title: Systemic energy homeostasis in Huntington's disease patients.
abstract: BACKGROUND
  Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an increased number of CAG repeats in the HTT gene. Apart from neurological impairment, the disease is also accompanied by progressive weight loss, abnormalities in fat and glucose homeostasis and a higher prevalence of diabetes mellitus, the causes of which are unknown. Therefore, a detailed analysis of systemic energy homeostasis in HD patients in relation to disease characteristics was performed.
  
  
  METHODS
  Indirect calorimetry combined with a hyperinsulinaemic-euglycaemic clamp with stable isotopes ([6,6-2H2]-glucose and [2H5]- glycerol) was performed to assess energy expenditure and glucose and fat metabolism in nine early stage, medication free HD patients and nine age, sex and body mass index matched controls.
  
  
  RESULTS
  Compared with controls, fasting energy expenditure was higher in HD patients (1616 ± 72 vs 1883 ± 93 kcal/24 h, p=0.037) and increased even further after insulin stimulation (1667 ± 87 vs 2068 ± 122 kcal/24 h, p=0.016). During both basal and hyperinsulinaemic conditions, glucose and glycerol disposal rates, endogenous glucose production and hepatic insulin sensitivity were similar between HD patients and controls. In HD patients, energy expenditure increased with disease duration but not with a greater degree of motor or functional impairment. Moreover, a higher mutant CAG repeat size was associated with lower insulin sensitivity (r=-0.84, p=0.018).
  
  
  CONCLUSIONS
  These findings suggest sympathetic hyperactivity as an underlying mechanism of increased energy expenditure in HD, as well as peripheral polyglutamine length dependent interference of mutant huntingtin with insulin signalling that may become clinically relevant in carriers of mutations with large CAG repeat sizes.
authors: Department of Neurology, Leiden University Medical Centre, K-05-Q 110, PO Box 9600, Albinusdreef 2, Leiden 2300 RC, The Netherlands. n.a.aziz@lumc.nl
authors: N Ahmad
authors: NA
authors: Aziz
authors: Hanno
authors: H
authors: Pijl
authors: Marijke
authors: M
authors: Frölich
authors: Marieke
authors: M
authors: Snel
authors: Trea C M
authors: TC
authors: Streefland
authors: Ferdinand
authors: F
authors: Roelfsema
authors: Raymund A C
authors: RA
authors: Roos
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002153:Calorimetry, Indirect; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D005934:Glucagon / Q000097:blood; D015309:Glucose Clamp Technique; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D018911:Trinucleotide Repeats
chemical_list: D001786:Blood Glucose; C086055:HTT protein, human; D000071058:Huntingtin Protein; D007328:Insulin; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D005934:Glucagon