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Mechanism provides clues for research into pancreatic diabetes

August 28, 2012
Basque Research
Mice develop pancreatic diabetes when they lack certain genes in the E2F group, and to understand how this happens, scientists have focused on the molecular mechanism behind it.

Mice develop pancreatic diabetes (type 3c) when they lack certain genes in the E2F group, and to understand how this happens, Olatz Zenarruzabeitia has focussed on the molecular mechanism behind it. This researcher works at the laboratory of Ana Zubiaga, Professor of Genetics of the University of the Basque Country (UPV/EHU); this was where an article that appeared in the journal Nature in 2010 on this line of research was published.

The keys in this process have now been described, and using them as a basis it has been possible to prevent mice lacking these E2F genes from developing pancreatic diabetes. In fact, 8 or 9 % of the diabetes suffered by humans belongs to this type, and so this mechanism could be used as a model in the long term for creating therapies. Zenarruzabeitia has defended her thesis dealing with these results under the title Mecanismos moleculares implicados en la homeostasis tisular: papel del eje E2F-p53 (Molecular mechanisms involved in tissue homeostasis: role of the E2F-p53 axis).

The E2F1 and E2F2 genes (belonging to the E2F group) play key roles in tissue homeostasis; or, to put it another way, in properly maintaining organs. They regulate cell proliferation which is indispensable for preventing alterations in homeostasis. As Zenarruzabeitia explains, in the specific case of pancreatic homeostasis, the damage caused by the lack of activity of or presence of these two factors is already known: "A few years ago we removed E2F1 and E2F2 from mice, and we saw that this led to pancreatic atrophy, the development of diabetes and premature death. In the current work, we have gone further into the molecular mechanism that explains this."

Not enough E2F, too much p53

When E2F1 and E2F2 are missing, the DNA replicates more than it should. Zenarruzabeitia has described the mechanism in depth; she has observed that this over-replication damages the DNA and the p53 gene pathway is activated; in other words, causing it to express itself more. That is the crux of the matter, since this gene leads to programmed cell death (apoptosis), and the appearance of alterations here is very damaging. As the researcher explains, in this case, "p53 is more active, which leads to the overexpression of the proteins involved in apoptosis. That is when pancreatic atrophy followed by diabetes occurs." So the lack of E2F1 and E2F2 combined with the gene p53 has much to do with the development of pancreatic diabetes, as confirmed in mice.

In this respect, Zenarruzabeitia has sought a model to prevent pancreatic diabetes appearing by also removing p53 from the mice already lacking E2F1 and E2F2: "We crossed mice that did not have E2F1 or E2F2 with others lacking p53, and that way we obtained mice that did not have any of the three. We saw that as they did not have p53, the pathway could not be activated. So there was no pancreatic atrophy and they didn't develop diabetes, either."

Despite having described the molecular mechanism only for the case of the pancreas, the results obtained also affect other organs. In fact, apoptosis is not restricted to the pancreas of mice lacking E2F1 and E2F2: "For example, they also suffer damage to the salivary gland and the testicles, and when p53 is de-activated, these organs also recover. We have seen that the atrophy recedes, since the weight and histology of the organ recover."

The description produced with respect to this mechanism in mice may also be of use in researching the same thing in humans. What is more, as Zenarruzabeitia points out, more and more cases of human diabetes (8-9 %) are linked to the loss in pancreatic mass, in other words, to type 3c diabetes. "The mechanism is not known; it is possible that what we have described in mice also occurs in humans. It could be a good model to go on studying this type of diabetes, which is seen more and more in humans." This model could be used to implement research that could help to gain a better understanding not only of 3c diabetes itself, but also of the disorders linked to pancreatic degeneration, so that, in the long term, the possibility of designing therapies based on E2F factor biology could come about.

Story Source:

The above story is based on materials provided by Basque Research. Note: Materials may be edited for content and length.

Cite This Page:

Basque Research. "Mechanism provides clues for research into pancreatic diabetes." ScienceDaily. ScienceDaily, 28 August 2012. <www.sciencedaily.com/releases/2012/08/120828093234.htm>.
Basque Research. (2012, August 28). Mechanism provides clues for research into pancreatic diabetes. ScienceDaily. Retrieved August 28, 2014 from www.sciencedaily.com/releases/2012/08/120828093234.htm
Basque Research. "Mechanism provides clues for research into pancreatic diabetes." ScienceDaily. www.sciencedaily.com/releases/2012/08/120828093234.htm (accessed August 28, 2014).

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