Could an experimental drug fight diabetes by regenerating insulin-producing cells?

• A recent study in mice finds that a two-drug combination may effectively reverse diabetes.
• The drugs work by ‘regrowing’ the cells in the pancreas that produce insulin.
• In just 3 months, these cells increased in number by up to 700%.
• While much more research is needed, the results are promising.

A new study, which appears in Science Translational Medicine , investigates an experimental drug combination for the treatment of type 1 and type 2 diabetes.

According to the paper, the treatment produced an up to 7-fold increase in the number of cells that produce insulin. It also improved blood sugar control in the animals.

The two drugs are exendin-4, which is a GLP1 receptor agonist — a family of drugs commonly prescribed for diabetes — and harmine, which inhibits an enzyme called dual tyrosine-regulated kinase 1A (DYRK1A).

Although scientists need to carry out much more research to confirm these benefits, the authors are excited by the prospect.

Because people with diabetes commonly take GLP1 receptor agonists already, the authors explain that adding a DYRK1A inhibitor to the mix could be a “simple, inexpensive, and highly scalable approach to diabetes treatment.”

The importance of beta cells in diabetes

Beta cells are situated in the mysterious-sounding islets of Langerhans in the pancreas. They are responsible for creating, storing, and releasing insulin. In people with type 1 diabetes, these cells are almost entirely absent, and in those with type 2 diabetes, their number is greatly reduced – by around 40–60% .

While effective diabetes drugs are available, none help restore beta cells.

Medical News Today spoke with one of the new study’s authors, Adolfo Garcia-Ocaña, PhD , chair and professor in the Department of Molecular & Cellular Endocrinology at City of Hope, CA.

He explained how they “ previously showed that several different inhibitors of an enzyme in beta cells called DYRK1A can induce the proliferation of adult human beta cells in a tissue culture dish for a few days.”

Beta cell proliferation is a process in which beta cells divide and become more numerous.

Other research also showed that DYRK1A inhibitors can increase the number of beta cells via a second mechanism: differentiation . This is where progenitor cells, which are similar to stem cells, are converted into fully functioning beta cells.

So, DYRK1A inhibitors have a two-pronged approach: They encourage progenitor cells to fully develop into beta cells and existing beta cells to divide and multiply.

Although this seems promising, according to the authors of the new study, “there is some doubt whether this will translate into clinically relevant increases in human beta cell mass.”

Other questions are also outstanding. For instance, scientists do not know whether DYRK1A inhibitors can help improve the survival of beta cells. This is an important question — if beta cells divide more rapidly but do not survive, they will be of little help.

Similarly, it is not clear whether these drugs can improve blood supply to the islets of Langerhans. This is another important question, as evidence suggests that restricted blood supply to the islets may impair insulin release from beta cells. It may also hamper their survival.

‘Hope for future regenerative therapies’ for diabetes

To investigate whether DYRK1A inhibitor harmine and the GLP-1 agonist exendin-4 support beta cell health, the scientists turned to a mouse model. They transplanted human islets containing beta cells into the kidneys of live mice that lacked an immune system.

For 3 months, the scientists gave the mice harmine and exendin-4. By the end, the beta cells had increased in number significantly. Beta cell function also improved, as did glycemic control.

Garcia-Ocaña told us that this combined effect of increased proliferation and differentiation are “aspects not seen this far by any drug tested” and that “the therapeutic implications of this drug combination for diabetes treatment are significant.”

There were also “hints” that the drug combo might enhance blood supply to the islets, which the authors believe may be the driving force behind the beta cell increase.

The scientists measured these benefits in mice with normal blood sugar control and mice with “severe diabetes.” Importantly, the mice did not experience hypoglycemia (low blood sugar levels), which can be fatal.

MNT also contacted Carel Le Roux, MBChB, MSC, FRCP, FRCPath, PhD , expert advisor to Lindus Health, and Director of the Metabolic Medicine Group at University College Dublin in Ireland.

“The combination of a DYRK1A inhibitor with exendin-4 increased human beta cell mass in vivo by four- to sevenfold in diabetic and nondiabetic mice over 3 months and reversed diabetes,” said Le Roux, who was not involved in the study.

“This is the first time scientists have developed a drug treatment that is proven to increase adult human beta 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 noted in a press release .

Le Roux is also hopeful about the future:

“If these results can be demonstrated in humans, it may allow patients with early evidence of beta cell failure to be rescued. It may also be transformative for the care of patients at risk of type 1 diabetes and type 2 diabetes.”

What about potential side effects?

The results are certainly encouraging, but there is a long road ahead. Firstly, what happens in a mouse does not necessarily happen in a human.

Also, as this is an entirely new approach, it is not clear how much regeneration and expansion of beta cells is necessary to make a meaningful difference to people with diabetes.

However, as the authors write, “a four- to sevenfold increase in human beta cell mass over 3 months, with normalization of glycemic control and in the absence of hypoglycemia as shown here in diabetic conditions, is promising.”

Another concern is that DYRK1A inhibitors may have unintended effects on other organs. DYRK1A receptors are widely distributed throughout the body. According to Garcia-Ocaña, “DYRK1A is an important protein that regulates multiple aspects of the life of the cell and its dysregulation can lead to pathological processes.”

Garcia-Ocaña told MNT how they limited these unwanted effects in other parts of the body by “using very low doses of DYRK1A inhibitors which make them safer.”

Also, the scientists noted no significant health issues in the mice. Although, again, humans are a different beast altogether.

Another concern is that there was a great deal of variation in how individual mice responded to the combined treatment. This might mean that the drug combination will not work well for some people.

Still, with the ongoing epidemic of diabetes, a 700% increase in beta cells is certainly worth following up. “Phase 1 clinical trials are underway at Mount Sinai in New York to test the safety and tolerability of harmine and future novel DYRK1A inhibitors,” Garcia-Ocaña told us.

He and his colleagues are currently working with the Wanek Family Project for Type 1 Diabetes . Because type 1 diabetes is an autoimmune disease, they “plan to test inducers of beta cell regeneration together with immunomodulators that regulate the immune system.”

“The goal is for the combination to allow new beta cells to thrive and improve insulin levels,” he explained.

If further work confirms these findings, this could be a genuine breakthrough in diabetes treatment. Garcia-Ocaña told us that “harmine is a natural product found in several plants and it is not difficult to obtain.” Combined with an increasing interest in DYRK1A inhibitors, this might mean that the drug, once it reaches the market, could be relatively accessible.

However, this “is hard to predict at this point,” he noted.