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Novel drug combination induces human beta-cell regeneration
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A novel combination of two distinct classes of molecules has been shown to induce proliferation in adult human beta cells at a rate of 5% to 8% in in vitro and 2% in in vivo transplant models, a rate far exceeding pancreatic beta-cell replication rates from other experimental drugs, according to findings published in Cell Metabolism.
The two drugs — a DYRK1A inhibitor combined with a transforming growth factor (TGF)-beta superfamily inhibitor — worked synergistically to induce “previously unattainable” rates of human beta-cell proliferation in human islet donors, human stem cell-derived beta cells and stem cells from people with type 2 diabetes, according to Andrew F. Stewart, MD, director of the Diabetes, Obesity and Metabolism Institute at the Icahn School of Medicine at Mount Sinai. Currently, none of the clinically available diabetes drugs can drive human beta-cell regeneration, Stewart said. The findings, he added, are notable, but several key obstacles remain before beta-cell regeneration becomes a reality in humans.
“We’ve got, for the first time, drugs that are capable of making the human beta cell regenerate, at rates that are fast enough to reverse type 1 and type 2 diabetes,” Stewart told Endocrine Today. “What we don’t have is a way to deliver them specifically to the pancreatic beta cell. The way I like to think of it is, we’re Amazon, and we have a parcel for you, but we don’t know your address.”
In gene expression profiles from fluorescence-activated cell sorted human beta cells, Stewart and colleagues observed an abundance of select members of the TGF-beta superfamily, a large group of related cell regulatory proteins. Treatment with the hallucinogenic alkaloid harmine, also known as telepathine, resulted in changes in TGF-beta superfamily members, Stewart said. The researchers then explored the effects of TGF-beta superfamily inhibitors on human beta-cell proliferation in human cadaver islets. Used alone, such inhibitors had no effect; however, when combined with harmine, the researchers observed a dramatic increase in human beta cells, as measured by Ki67 labeling.
“Proliferation rates (labeling indices) averaged in the 5% to 8% range; the large error bars reflect even higher proliferation rates in occasional human islet preparations, sometimes achieving Ki67 labeling indices as high as 15% to 18%,” the researchers wrote.
The beneficial effects also extended to other DYRK1A inhibitors besides harmine, including INDY and leucettine-41, they wrote.
“In addition, in dose-response studies, the combinations fulfilled formal criteria for pharmacologic synergy,” the researchers wrote.
Several obstacles remain before beta-cell regeneration becomes a reality, Stewart said. Researchers must learn how to target drugs specifically to the beta cell so that they do not adversely affect other tissues. Harmine, for example, is a hallucinogen and affects the brain.
The other hurdle, Stewart said, is learning how to control autoimmunity in type 1 diabetes.
Still, Stewart said the findings support the possibility that restorative treatment of beta-cell deficiency in both type 1 and type 2 diabetes is achievable.
“We’ve gone from ‘it’s impossible’ 3 years ago to ‘it’s clearly possible’ now, and we even have grades of proliferation that are therapeutically realistic and relevant,” Stewart said. “This is, for us, the next stop on the train to elimination of diabetes.” – by Regina Schaffer
For more information:
Andrew F. Stewart, MD, can be reached at the Icahn School of Medicine at Mount Sinai, Diabetes, Obesity and Metabolism Institute, 1 Gustave L. Levy Place, New York, NY 10029; email: Andrew.stewart@mssm.edu.
Disclosures: Stewart and one study co-author report they are inventors on a patent that has been filed by the Icahn School of Medicine at Mount Sinai. Three of the study authors report they are employees of Semma Therapeutics.
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Wang P, et al. Cell Metab. 2018;doi:10.1016/j.cmet.2018.12.005.
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