Novel Combination Treatment is Potent Driver of Beta Cell Proliferation in Type 1 Diabetes Model

A novel approach to the treatment of diabetes that combines the natural product harmine with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) rapidly reversed diabetes in mouse models of the disease and increased human β cell mass by as much as 7-fold over 3 months, according to findings of preclinical research published this week in Science Translational Medicine. The effects were observed for at least a month after the treatment was withdrawn.¹

Based on initial analysis, the dramatic increase in β cell mass was likely through mechanisms that included enhanced β cell proliferation, function, and survival, according to study authors from City of Hope in Los Angeles and Mount Sinai Health System in New York.¹

The 2 institutions have collaborated on the work since 2015 when research began at Mount Sinai’s Icahn School of Medicine led by Andrew F Stewart, MD, Fishberg professor of medicine and director of the Mount Sinai Diabetes, Obesity and Metabolism Institute. Stewart colleague Adolfo Barcia Ocana, PhD, formerly at Mount Sinai and now chair of the department of molecular and cellular endocrinology at City of Hope, and his team designed the studies and performed the detailed animal transplant and drug treatment.²

“This is the first time scientists have developed a drug treatment that is proven to increase adult human β cell numbers in vivo. This research brings hope for the use of future regenerative therapies to potentially treat the hundreds of millions of people with diabetes,” Garcia-Ocaña said in a City of Hope news release.²

The Mount Sinai/City of Hope team had previously shown that several different inhibitors of an enzyme in β cells called dual tyrosine-regulated kinase 1A (DYRK1A) can induce the proliferation of adult human β cells in a tissue culture dish for a few days.² It was also known that drugs that stimulate the GLP-1 receptor on β cells drive inhibition of DYRK1A. Moreover, combined DYRK1A inhibition and GLP-1 receptor agonism had been shown to induce β cell replication in human pancreatic islet cells ex vivo.² Prior to this study, however, there had been no demonstration of an ability to expand human β cell numbers in vivo. In this study that was accomplished via human islet grafts used in an animal model over many months.¹

This is the first time scientists have developed a drug treatment that is proven to increase adult human β cell numbers in vivo. This research brings hope for the use of future regenerative therapies to potentially treat the hundreds of millions of people with diabetes.

For the study, researchers transplanted a small number of human β cells into immunodeficient mice with a streptozotocin-induced model of diabetes.¹ Treatment with a combination of a DYRK1A inhibitor with exendin-4 increased human β cell mass in vivo by a mean of 4- to 7-fold in mice with and without diabetes. The team reported the remarkable β cell proliferation occurred without any alteration in human α cell mass. The increase in human β cell survival was mediated, in part, by the islet prohormone VGF, according to the study.¹

Measurement of the mass of b cells in the pancreatic islet grafts was the province of Sarah A Stanley, MBBCH, PhD, associate professor of medicine (endocrinology, diabetes, and bone disease) and neuroscience, at Icahn Mount Sinai. Stanley used an advanced laser microscopy tool that renders biological tissue transparent and allowed accurate quantitative assessment of engrafted β cells for the first time.²

Harmine, the product used combination with exendin-4 in this study, is a potent inhibitor of DYRK1A. The Mount Sinai research team recently completed a phase 1 clinical trial to evaluate the safety and tolerability of the β-carbopoline alkaloid in healthy human volunteers. Also under investigation at Mount Sinai are next generation DYRK1A inhibitors, with that research under the direction of Robert J DeVita, PhD, professor of pharmacological sciences and director of the Marie-Josée and Henry R Kravis Drug Discovery Institute at Mount Sinai. First-in-human trials may follow in 2025, pending results of studies to evaluate toxicity and estimate dosing.²

As for the future of the DYRK1A inhibitor–GLP1RA combination for diabetes treatment, Science Translational Medicine editor Catherine Charneski calls it promising while advising that additional work is necessary “to confirm the mechanisms of action and whether the therapeutic benefits and safety of the approach would translate to humans.”¹

References

1. Rosselot C, Li Y, Wang P, et al. Harmine and exendin-4 combination therapy safely expands human β cell mass in vivo in a mouse xenograft system. Sci Transl Med. 2024;16(755). doi: 10.1126/scitranslmed.adg34
2. City of Hope and Mount Sinai scientists first to demonstrate a combination treatment can increase human insulin-producing cells in vivo. News release. City of Hope. July 10, 2024. Accessed July 12, 2024. https://www.cityofhope.org/city-of-hope-and-mount-sinai-scientists-first-to-demonstrate-a-combination-treatment-can-increase