It was nothing extraordinary: a mom sharing a digital photo of her 4-year-old daughter in a red-velvet dress, striking a ballet pose.
Yet to Melissa Bilotti, 35, and Michael Rickels, medical director of the Pancreatic Islet Cell Transplant Program at Penn Medicine, the moment was anything but ordinary.
During her teens and 20s, Bilotti’s frequent episodes of hypoglycemia, or low blood sugars, due to type 1 diabetes had led to severe episodes that left her passed out, cold.
Typically, hypoglycemia is accompanied by symptoms such as tremors, sweating and heart palpitations that prompt people to eat or drink to raise their blood sugar levels. But Bilotti is among those who do not experience these early warning signs, putting her at even greater risk.
“I remember waking with my head pounding, tears running down my face, looking up at an EMT,” said Bilotti, who lives in the Allentown area, where she works as a pipeline scheduler. “I want you to listen to me,” the EMT said. “My partner and I responded to a call like this a week ago. Another young type 1 diabetic with a blood sugar of 27. Yours is 18. That person didn’t make it.’ ”
“That will stay with me forever,” said Bilotti.
Worried about getting the disease under control, Bilotti opted for an experimental pancreatic islet transplantation at the Hospital of the University of Pennsylvania seven years ago.
In a healthy person, islets in the pancreas contain beta cells that produce insulin to fight high blood sugars and alpha cells that manufacture glucagon, which counteracts low sugars.
But in people with type 1 diabetes, the immune system destroys beta cells, so patients must inject insulin. Meanwhile, alpha cells do not function normally, leaving patients vulnerable to hypoglycemia.
In 2004, Penn became one of five federally sponsored centers to run a Phase 3 clinical trial of pancreatic islet transplantation – instead of whole pancreas transplants -- for people with complicated diabetes who couldn’t sense their own hypoglycemia.
“A pancreas transplant has many issues, including major surgery and prolonged hospitalization,” said Ali Naji, director of the Pancreatic Islet Cell Transplantation Program, the leader of the Penn trial who performed Bilotti’s procedure. “This way there is no surgery, no incision, only a 20- to 25-minute infusion of islets into the liver.”
During an islet transplantation, specific cells from a deceased donor’s pancreas are separated from other digestive enzyme portions of the organ, and the highly purified human islets containing new beta and alpha cells are infused into the recipient’s liver. The cells immediately begin to produce insulin and glucagon and normal glucose metabolism, including sensitivity to hypoglycemia, is restored.
To prevent rejection of the foreign islets, patients must take immunosuppressant drugs that have the potential to cause adverse side effects. While this currently limits the number of type 1s eligible for islet transplant, with careful patient selection, most tolerate immunosuppression without long-term problems, said Rickels.
For patients such as Bilotti, who experience life-threatening hypoglycemia, Rickels called the islet transplant a “trade-off” between risks posed by immunosuppressant drugs and the benefits of eliminating hypoglycemia and stabilizing blood glucose levels.
“A major focus of current research is how to induce immunologic tolerance [where the body would not attack the foreign islets] in patients’ who have received a transplant,” said Naji.
After reading an article about a Minnesota man who had received an experimental pancreatic islet transplantation, Bilotti found that her research eventually led her to Penn’s program. On March 31, 2011, she received her infusion.
Today, Bilotti no longer requires injected insulin and is aware of even slight drops in her blood sugar. Her most recent A1C, a test that measures the three-month range of blood sugars, is a normal 5.4.
Of the 11 patients in the Penn trial who received transplantations between 2008 and 2014, seven were able to stop insulin after the first transplant while the remaining four stopped the hormone following a second transplant. More than half have remained off insulin for five or more years, with the first transplant patient insulin-free for 10 years.
“The next step is to make islet transplantation the standard of care for certain difficult cases of type 1 diabetes,” Naji said. “Right now, based on our successful trials, we are applying to receive a biologic license application from the FDA, which will allow us to do the transplant at Penn and have insurance companies pay for it."
While pancreatic islet transplantation is not generally available in the U.S., it is in Canada, Australia and several countries in Europe. This can be attributed to very different regulatory environments “where they have national health-care systems and where islets are treated like other transplanted organs, rather than manufactured biologic products, as is the case in the U.S.,” Rickels said.
Four years ago, Bilotti, newly married, wanted to start a family. But when she entered the study, she had signed an agreement not to become pregnant during the course of the program so researchers could see whether there were long-term complications from the procedure and that the new islets remained functional. After petitioning the National Institutes of Health, which funded the study and refused to revoke the agreement, Bilotti had to leave the trial.
“That doesn't mean we stop caring for you,” Naji said, “but you are not in the clinical islet transplantation program as funded and recorded by the NIH.”
After consulting with experts around the world, her endocrinologists reduced her immunosuppressant drugs and put her on insulin to deal with the increased stress that pregnancy placed on her metabolism and the new islets.
“One of the amazing things was that she was able to do so well on reduced immunosuppressants,” Naji said. “Insulin gave her a helping hand but after the baby was born, she immediately was able to go off.”
Two years later, she gave birth to a second healthy little girl.
To Rickels, Bilotti is a “superstar.”
“It takes enormous courage to participate in experimental therapy and then a second dose of courage to become pregnant,” said Rickels. “It was one of the most rewarding outcomes we’ve seen from this program.”
Bilotti puts it more simply: “I got my life back.”