Effective Therapeutic Rate

A combination of two drugs enhances the production of beta cells such that they proliferate at the highest rate ever observed in humans – a rate of 5 to 8 percent per day.

“Beta cell regeneration is a ‘holy grail’ for the treatment of diabetes,” said Dr. Peng Wang, associate professor of Medicine at Mount Sinai and first author on the study, in a statement. “We are excited to finally have drugs that can induce beta cell proliferation at rates that are likely to be effective in people with type 1 and type 2 diabetes.”

As reported in Cell Metabolism, one of the drugs in the cocktail inhibits an enzyme known as dual specificity tyrosine-regulated kinase 1A (DYRK1A) and the other inhibits transforming growth factor beta superfamily members (TGFβSF). Together, these two drugs caused the beta cells to proliferate at a surprisingly fast rate.

“We are very excited about this new observation because, for the first time, we are able to see rates of human cell beta cell replication that are sufficient to replenish beta cell mass in human beings,” said Dr. Andrew Stewart, director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute. “We have discovered a drug combination that makes beta cells regenerate at rates that are suitable for treatment.”

Next Steps

“The next big hurdle is figuring out how to deliver them directly to the pancreas,” said Dr. Stewart.

“There are still challenges ahead, but this work brings us a little closer to therapies that can restore insulin production in people with the disease, and ultimately produce a cure,” added study author Dr. Francis J. Martin.

Journal Article Summary

• Adult human pancreatic beta cells can be induced to proliferate at high rates
• This action is driven by the synergy between DYRK1A inhibitors and TGFβ superfamily inhibitors
• Reflects activation of cyclins and CDKs accompanied by CDK inhibitor suppression
• Proliferation occurs in type 2 diabetic beta cells, with enhanced differentiation
• These beneficial effects extend from normal human beta cells and stem cell-derived human beta cells to those from people with type 2 diabetes, and occur both in vitro and in vivo.

Source: Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells (link)