keaney J, Campbell M (2015) The dynamic blood–brain barrier. FEBS J 282:4067–4079. doi: 10.1111/febs.13412 CrossRefPubMedGoogle Scholar
  34. Klopstock T, Elstner M, Bender A (2011) Creatine in mouse models of neurodegeneration and aging. Amino Acids 40:1297–1303. doi: 10.1007/s00726-011-0850-1 CrossRefPubMedGoogle Scholar
  35. Kovac S, Abramov AY, Walker MC (2013) Energy depletion in seizures: anaplerosis as a strategy for future therapies. Neuropharmacology 69:96–104. doi: 10.1016/j.neuropharm.2012.05.012 CrossRefPubMedGoogle Scholar
  36. Lalic NM, Maric J, Svetel M et al (2008) Glucose homeostasis in Huntington disease: abnormalities in insulin sensitivity and early-phase insulin secretion. Arch Neurol 65:476–480. doi: 10.1001/archneur.65.4.476 CrossRefPubMedGoogle Scholar
  37. Laron Z (2009) Insulin and the brain. Arch Physiol Biochem 115:112–116. doi: 10.1016/S0140-6736(66)90770-7 CrossRefPubMedGoogle Scholar
  38. Li XJ, Orr AL, Li S (2010) Impaired mitochondrial trafficking in Huntington’s disease. Biochim Biophys Acta Mol Basis Dis 1802:62–65CrossRefGoogle Scholar
  39. Li X, Valencia A, McClory H et al (2012) Deficient Rab11 activity underlies glucose hypometabolism in primary neurons of Huntington’s disease mice. Biochem Biophys Res Commun 421:727–730. doi: 10.1016/j.bbrc.2012.04.070 CrossRefPubMedGoogle Scholar
  40. Lim D, Fedrizzi L, Tartari M et al (2008) Calcium homeostasis and mitochondrial dysfunction in striatal neurons of Huntington disease. J Biol Chem 283:5780–5789. doi: 10.1074/jbc.M704704200 CrossRefPubMedGoogle Scholar
  41. Mangia S, DiNuzzo M, Giove F et al (2011) Response to ‘comment on recent modeling studies of astrocyte-neuron metabolic interactions’: much ado about nothing. J Cereb Blood Flow Metab 31:1346–1353. doi: 10.1038/jcbfm.2011.29 CrossRefPubMedPubMedCentralGoogle Scholar
  42. McClory H, Williams D, Sapp E et al (2014) Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington’s disease mice. Acta Neuropathol Commun 2:179. doi: 10.1186/s40478-014-0178-7 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Mergenthaler P, Lindauer U, Dienel GA, Meisel A (2013) Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci 36:587–597. doi: 10.1016/j.tins.2013.07.001 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Milakovic T, Johnson GVW (2005) Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin. J Biol Chem 280:30773–30782. doi: 10.1074/jbc.M504749200 CrossRefPubMedGoogle Scholar
  45. Mochel F, Duteil S, Marelli C et al (2010) Dietary anaplerotic therapy improves peripheral tissue energy metabolism in patients with Huntington’s disease. Eur J Hum Genet 18:1057–1060. doi: 10.1038/ejhg.2010.72 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Mochel F, Hainque E, Gras D et al (2015) Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency. J Neurol Neurosurg Psychiatry. doi: 10.1136/jnnp-2015-311475 PubMedCentralGoogle Scholar
  47. Naseri NN, Xu H, Bonica J et al (2015) Abnormalities in the tricarboxylic acid cycle in Huntington disease and in a Huntington disease mouse model. J Neuropathol Exp Neurol 74:527–537. doi: 10.1097/nen.0000000000000197 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Nomura N, Verdon G, Kang HJ et al (2015) Structure and mechanism of the mammalian fructose transporter GLUT5. Nature 526:397–401. doi: 10.1038/nature14909 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Olson AL, Pessin JE (1996) Structure, function, and regulation of the mammalian facilitative glucose transporter gene family. Annu Rev Nutr 16:235–256. doi: 10.1146/ CrossRefPubMedGoogle Scholar
  50. Patel AB, Lai JC, Chowdhury GM et al (2014) Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle. Proc Natl Acad Sci USA 111:5385–5390. doi: 10.1073/pnas.1403576111 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Pedersen BP, Kumar H, Waight AB et al (2013) Crystal structure of a eukaryotic phosphate transporter. Nature 496:533–536. doi: 10.1038/nature12042 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Pellerin L, Magistretti PJ (2012) Sweet sixteen for ANLS. J Cereb Blood Flow Metab 32:1152–1166. doi: 10.1038/jcbfm.2011.149 CrossRefPubMedGoogle Scholar
