Systemic energy homeostasis in Huntington's disease patients
Résumé
Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an increased number of CAG repeats in the 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, we aimed to perform a detailed analysis of systemic energy homeostasis in HD patients in relation to disease characteristics. Indirect calorimetry combined with a hyperinsulinemic-euglycemic 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. Compared with controls, fasting energy expenditure was higher in HD patients (1616±72 vs. 1883±93kCal/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 hyperinsulinemic 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). 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 signaling that may become clinically relevant in carriers of mutations with large CAG repeat sizes.
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