Long Trail Leads to New Ideas for Diabetes Therapy
HHMI scientists have identified a cellular pathway that may be key to sparking growth of pancreatic beta cells in mice and humans.
Diabetes researchers have been stymied for years in their efforts to develop a more complete understanding of what regulates the growth of the islet beta cells in the pancreas that produce insulin. When these cells die, their disappearance prevents the body from keeping blood sugar levels under control. To date, no one has figured out how to jumpstart the growth of new beta cells.
Now, new research by Howard Hughes Medical Institute scientists has identified a cellular pathway that may be key to sparking growth of pancreatic beta cells in mice and humans—a long-sought goal for the treatment of diabetes.
In research published in an advance online publication in the journal Nature, Howard Hughes Medical Institute (HHMI) investigator Seung K. Kim and his colleagues describe a cellular signaling pathway that reveals why it’s been so hard to prompt regrowth of beta cells. “We found a pathway that links signaling from the cell surface all the way into the nucleus,” says Kim, who is also a developmental biologist at Stanford University. “This pathway was previously unrecognized as a regulator of gene expression that controls various aspects of beta-cell growth.”
If you can stimulate beta cells to re-express the receptor in adults, then you could conceive of trying to stimulate those cells to grow.
Seung K. Kim
Kim, who has an interest in pancreatic cancer and pancreas evolution, discovered some years ago that fruit flies have cells equivalent to those of human pancreas islets. His group demonstrated that those endocrine cells in fruit flies work the same way as human islet cells—they respond to glucose, measure its levels, and produce molecules like glucagon and insulin, hormones that regulate metabolism. Before Kim's discoveries, scientists did not know if fruit flies had the equivalent of a pancreas—but his findings provide evidence that evolution has used, preserved, and refined the molecular regulators that control metabolism and growth from insects to humans.
Prior research had shown that beta cells’ ability to expand declines in both mice and humans as they age, but it remained unclear why that was the case. So Kim—whose research moves easily between fly, mouse, and human cells—began to hunt down the cause. Like peeling back the layers of an onion, one piece of the signaling cascade at a time, they found that the problem can be traced to a receptor on the beta-cells’ surface that disappears as an animal gets older.
“The loss of that receptor is an important feature that’s programmed as you age, and may underlie the decline of beta-cell proliferation that you normally see,” Kim says.
To test this theory, first the researchers created mice in which they could deactivate the receptors, known as platelet-derived growth factor (PDGF) receptors. When they prematurely deactivated them in three-week old mice—which would normally be experiencing beta-cell expansion to keep up with their growing bodies —they found that the mice developed mild diabetes. Then, Kim and his colleagues went in the opposite direction. They activated the pathway in older mice, up to 14 months of age, which had lost their ability to grow new beta cells. But on activation, their beta cells began growing as they would in a two-month old mouse.
“This told us that activating the pathway might overcome normal restrictions imposed by aging,” Kim says. More significantly, the expanded beta cells didn’t cause the mice to lose control of insulin regulation and become hypoglycemic. “That’s important. Because you don’t want the additional beta cells to lose control of key functions. And even though there were more of them, these beta cells managed to modulate their function appropriately—according to the requirements of the animal,” he says.
If researchers can find a way to stimulate the expansion of beta cells in people, the cells should ultimately be able to self-regulate according to the body’s own needs. So Kim delved further into the molecular pathway. “We were trying to understand what regulates a regulator of a regulator,” he says. He found that once the PDGF receptor is activated, it triggered production of one molecule—called Ezh2—that controls regulation of another molecule—called p16INK4a—that regulates beta-cell proliferation. When they looked for similar markers of the signaling pathway in pancreatic cells from juvenile and adult human donors, they found that the fundamental features remained the same. “This starts to unify ideas and observations that haven’t yet been linked into a model of how beta cells control their growth,” Kim says.
Insights about pancreatic development and growth may also help expose new treatments for endocrine cancers of the pancreas and other tissues, says Kim, who has trained as a developmental biologist, internist, and oncologist. Knowledge gained from studies of regenerating cells could be exploited to treat cancers. "On the one hand we're trying to figure out how to grow cells, and on the other hand we're trying to figure out how to kill them."
Kim is now working to understand better what regulates the age-dependent change in PDGF receptors. Such knowledge could ultimately help lead to therapies for diabetes if beta-cell destruction was suppressed early enough, before the beta cell population had disappeared completely. “You could imagine a one-two punch: If you can stimulate beta cells to re-express the receptor in adults, then you could conceive of trying to stimulate those cells to grow.”
Not only that, but if they can find the native pathways that regulates the loss of PDGF receptors, Kim hopes that it would be helpful for the oncology field, too, as something that could be employed to stop uncontrolled cancer growth. “We’re hopeful this will also help explorations of targeted therapies for endocrine and neuroendocrine tumors,” Kim says.