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Beta Cells Turn Younger, Not Older, During Type II Diabetes

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By Anette Breindl
Science Editor

In findings that, in the opinion of senior author Domenico Accili, turn the current approach to treating Type II diabetes on its head, researchers at Columbia University have discovered that in Type II diabetes, the insulin-producing pancreatic beta cells whose failure is at the core of the disease do not die. Quite the opposite: They become more stem cell-like.

That's the conclusion that Accili, who is at Columbia University, and his colleagues reached after performing lineage tracing studies on pancreatic beta cells in mouse models of Type II diabetes.

"It is remarkable that during a disease process such as Type II diabetes, cells lose their specialized properties and become more stem-like," Accili told BioWorld Today. "It's known in a culture dish. But that it happens in an animal during a disease state is novel. . . . I'm not sure there is any precedent for it."

In fact, the findings, which appeared in the Sept. 13, 2012, issue of Cell, are pretty much the opposite of what the team expected when they started their tracing studies.

The work was part of a study on the transcription factor FOXO1, which Accili described as an "overarching interest" of his research.

"What we were trying to demonstrate was that it is important for the sensing of nutrients – how cells behave when there are sugars and lipids around," Accili said.

Normally, FOXO1 is inactive when nutrients are present. But when cells are stressed through rapid changes in nutrient levels – as is often the case during the stage that precedes outright diabetes – FOXO1 first becomes activated, but ultimately is silenced.

Accili and his team wanted to see whether those changes in FOXO1 activity were a cause, or a consequence, of diabetes, and so they first looked at FOXO1 knockout mice. Such animals became extremely sensitive to cellular stress and were more likely than controls to develop diabetes during pregnancy and as they aged.

Those findings showed that changes in FOXO1 expression are a cause of diabetes and not just one of its symptoms. But the real surprise came when the team performed lineage tracing studies to see what happened to pancreatic beta cells. Specifically, they wanted to see whether pancreatic beta cells died during diabetes – which was Accili's hunch – or whether they simply became less functional.

"We were expecting cell death," Accili said. Instead, the pancreatic beta cells "were still alive. But they had lost all the properties that allow us to call a beta cell a beta cell" – most notably, they no longer produced insulin.

That, he added, led naturally to the next question: "If they are not beta cells, what are they?"

The answer was twofold. Many of the pancreatic beta cells started expressing markers of stem and progenitor cells. Some of those progenitor cells, in turn, went over to the dark side altogether. They ultimately turned into glucagon-producing alpha cells, a cell type that raises blood sugar. The last two diabetes drugs approved by the FDA, Accili noted, target glucagon production rather than focusing on insulin.

For now, the findings are in the realm of basic research. But they do, Accili said, basically imply that the current treatment of diabetes is exactly backward.

Rather than trying to "flog" beta cells into producing more insulin, he said, treatments should aim at "giving beta cells a rest" to allow them to recover rather than doing the cellular equivalent of curling up in the fetal position. Such a change in strategy, he said, would be "a real sea change."

Accili and his team currently are investigating whether the same process of beta cell de-differentiation takes place in humans. If it does, then longer term, a possible treatment option might be to coax progenitor cells back into beta cell status. Looking on the bright side, the fact that beta cells can turn into alpha cells via a less differentiated intermediate, he said, shows that "progenitor cells retain the ability to give rise to a fully differentiated cell. It's just not the one we wanted" – at least for the time being.