Adding a glucagon-like peptide-1 (GLP-1) receptor agonist — a drug class that is commonly used to treat type 2 diabetes — to a dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitor induced a 5% to 6% increase in human beta cell replication in the laboratory.
This is much higher percentage than has been seen in previous studies using a DYRK1A inhibitor alone, and “may be in a range that could allow for restoration of normal beta cell mass in people with type 2 diabetes and type 1 diabetes,” say the investigators of this early-stage research.
Scientists have gone from saying “it’s impossible to make beta cells proliferate,” to, in 2015, “it’s possible, but not at a fast enough rate,” to now, “it’s possible at rates that are fast enough,” senior author of the new study, Andrew F. Stewart, MD, Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News.
Beta Cell Mass Is Reduced but Still Present in Diabetes
“In type 1 diabetes, beta cell mass is decreased by [roughly] 90%, and in type 2 diabetes, it is decreased by about 50%,” explained Stewart, director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute.
In attempts to remedy this, scientists have performed whole pancreas and pancreatic islet cell transplants, but this has only been done in a few thousand patients of the approximately 400 million people with diabetes worldwide. And this procedure currently has the drawback of still requiring patients to take lifelong immunosuppression.
Stem cell-derived beta cell replacement therapy, another potential technique, is still experimental and is expensive.
Therefore, other researchers are using a different approach and looking for ways to increase the human body’s ability to produce beta cells.
As reported in 2015, Stewart’s team published a study in Nature Medicine that showed that the oral DYRK1A inhibitor, harmine, induced a 2% per day increased rate of cell proliferation in human beta cell cultures.
Other researchers at Stanford University, Joslin Diabetes Center and Broad Institute in Boston, and Novartis-GNF have reported a similar rate of increased beta cell proliferation with other DYRK1A inhibitors.
But this rate is “modest” and the effects of DYRK1A inhibitors are not limited to beta cells. For example, harmine is one component of a hallucinogenic Amazonian tea/infusion called ayahuasca — so it is possible, but uncertain, that harmine may have psychoactive effects.
“Thus, there is a pressing need to identify drugs that provide accelerated human beta cell proliferation and improved beta cell specificity,” write Ackeifi and colleagues in the new study.
Islet Cells From Normal and Diabetic Cadavers
For this new work, the researchers obtained human islet cells from 111 cadaveric donors who were not diabetic and 11 cadaveric donors who had type 2 diabetes.
They first investigated whether adding a GLP-1 receptor agonist to a DYRK1A inhibitor would synergistically induce adult human cadaveric beta cells to replicate in cell cultures. GLP-1 receptor agonists are more specific for beta cells than DYRK1A inhibitors.
They combined 10 µM harmine with a range of doses of GLP-1 and observed a dose-related, progressive increase in proliferation of beta cells.
“To our surprise and delight,” Stewart said, “we suddenly saw high replication rates of 5% to 8% a day, some as high as 20%.”
Moreover, “the synergistic ability of harmine to drive beta cell proliferation in combination with GLP-1 was apparent for every DYRK1A inhibitor tested (harmine, INDY, leucettine, 5-IT, and GNF4877),” the researchers report, suggesting this is a “class effect” for DYRK1A inhibitors in general.
Similarly, “synergy was also apparent for harmine in combination with all five GLP-1 agonists tested, including several approved for clinical use: exendin-4, liraglutide, lixisenatide, and semaglutide,” suggesting this is also a class effect for the other half of the drug combination.
To put this into perspective, in humans, pancreatic beta cells proliferate from birth with a peak rate of 2% per day at age 1, and then proliferation declines rapidly, Stewart noted.
So it takes only a few years to grow all of one’s beta cells for life.
A replication rate of 5%, or even 2% in type 2 diabetes, he continued, “should be able to restore beta cell mass in 2 years.”
The GLP-1 agonist–DYRK1A inhibitor combination enhanced human beta cell proliferation, human insulin secretion, and blood glucose control not only in the cell cultures, but also in further studies of human islets transplanted into mice that were and were not diabetic.
No adverse events were observed in the mouse studies during a 1-week period.
The combination provided an improved, although not complete, degree of human beta cell specificity.
It’s also possible that another class of type 2 diabetes drugs, the oral dipeptidyl peptidase 4 (DPP4) inhibitors, may also work synergistically with DYRK1A inhibitors, since the former are also ‘incretins’ and work by stimulating GLP-1 release.
“These findings suggest that any DYRK1A inhibitor administered with any GLP-1 agonist currently in widespread use in people with type 2 diabetes — and by extension with any DPP4 inhibitor drug that augments circulating GLP-1 — would be able to generate substantial rates of human beta cell proliferation,” say the authors.
Stewart explained that, in tissue culture, human beta cells live only about a week, but if transplanted into mice with no immune system, the human beta cells can live for a year or more.
So long term studies are now needed to assess how long beta cell proliferation continues, if it ceases when the two drugs are discontinued, and whether there are adverse effects on other organs.
The team is thus conducting a 1-year study to determine how long the cells continue to proliferate in the cell cultures, and how the islets that are transplanted into the mice fare over time.
“We’ll know a lot more in 6 months,” Stewart added.
The researchers will then have to demonstrate the preclinical safety of any potential drug combination in animal models, to show, among other things, that this would not harm the liver, muscle, spleen, or other organs.
They would also have to determine an optimal dose and type of dosing.
But for a patient with type 1 diabetes who is already confronted with lifelong injections of insulin, injecting a GLP-1 receptor agonist for a year or two to recover beta cell function and then stopping all drugs for good may be a choice some would accept, according to Stewart.
“Beta cell proliferation was once unthinkable, but now it is absolutely possible,” he reiterated. Although it is too early for clinical studies — and Stewart stressed there is a still a long way to go — he is buoyed by the prospects.
“The field is moving rapidly,” he concluded.
For a video about this study click here.
The study was funded by grants from the National Institutes of Health and the JDFR and by the Icahn School of Medicine at Mount Sinai. Stewart has disclosed no relevant financial relationships.
Sci Transl Med. Published online February 12, 2020. Abstract