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β-cell dysfunction in Huntington's disease

Bacos, Karl LU (2009) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2009:49.
Abstract
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... (More)
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. (Less)
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author
supervisor
opponent
  • Professor Aronin, Neil, University of Massachusetts Medical School
organization
publishing date
type
Thesis
publication status
published
subject
keywords
metabolism, secretion, Insulin, trafficking, R6/2 mouse, granule, exocytosis, neurodegeneration, huntingtin
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2009:49
pages
140 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Segerfalk lecture hall, Wallenberg Neuroscience Center, BMC, Sölvegatan 19, Lund
defense date
2009-05-08 13:00
ISSN
1652-8220
ISBN
978-91-86253-37-0
language
English
LU publication?
yes
id
8a1ce4ac-2af1-489d-bf49-343182e58139 (old id 1384176)
date added to LUP
2009-04-17 08:10:55
date last changed
2016-09-19 08:44:48
@phdthesis{8a1ce4ac-2af1-489d-bf49-343182e58139,
  abstract     = {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.<br/><br>
<br/><br>
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.},
  author       = {Bacos, Karl},
  isbn         = {978-91-86253-37-0},
  issn         = {1652-8220},
  keyword      = {metabolism,secretion,Insulin,trafficking,R6/2 mouse,granule,exocytosis,neurodegeneration,huntingtin},
  language     = {eng},
  pages        = {140},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {β-cell dysfunction in Huntington's disease},
  volume       = {2009:49},
  year         = {2009},
}