Millions of people with type 1 or 2 diabetes worldwide rely on insulin injections or medications to keep their blood sugar in check. The disease results from the destruction of the pancreas’s finite number of beta cells—the body’s only source of insulin. But what if there were a way to regrow these insulin-producing cells so people with diabetes could make the hormone on their own again? Scientists have discovered a possible drug recipe that robustly replenishes that stock of beta cells—with the help of new blockbuster obesity drugs such as Ozempic and a natural psychoactive compound.
A study published this month in Science Translational Medicine reported that combining a hallucinogenic drug called harmine—one of several compounds found in the psychedelic drink ayahuasca—with one of the new weight-loss medications can increase the number of human insulin-producing cells by approximately 700 percent. The researchers took living, or in vivo, human beta cells and transplanted them into the kidneys of diabetic and nondiabetic mice. After treating the animals for three months with both drugs, insulin production increased, blood glucose levels stabilized and the beta cell mass—the total number of cells—increased. What’s more, the newly grown beta cells were preserved one month after stopping treatment. The findings are a promising step but still need to be replicated in human trials.
“This work really rigorously attacked in a number of different ways whether or not you can treat human beta cells in vivo and get them to [expand in number],” says endocrinologist Justin P. Annes, an associate professor of medicine at Stanford University, who investigates beta cell regeneration but was not involved in the study. “I think regenerative medicine for diabetes has the potential to really revolutionize care and is a very important area for us to continue to pursue.”
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Most insulin-producing cells develop when we’re babies and are largely the only ones we’ll carry throughout life, explains study co-author Andrew F. Stewart, scientific director of the Diabetes, Obesity, and Metabolism Institute at the Icahn School of Medicine at Mount Sinai. Accepted scientific wisdom says that “once they’re made, they’re never made again,” he notes.
This limited bank of beta cells is particularly precarious for people with diabetes. In those with type 2 diabetes, beta cells become dysfunctional or less effective at producing insulin over time; type 1 diabetes is an autoimmune disease in which the body attacks beta cells. Harmine is one of the few compounds that can replenish human beta cells. This plant-based ingredient is commonly used in ayahuasca, a spiritual drink long used by Indigenous groups in South America.
Stewart’s lab first showed harmine’s effects on beta cells in 2015. The drug works by blocking an enzyme that stops cell replication called dual-specificity tyrosine-regulated kinase-1a (DYRK1A). Harmine essentially allows the replication switch to stay on and produce more beta cells, but using the drug alone grows new beta cells at levels too low to help most people with diabetes, Stewart says. He and his colleagues have tried to enhance harmine’s effects by pairing it with other drugs, including the widely used diabetes and weight-loss medications Ozempic, Wegovy, Mounjaro and Zepbound.
These drugs, which mimic the gut hormone glucagon-like peptide-1 (GLP-1), can help treat those with type 2 diabetes by stimulating the production of insulin and improving the function of beta cells. Early experiments showed that GLP-1 drugs can also increase beta cell replication in young mice. “Everybody was so happy thinking these drugs [were] going to increase proliferation and regeneration, in addition to increasing insulin secretion,” says Adolfo Garcia-Ocaña, a co-author of the study and chair of the Department of Molecular & Cellular Endocrinology at City of Hope’s location in Duarte, Calif. But scientists were disappointed when they didn’t see the same results in adult human beta cells, he says.
Garcia-Ocaña, Stewart and their colleagues found in 2020 that pairing harmine with various GLP-1 drugs—including semaglutide (Ozempic and Wegovy) and liraglutide (Victoza and Saxenda)—had the potential to increase the number of human beta cells.
In the new study, the researchers transplanted grafts of living human pancreatic islets (cell clusters containing beta cells) into the kidneys of diabetic and nondiabetic mice. They then administered harmine and exendin-4, a naturally occurring version of the GLP-1 drug exenatide, through an implanted mini pump. At the end of the study period, they surgically removed the kidneys and used three-dimensional imaging techniques to measure the amount of beta cell growth. The drug combination of harmine and exendin-4 resulted in a beta cell mass that was higher than either drug alone and, in the diabetic mice, approximately seven times greater than the control treatment of water.
The drug treatment also quickly lowered and stabilized blood glucose levels and increased insulin approximately by a factor of four. This suggests two good things, Stewart says: “Near immediate improvement in beta cell function and slow but steady increase in beta cell numbers.” Additionally, the team monitored the nondiabetic mice for one month after stopping treatment and found that the beta cell mass did not change—in other words, the cells survived.
“The durability of the mass expansion and the potential ability to reverse diabetes, I think, is really an impressively done piece of work,” Annes says. The treatment helped, but it’s unclear if regeneration of new beta cells or improved function of existing ones played a bigger role, he adds. Longer-term studies are needed to tease out the full effects.
The team is still investigating the exact mechanisms behind the study’s results. Garcia-Ocaña suggests GLP-1 drugs may increase important signaling molecules involved in activating cell replication. Harmine removes the brakes on cell replication, and GLP-1 may be further helping kick the process into gear, he explains.
The study researchers hope their regeneration technique could lead to a new diabetes treatment that might be more accessible compared with existing therapies such as human islet cell transplants or whole pancreas transplants. But human clinical trials need to test its safety and tolerability, Garcia-Ocaña and Stewart say.
Stewart’s group at Mount Sinai is currently wrapping up a phase 1 clinical trial to see how well healthy people can tolerate different dosages of harmine, which, in some forms, can cause hallucinogenic effects, as well as nausea, vomiting and diarrhea. Utilizing drugs that promote cell proliferation also raises concerns about whether unwanted cell growth could increase the risk of cancer. DYRK1A inhibitors such as harmine can affect other tissues in the body if they are not designed to target specific cells. The recently published study, however, found the treatment did not increase the number of alpha cells, another cell type in pancreatic islets, which is a promising sign that the effects were targeted, Annes says. The researchers also found that using a more selective and potent form of harmine at a lower dose still increased beta cell mass four- to fivefold.
The slow cell division speeds seen in the study offer another layer of safety but don’t explain how the treatment achieved such a robust increase in beta cell mass. “How do you get so many more cells if you’re not really dividing that fast?” Annes says. One possibility, he suggests, could be that the treatment is causing existing nonbeta cells to change into beta cells.
Clinical trials are also needed to see if the treatment works in humans and which people would benefit most. Laura C. Alonso, chief of the Division of Endocrinology, Diabetes and Metabolism at NewYork-Presbyterian/Weill Cornell Medical Center and director of the Weill Center for Metabolic Health, says that the drugs may be “a very interesting combination” for some people with type 2 diabetes and obesity but that people with type 1 diabetes have a much smaller set of beta cells to work with. They would have to grow a huge amount of beta cells to meaningfully increase their capacity for secreting insulin, says Alonso, who was not involved in the new study. “I would posit that the immune system can destroy them faster than we can make them [through this process],” she adds.
The regenerative technique would need to be combined with therapies that tweak the immune system, Garcia-Ocaña says. “We have found the faucet, and we can open it and regenerate beta cells, but if we don’t put a stopper in the sink, then we’re not going to get anything,” he says. He’s working with other researchers at City of Hope to develop immunotherapies, such as treatments that train the immune system to stop attacking beta cells and drugs that reduce the immunogenicity of beta cells—or disguise them so they aren’t recognized by the immune system.
GLP-1 drugs are already widely used among people with type 2 diabetes and have been proven to have multiple beneficial health effects, Garcia-Ocaña says. “Harmine can add more to that effect because you can have more insulin-producing cells in the body,” he says.