A promising new study paves the way for a new pharmacologic treatment for beta-cell regeneration in patients with diabetes.
Pancreatic β cells are reduced by 40-60% in patients with type 2 diabetes, and 70-97% in patients with type 1 diabetes. The only currently available treatment for β cell replacement is a pancreas transplant. However, this is not an option that is scalable to hundreds of millions of people affected by diabetes. Although several molecules are under investigation, there are not currently any treatments available to regenerate β cells in patients. GLP-1 agonists are among the most widely prescribed pharmacologic agents in patients with type 2 diabetes and have high specificity to β cells. These agents, along with DPP-4 inhibitors, have been found to regenerate β cells in mice models, but have not been seen to influence human β cells. DRK1A plays a role in apoptosis, cell regulation, splicing, and cell signaling pathways. Inhibition has been demonstrated to play a role in several disease processes, including Down Syndrome, cancer, neurodegenerative diseases, and diabetes. Several studies have been completed that demonstrate the induction of proliferation of pancreatic β cells both in vitro and in vivo in rats and humans in about 1-3% of cells. However, DRYK1A inhibitors lack specificity to β cells, potentially leading to unwanted toxicity.
The objective of this study is to evaluate the ability of GLP-1 analogs to enhance DYRK1A inhibitor-induced human β cell proliferation with superior specificity for human β cells. Human pancreatic islets from 111 cadaveric donors were used both ex vivo and transplanted into euglycemic and STZ-diabetic immunodeficient mice. Mice were given either saline, the DYRK1A inhibitor harmine, exenatide, or a combination of harmine and exenatide for a total of two weeks. Cells were analyzed for proliferation markers with immunolabeling.
Ex-vivo studies demonstrated a negligible effect of GLP-1 agonists on β cell proliferation, while harmine induced proliferation in ~2% of cells, and the combination induced proliferation in ~5% of cells. A variety of doses were tested, establishing a dose-related progressive increase in proliferation. A total of five different DYRK1A inhibitors were tested along with a variety of GLP-1 agonists, including extendin-4, liraglutide, lixisenatide, and semaglutide. Both drug classes demonstrated a class effect. In diabetic immunodeficient mice, the animals treated with either harmine or exenatide alone remained severely diabetic throughout the study.
In contrast, both the positive controls and mice treated with the combination showed normal glucose levels. Euglycemic mice were also tested with saline, harmine alone, exenatide alone, or a combination. This test found that both low and high doses of harmine worked in synergy with the GLP-1 agonist to induce further increases in β cell proliferation compared to harmine alone. Induction rates in vivo were found to be lower at 1.1%, although this rate is higher than harmine alone, which has a rate of ~0.6%. Lastly, veterinary pathologists did not find any adverse effects in the mice pancreas or any other organs, indicating the safety of the drug combination.
This study is a promising start to a new therapy type for patients with diabetes and will likely lead to additional research. Several weaknesses of the study identified include the need to find a way to protect newly generated β cells in people with T1D, improvement in β cell specificity, the need for longer-term studies to both identify if there is a risk of oncogenic transformation in β cells or cells outside the islet and whether and how long the beneficial effects last, identifying the optimal dose of harmine or harmine-like compounds tolerable to humans and determining cost and scalability of this type of treatment.
Although additional studies would be needed to apply this treatment in clinical practice, this study will likely lead to further research and is an area to be watching in the future.
- GLP-1 agonists and DYRK1A inhibitors work in synergy to increase adult human β cell proliferation in both ex vivo and mice models.
- The combination treatment did not cause any safety concerns, although longer-term studies are needed.
- Additional studies in humans are needed before treatment with this drug combination could be utilized clinically.
References for “A New Way to Potentiate Beta-Cell Regeneration”:
Ackeifi, Courtney et al. “GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration.” Science translational medicine, vol. 12,530 (2020): eaaw9996. doi:10.1126/scitranslmed.aaw9996
Jarhad, Dnyandev B et al. “Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors as Potential Therapeutics.” Journal of medicinal chemistry vol. 61,22 (2018): 9791-9810. doi:10.1021/acs.jmedchem.8b00185
Jessica Rogers, PharmD candidate, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences