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D04 Blood glucose and insulin levels following an oral glucose challenge are promising biomarkers in the zQ175 knock-in mouse model of huntington’s disease
  1. An Tanghe,
  2. Lentel Pringels,
  3. Tom Vandooren,
  4. Gerard Griffioen
  1. rMYND nv, Heverlee, Belgium


Background The neurological impairments that typify Huntington’s disease (HD) are caused by neurotoxic effects of mutant Huntingtin in striatum and cerebral cortex. Huntington patients however also suffer from non-motor symptoms, including metabolic alterations. Interestingly, the latter symptoms typically set on several years before the motor symptoms. Dysfunction of the hypothalamus, the brain part that controls energy balance by integrating both central and peripheral signals, is postulated to be at least partly responsible for these non-motor symptoms, in mice and humans (Hult et al., 2011; Petersén and Björkvqvist, 2006).

Aim We set out to explore the potential of metabolic parameters as biomarkers and surrogate endpoints for assessing the efficacy of experimental Huntington therapies in the zQ175 knock-in mouse model.

Method The zQ175 model faithfully recapitulates many of the clinical phenotypes of HD in the absence of overexpression artefacts (Menalled et al., 2021). We subjected these mice to an oral glucose tolerance test (OGTT), entailing the measurement of blood glucose levels and insulin secretion levels at different time-points post oral glucose administration.

Result When challenged with glucose in an OGTT, zQ175 mice show prolonged blood glucose levels and lower insulin secretion levels compared to wild type controls. In homozygous mice these deficits were observed at younger age than in heterozygous mice, in line with the more aggressive progression of pathology development. Deregulation of glucose metabolism is also manifest from the observation that the zQ175 mice drink more than control mice.

Conclusion These metabolic parameters entail clinically compliant read-outs for diagnostic purposes of disease onset and progression in carriers with extended CAG repeat Huntingtin, as well as surrogate endpoints to assess therapies both in preclinical models and subsequently in patients aimed at countering neuronal toxicity of pathological Huntingtin.

  • zQ175 knock-in model
  • drug development
  • preclinical testing
  • metabolism
  • biomarker
  • glucose
  • insulin

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