Novel Drug Combination Advances Beta Cell Regeneration in Diabetes

Researchers from the Icahn School of Medicine at Mount Sinai achieved significant beta cell proliferation using a combination of pharmacologic and genetic inhibition.

With Andrew Stewart, MD, and Lori Sussel, PhD

Given that the onset and progression of diabetes result from a reduction in the numbers and function of pancreatic beta cells, researchers have been exploring approaches to reestablish natural insulin production.

Researchers from the Icahn School of Medicine at Mount Sinai in New York City, describe their discovery of a novel combination of 2 classes of drugs that induces the highest rate of proliferation of adult human beta cells,1 as published in Cell Metabolism.

Andrew Stewart, MD, director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute and lead author of the study, spoke to EndocrineWeb about the findings reported by his research team, which is highlighted in the following video.

Novel Drug Combination Advances Beta Cell Regeneration in Type 2 Diabetes

Dr. Stewart, Peng Wang PhD, and their research team discovered that combining pharmacologic and genetic inhibition of two types of molecules in beta cells—DYRK1A and SMADs—achieved a remarkable rate of human beta cell proliferation both in vivo and in vitro.1

“In fact, the combination of harmine with any of the drugs that inhibit TGFβSF signaling acted synergistically and led to average replication rates between 5% to 8%—rates that had never before been observed with any class of therapeutic molecules and which ‘far exceed’ those with normal physiological pancreatic beta cell replication in the first year of life,” Dr. Stewart told EndocrineWeb.

The study findings also indicated that there was a “class effect” observed with different DYRK1A inhibitors and different TGFSF inhibitors.1 The authors reported that in three models: two human, one mouse, this drug combination also led to actual increases in beta cell numbers. All of these beneficial effects were attributed, in part, to modulation of the chromatin-modifying, epigenetic-modulating enzymes of the Trithorax family, said Dr. Stewart.

Research Gains Indicate Progress Towards a Cure for Type 2 Diabetes

Calling on the research team’s two earlier publications, Dr. Stewart said they had originally identified that harmine analogs were able to induce beta cell proliferation at a rate of about 2% per day as well as increasing islet mass and improving glycemic control in in vivo-based models.1

Dr. Stewart said, “We determined that he likely target of harmine analogs are dual-specificity tyrosine-regulated kinase-1a (DYRK1A) acting upon the nuclear factors of activated T cells (NFAT) family of transcription factors, to mediate human beta cell replication.”

“For patients with type 2 diabetes (T2D), it would be conceivable to reverse the depletion of beta cells in a year or so at that rate; however, patients with type 1 diabetes (T1D) are more challenging,” he told EndocrineWeb; To explain this, he said that it is believed that drug-induced beta cell regeneration would need to be accompanied by treatments that are able to prevent the autoimmunity associated with T1D,2 a major current goal of diabetes research.

This is based on earlier research in which this research team had focused on rare, benign insulinomas as potentially holding the “genomic recipe” for beta cell replication.2,3 They showed that insulinomas have a genetic defects in SMAD that causes or enables them to make beta cells proliferate.

Dr. Stewart et al then hypothesized that combination treatment with harmine and drugs that inhibit SMAD might be able to further increase the rate of replication found with harmine monotherapy, so they focused on transforming growth factor beta superfamily (TGFβSF) receptor inhibitors, which regulate SMADs, in this latest study.1

Stimulating beta cells to proliferate as a means to reverse type 2 diabetes.

Replication Possible but Delivery Vehicle Remains Elusive

In explaining where current regenerative beta cell research is in therapeutic use, “the replication rates are likely rapid enough to ‘refill the beta cell tank’ in T1D and T2D,” Dr. Stewart said. To move forward, “we need to develop a means to target the combination treatment specifically to pancreatic beta cells, so as to exert maximal benefit without risking stimulating the proliferation of other, non-beta cells.”

Lori Sussel, PhD, professor of pediatrics and cell & developmental biology at the Barbara Davis Center for Diabetes at the University of Colorado in Denver, said, “these results are exciting in the sense that they were able to achieve more beta cell proliferation then has ever been seen previously. Further, this study demonstrated that it is possible to increase proliferation without compromising beta cell function.”

Regarding the challenges facing the next stage of research, “moving forward, it will be difficult to specifically target only beta cells, and there must be a means to ensure that the therapy doesn’t result in too great a proliferation of beta cells”, which could lead to too much insulin or, possibly, tumors, she told EndocrineWeb.

“We also don’t yet know the long-term effect of these inhibitors.” On the positive side, she offered “there is a more immediate potential – using this therapy to facilitate the proliferation of beta cells derived from human embryonic stem cells in vitro,” she said.

Dr. Stewart acknowledged that there are several other investigators and research teams involved in similar beta cell work, including Anil Bhushan, PhD, at University of California, San Francisco; Alan Schneyer, PhD, at University of Massachusetts-Amherst; Rohit Kulkarni, MD, at Joslin Clinic and Harvard in Boston, Massachusetts; Bridget Wagner, PhD at the Broad Institute in Boston, Massachusetts; Seung Kim, MD PhD, at Stanford University in California, and George Gittes, MD, at the University of Pittsburgh in Pennsylvania.

Looking Ahead—Need for a Viable Vehicle to Target Therapy

The tremendous strides these researchers have made in a relatively short time provide hope that new treatments will improve treatment for T1D and T2D, helping to restore the body’s ability to produce insulin, according to Dr. Stewart. It is impossible to guess when these findings might translate into a treatment or possible cure as the need to develop a method for accurate targeting of the drugs to pancreatic beta cells remains elusive, and it is also essential that methods are developed to control autoimmunity in T1D. 

“All in all, progress is moving rapidly”, Dr. Stewart said. “In only three years, we have moved from having no beta cell regenerative drugs to now having several. Developing methods to target these drugs to beta cells is the next challenge before clinical trials can begin. The NIH, the JDRF, and the ADA are committed to supporting research in this area.”

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH), Juvenile Diabetes Research Foundation (JDRF), and The Icahn School of Medicine at Mount Sinai.

There were no financial conflicts in reporting on this study.

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