New insight into how an old TB vaccine lowers blood sugar in Type 1 diabetes

Last summer, a team of scientists at Massachusetts General Hospital presented evidence showing that the tuberculosis vaccine bacillus Calmette-Guérin (BCG) restores beneficial immune cells in a way that could help treat Type 1 diabetes. Now the team is building on that base of research with strong data indicating that two doses of the vaccine restore blood sugar to near-normal levels for as long as eight years—and they're providing more insight into how the improvement happens.

During a small phase 1 study in 52 people with Type 1 diabetes, the MGH researchers found that two doses of BCG given four weeks apart produced improvements in blood sugar, even among people who had suffered from the disease for many years before getting the vaccine. In the new paper, they explain that the benefits come from a novel metabolic process that increases the amount of glucose consumed by cells. They published their findings in the journal NPJ Vaccines.

"BCG not only resets the immune response at the DNA level, but it also resets the metabolism for high sugar elimination," said principal investigator and senior author Denise Faustman, M.D., Ph.D., director of the MGH Immunobiology Laboratory, in an interview with FierceBiotechResearch.

The MGH team initially became interested in studying BCG in diabetes because of its ability to boost the body’s production of tumor necrosis factor (TNF), a protein that helps eliminate wayward immune cells that destroy insulin-producing pancreatic islets. Animal studies and early research in people suggested the vaccine worked, but the researchers weren’t quite sure how.

Last year, they showed that BCG restores regulatory T cells, or Tregs, by permanently switching on certain genes. That’s important, because Tregs have the ability to stop the destruction of pancreatic islets.

During the new study, Faustman and her team observed that BCG administration also shifts glucose metabolism from "oxidative phosphorylation," the most common way for cells to convert glucose to energy, to "aerobic glycolysis," a process in which cells consume much larger amounts of glucose. They made the discovery by scrutinizing DNA and RNA collected from patients during the study.

"When you flip to aerobic glycolysis, cells like lymphocytes use 10 to 20 times more sugar," Faustman said.

MGH has raised more than $20 million to fund its BCG research in diabetes, all of which has come from foundations interested in fostering a therapy that has already been proven to be safe and that is available as an inexpensive generic. One of the team’s biggest supporters is retired Chrysler CEO Lee Iacocca’s family foundation.

MGH is now about halfway through a five-year phase 2 study of BCG in 150 diabetes patients, Faustman said. The study is randomized and placebo-controlled, and all of the patients have had the disease for many years, as was the case in the phase 1.

What's significant about that, Faustman said, is that it's long been believed that reversing the course of diabetes many years after diagnosis is impossible. "Up until now all immune-based trials in diabetes have involved patients with newly diagnosed disease," she said. "Nobody thought you could intervene with an immunotherapy in people 10, 20 years out. To have data showing durability for 8 years, without revaccination, is remarkable."

The MGH researchers plan to present additional data from the phase 1 trial on Saturday at the 78th Scientific Sessions of the American Diabetes Association in Orlando, Florida.