Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

β-cell dysfunction in Huntington's disease

Author

  • Karl Bacos

Summary, in English

Huntington's disease (HD), a fatal neurodegenerative disorder, is associated with an increased risk of diabetes mellitus. The reason for this is unknown, but considering the functional similarities of neurons and the insulin secreting pancreatic β-cell, pathological mechanisms may be shared by both cell types and account for neuronal as well as endocrine dysfunction. Hence, finding the mechanisms behind β-cell dysfunction in HD could identify potential therapeutic targets for the neuronal disease.



Upon characterization of the R6/2 mouse model we found that mutant huntingtin renders β-cells replication-deficient. This results in a reduced β-cell mass in R6/2 compared to WT mice. In addition, islet insulin content is reduced and a dramatic degranulation of β-cells is evident. As a consequence, insulin secretion is severely blunted and R6/2 mice become glucose intolerant. In our present studies we could, however, not find any morphological alterations in pancreatic sections from HD patients. Thus, what pathogenetic defects that underlie the secretory deficiency evident in HD patients remain to be resolved. In an effort to identify such defects we created an in vitro model of the HD β-cell and found that glucose-stimulated insulin secretion is significantly blunted by mutant huntingtin. Because metabolic perturbations have been identified in HD and are a possible cause of the secretory defect, we investigated cellular metabolism. However, we found glucose oxidation and mitochondrial respiration, as well as expression levels of metabolic enzymes, unaltered. This suggests that metabolic aberrations do not contribute to cell dysfunction in our model. Next we analyzed vesicular trafficking as this has been found aberrant in HD and is vital for sustained insulin release. These studies showed that the transport of insulin granules along microtubule filaments is perturbed. Furthermore, we found that mutant huntingtin interacts aberrantly with β-tubulin. Therefore we hypothesize that mutant huntingtin acts as a physical block for vesicular transport. This mechanism is likely not specific for β-cells and might therefore contribute to the trafficking defects seen in neurons. Thus, attenuating the huntingtin/β-tubulin interaction may have beneficial effects in HD patients.

Department/s

  • Department of Experimental Medical Science

Publishing year

2009

Language

English

Publication/Series

Lund University Faculty of Medicine Doctoral Dissertation Series

Volume

2009:49

Document type

Dissertation

Publisher

Department of Clinical Sciences, Lund University

Topic

  • Endocrinology and Diabetes

Keywords

  • metabolism
  • secretion
  • Insulin
  • trafficking
  • R6/2 mouse
  • granule
  • exocytosis
  • neurodegeneration
  • huntingtin

Status

Published

Supervisor

  • Hindrik Mulder
  • Patrik Brundin

ISBN/ISSN/Other

  • ISSN: 1652-8220
  • ISBN: 978-91-86253-37-0

Defence date

8 May 2009

Defence time

13:00

Defence place

Segerfalk lecture hall, Wallenberg Neuroscience Center, BMC, Sölvegatan 19, Lund

Opponent

  • Neil Aronin (Professor)