Reprogramming Alpha Cells To Fight DiabetesEditor's Choice
Main Category: Diabetes
Also Included In: Genetics
Article Date: 25 Feb 2013 - 0:00 PST
Reprogramming Alpha Cells To Fight Diabetes
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Rather than trying to reactivate the insulin-producing beta cells, researchers say that reprogramming the alpha cells into beta cells may be a better route to take in order to treat type 2 diabetes.
The scientists, from the Perelman School of Medicine, University of Pennsylvania, explained in the Journal of Clinical Investigation that they managed to treat human and mouse cells with compounds that altered the chromatin (cell nuclear material) in alpha cells so that they induced the expression of beta cell genes. Put simply, they managed to get the alpha cells, which exist in the pancreas alongside the beta cells, to behave like beta cells.
Insulin is produced by the beta cells in the Islets of Langerhans, in the pancreas.
Lead author Klaus H. Kaestner, Ph.D., professor of Genetics and member of the Institute of Diabetes, Obesity and Metabolism, said:
"This would be a win-win situation for diabetics - they would have more insulin-producing beta cells and there would be fewer glucagon-producing alpha cells."
Patients with type 2 diabetes have two problems (among others) relating to beta and alpha cells:
- They lack insulin (which beta cells produce)
- They produce too much glucagon (which the alpha cells produce)
In both types of diabetes - types 1 and 2 - there are not enough beta cells. In theory, transplanting beta cells should halt the disease in patients with type 1 diabetes (plus controlling immunosuppression). The problem is generating enough of these cells, either from embryonic stem cells or reprogramming mature cell types, in the laboratory. In a previous study published in Cell Reports in November 2012, Danish researchers found that in the laboratory beta cells can develop better from stem cells in 3D.
Glucagon, which elevates glucose levels in the blood, is synthesized by the alpha cells, another type of endocrine cell in the pancreas.
Treatment of human islets with the histone methyltransferase inhibitor Adox results in co-localization of the beta-cell specific transcription factor PDX1 (white) in a substantial sub-population of glucagon-positive cells (red), indicating partial endocrine cell-fate conversion
"We treated human islet cells with a chemical that inhibits a protein that puts methyl chemical groups on histones, which - among many other effects - leads to removal of some histone modifications that affect gene expression.
We then found a high frequency of alpha cells that expressed beta-cell markers, and even produced some insulin, after drug treatment."
Histones are complex proteins around which DNA strands are wrapped in the nucleus of a cell.
The scientists found that several of the genes in the alpha cells are marked by both activating- and repressing-histone modifications. Included were a large number of genes in beta-cell function. In one state, when a specific gene was switched off, it became readily activated by removing a modification that suppresses the histone.
Kaestner said "To some extent human alpha cells appear to be in a 'plastic' epigenetic state. We reasoned we might use that to reprogram alpha cells towards the beta-cell phenotype to produce these much-needed insulin-producing cells."
In an Abstract in the same journal, the authors concluded:
"Thus, mammalian pancreatic islet cells display cell-type - specific epigenomic plasticity, suggesting that epigenomic manipulation could provide a path to cell reprogramming and novel cell replacement-based therapies for diabetes."
The study was sponsored by the Beckman Research Center/NIDDK/Integrated Islet Distribution Program (10028044) and the National Institute of Diabetes and Digestive and Kidney Diseases (U01 DK070430, U42 RR006042, U01DK089529, R01DK088383, U01DK089569).
Not the first time alpha cells have been seen as potential beta cellsResearchers from the Max-Planck Institute for Biophysical Chemistry, Germany, the University of Göttingen in Germany, and the JDRF Center for Beta Cell Therapy in Diabetes, Belgium, talked about using glucagon-producing alpha cells and turning them into insulin-producing beta cells in a report in the journal Cell in August 2009.
They discovered that new insulin-producing beta cells in mice can be generated from alpha cells by modifying the expression of Pax4 (a gene) in alpha cells.
Written by Christian Nordqvist
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today
Nuria C. Bramswig, Logan J. Everett, Jonathan Schug, Craig Dorrell, Chengyang Liu, Yanping Luo, Philip R. Streeter, Ali Naji, Markus Grompe and Klaus H. Kaestner
J Clin Invest. Feb 2013. doi:10.1172/JCI66514.
20 May. 2013. <http://www.medicalnewstoday.com/articles/256820.php>
Please note: If no author information is provided, the source is cited instead.
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