The Problem of Not Enough Beta Cells in Type 1 Diabetes
Susan Bonner-Weir, Ph.D.
Joslin researchers lead in pursuing several strategies to replenish the insulin-producing beta cells destroyed in the disease
Here’s how it’s supposed to work: Sprinkled throughout the pancreas, tiny collections of beta cells generate the small amount of insulin needed each day, with their production exquisitely calibrated minute-by-minute with blood glucose levels.
But in type 1 diabetes, an autoimmune attack seeks and destroys these important but fragile cells.
Joslin scientists are leading the way in the quickly advancing research to find new sources for beta cells—including “progenitor” cells located in the pancreas that can morph into beta cells—and to develop innovative ways to make more copies of surviving cells.
Just as critical are efforts to ensure that any newly formed beta cells are fully functional and that they can survive the ordeal of transplantation.
An alternate source?
Susan Bonner-Weir, Ph.D., and her colleagues have amassed evidence of an important potential source of new beta cells within the pancreas. Her lab showed that in rats and mice that are neonatal or have had pancreatic injury, cells in the nearby pancreatic ducts, which act like pipes for digestive enzymes, can differentiate into beta cells and the other pancreatic cells.
“But which cell in the duct tree is the progenitor?” Dr. Bonner-Weir asks. Working with both mice and human cells, her lab is puzzling out exactly which cells can switch, and what signals those cells to make the transition and then proliferate.
Gordon Weir, M.D., looks at the replication of existing adult human beta cells. In one effort funded by the Juvenile Diabetes Research Foundation, he experiments with human islets that are transplanted into mice whose immune systems have been shut down, examining potential ways to make them divide more quickly. “This is the only way you really can look at human tissue in an in vivo situation,” he explains.
The lab of Rohit Kulkarni, M.D., Ph.D., creates genetically engineered mouse models that help to understand beta-cell regeneration issues related to both type 1 and type 2 diabetes, particularly looking at the replication of surviving cells. “We can clearly show that beta-cell replication occurs in diet-induced obesity and pregnancy in mice,” Dr. Kulkarni says. “That’s why we pursue the strategy of replication, because if it’s happening naturally, we can target that to push it up.”
Growing in maturity
Both Dr. Kulkarni and the team of Arun Sharma, Ph.D., and Dr. Bonner-Weir work on the issues involved in making replacement beta cells fully functional—able to release sufficient amounts of insulin when prompted by glucose in the blood.
“Insulin-producing cells must go through several steps, which eventually result in a mature glucose-responsive beta cell,” notes Dr. Sharma. His work has shown that a protein known as MafA, a transcription factor (master gene regulator), regulates the ability of beta cells to produce insulin in response to glucose. In newborn mice and diabetic mice, levels of MafA activity are much lower than in adult mice, but if the scientists boost MafA levels in these mice, they can kick-start the production of insulin in response to glucose.
Dr. Kulkarni works in collaboration with SysCODE (the System-based Consortium for Organ Design and Engineering), systematically sweeping through all the genes and proteins that may be important in beta-cell maturation from embryonic to newborn to adult stages. “We’ve come up with some very interesting candidates that may help to get a much better beta cell that can secrete more insulin in response to glucose,” he says.
In parallel, Dr. Kulkarni is working to derive insulin-secreting cells by engineering skin cells obtained from patients with type 2 diabetes. “This approach will allow accelerating therapies on an individualized basis for patients with type 2 diabetes who have no autoimmune problems,” he says.
Overall, Joslin continues to be a major driver in the quest to find a suitable source of beta cells and to eventually cure type 1 diabetes.
“I won’t tell you that a cure will happen next year, because the challenges are difficult and there are always surprises,” says Dr. Weir. “But we know where we need to go, and we’ve got to be impressed by these kinds of advances.”
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Answers in a capsule
For decades, type 1 diabetes researchers have struggled to package pancreatic islets containing beta cells and other hormone-producing cells within a membrane so that they are guarded against autoimmune attack after transplants.
“Encapsulation continues to be a maddening and attractive concept,” says Dr. Gordon Weir. “You lock the cells up in a membrane that screens out the cells that attack the islets, and yet the holes are big enough that nutrients and oxygen get in perfectly well, and insulin gets out.”
Today, the Weir lab has high hopes for its joint work with the lab of Massachusetts Institute of Technology’s Drs. Robert Langer and Dan Anderson, testing innovative capsules (above) built of materials derived from seaweed using nanotechnology engineering.