  53. Peng SSY, Chen CYA, Xu N, Bin Shyu A (1998) RNA stabilization by the AU-rich element binding protein, HuR, an ELAV protein. EMBO J 17:3461–3470. doi: 10.1093/emboj/17.12.3461 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Powers WJ, Videen TO, Markham J et al (2007) Selective defect of in vivo glycolysis in early Huntington’s disease striatum. Proc Natl Acad Sci 104:2945–2949. doi: 10.1073/pnas.0609833104 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Quistgaard EM, Löw C, Moberg P et al (2013) Structural basis for substrate transport in the GLUT-homology family of monosaccharide transporters. Nat Struct Mol Biol 20:766–768. doi: 10.1038/nsmb.2569 CrossRefPubMedGoogle Scholar
  56. Quistgaard EM, Löw C, Guettou F, Nordlund P (2016) Understanding transport by the major facilitator superfamily (MFS): structures pave the way. Nat Rev Mol Cell Biol 17:123–132. doi: 10.1038/nrm.2015.25 CrossRefPubMedGoogle Scholar
  57. Roos RAC (2010) Huntington’s disease: a clinical review. Orphanet J Rare Dis 5:40. doi: 10.1186/1750-1172-5-40 CrossRefPubMedPubMedCentralGoogle Scholar
  58. Russo CV, Salvatore E, Saccà F et al (2013) Insulin sensitivity and early-phase insulin secretion in normoglycemic Huntington’s disease patients. J Huntingt Dis 2:501–507. doi: 10.3233/JHD-130078 Google Scholar
  59. Seidner G, Alvarez MG, Yeh J-I et al (1998) GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet 18:188–191. doi: 10.1038/ng0298-188 CrossRefPubMedGoogle Scholar
  60. Semenza GL (2001) Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 7:345–350. doi: 10.1016/S1471-4914(01)02090-1 CrossRefPubMedGoogle Scholar
  61. Siegel A, Roeling TA, Gregg TR, Kruk MR (1999) Neuropharmacology of brain-stimulation-evoked aggression. Neurosci Biobehav Rev 23:359–389. doi: 10.1016/S0149-7634(98)00040-2 CrossRefPubMedGoogle Scholar
  62. Simpson IA, Dwyer D, Malide D et al (2008) The facilitative glucose transporter GLUT3: 20 years of distinction. Am J Physiol Endocrinol Metab 295:E242–E253. doi: 10.1152/ajpendo.90388.2008 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Squitieri F, Ciarmiello A (2010) Editorial: key role of nuclear medicine in seeking biomarkers of Huntington’s disease. Eur J Nucl Med Mol Imaging 37:1124–1127. doi: 10.1007/s00259-010-1439-8 CrossRefPubMedGoogle Scholar
  64. Sun L, Zeng X, Yan C et al (2012) Crystal structure of a bacterial homologue of glucose transporters GLUT1–4. Nature 490:361–366. doi: 10.1038/nature11524 CrossRefPubMedGoogle Scholar
  65. Vander Heiden MG, Plas DR, Rathmell JC et al (2001) Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol 21:5899–5912. doi: 10.1128/MCB.21.17.5899-5912.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Vannucci SJ, Maher F, Simpson IA (1997) Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia 21:2–21. doi: 10.1002/(SICI)1098-1136(199709)21:1<2:AID-GLIA2>3.0.CO;2-C CrossRefPubMedGoogle Scholar
  67. Vannucci SJ, Koehler-Stec EM, Li K et al (1998a) GLUT4 glucose transporter expression in rodent brain: effect of diabetes. Brain Res 797:1–11. doi: 10.1016/S0006-8993(98)00103-6 CrossRefPubMedGoogle Scholar
  68. Vannucci SJ, Reinhart R, Maher F et al (1998b) Alterations in GLUT1 and GLUT3 glucose transporter gene expression following unilateral hypoxia-ischemia in the immature rat brain. Brain Res Dev Brain Res 107:255–264. doi: 10.1016/S0165-3806(98)00021-2 CrossRefPubMedGoogle Scholar
  69. Wilhelm I, Fazakas C, Krizbai IA (2011) In vitro models of the blood–brain barrier. Acta Neurobiol Exp (Wars) 71:113–128Google Scholar
  70. Wisedchaisri G, Park M-S, Iadanza MG et al (2014) Proton-coupled sugar transport in the prototypical major facilitator superfamily protein XylE. Nat Commun 5:4521. doi: 10.1038/ncomms5521 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Wien 2017

Authors and Affiliations

  • Veronica Morea
    • 1
  • Eris Bidollari
    • 2
    • 3
  • Gianni Colotti
    • 1
  • Annarita Fiorillo
    • 1
  • Jessica Rosati
    • 3
  • Lidia De Filippis
    • 3
  • Ferdinando Squitieri
    • 4
    Email author
  • Andrea Ilari
    • 1
    Email author
  1. 1.National Research Council of Italy (CNR), Institute of Molecular Biology and Pathology c/o Department of Biochemical SciencesSapienza University of RomeRomeItaly
  2. 2.Department of Biochemical SciencesSapienza University of RomeRomeItaly
  3. 3.IRCCS Casa Sollievo della Sofferenza HospitalSan Giovanni RotondoItaly
  4. 4.Huntington and Rare Diseases UnitIRCCS Casa Sollievo della Sofferenza Hospital c/o Mendel Institute of Human GeneticsRomeItaly

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