JUPITER, Fla. & NEW YORK—With insulin prices skyrocketing into the proverbial heavens, people with diabetes are no doubt eager to find new therapies that could possibly improve their lives. Now, researchers at both Scripps Research and Mount Sinai have shared news of recent work that could move the industry one step closer to such therapies.
Scientists at Scripps Research have found a new biological mechanism of insulin signaling. Their study, involving the roundworm C. elegans, revealed that a “decoy” receptor is binding to insulin molecules and preventing them from signaling for increased insulin production.
“This truncated, ‘decoy’ receptor that we’ve found adds yet another layer of complexity to our understanding of insulin signaling,” said lead author Dr. Matthew Gill, an associate professor in the department of Molecular Medicine at Scripps Research in Florida.
The research appears in the journal eLife and reveals a part of the insulin signaling system that may offer insights into the cellular insulin resistance associated with type 2 diabetes. The researchers are now assessing whether a similar decoy receptor exists in humans. If so, it could present a new target for research.
Since the 1990s, researchers have recognized that insulin signaling is also an important regulator of longevity. Mutations in the gene that encodes the C. elegans insulin receptor DAF-2 can more than double the worm’s lifespan by reducing insulin signaling. Gill and colleagues focused on a form of the receptor known as DAF-2B. DAF-2B is a truncated version of the receptor that contains the usual binding site for insulin, but it doesn’t respond as the normal version would by signaling to initiate insulin production.
The team confirmed that DAF-2B is active throughout a worm's lifespan. They used CRISPR gene-editing technology to tag the receptor with a fluorescent molecule to track its location in the worm’s body. From these experiments they learned that DAF-2B is secreted into the space surrounding the tissues of the worm. It acts as a decoy to capture insulin molecules, and to thereby reduce insulin signaling.
“Normally insulin molecules float around and interact with insulin receptors to create insulin signals, but when they bind to these decoy receptors, they generate no signal, so producing these decoys appears to be a way to modulate insulin signaling,” Gill noted.
The scientists found that overproducing DAF-2B could tip worms into a semi-dormant state that normally occurs when food is scarce and insulin signaling is low. Overproduction of DAF-2B increased worm lifespan as well. The discovery of this mechanism for regulating insulin signaling is a significant advancement on its own, but it also suggests a new way of thinking about diabetes and perhaps even aging. The precise causes of the insulin resistance underlying diabetes, and seen to some extent with normal aging, have never been fully elucidated.
“One possibility is that insulin resistance is caused by the abnormal overproduction of a truncated, ‘decoy’ insulin receptor like the one we’ve found,” added Gill.
DAF-2B is produced from the same gene as the DAF-2 receptor; it results when the RNA transcript copied from the gene is spliced and re-spliced in an alternative form. This splicing process is known to occur for many genes, but Gill points out that it’s often dysregulated with aging or certain kinds of disease.
“You can imagine that in the prime of life, splicing and expression of this truncated isoform, DAF-2B, is tightly regulated, but then with a broader change in the splicing system due to disease or aging it becomes dysregulated and leads to insulin resistance,” stated Gill.
If humans also have a decoy insulin receptor like DAF-2B, then reversing its dysregulation could potentially be a new strategy for better metabolic health. Gill and his colleagues are now studying isoforms of the human insulin receptor to determine if any of them may function as a decoy receptor.
Now let’s move onto the Icahn School of Medicine at Mount Sinai, where researchers have discovered a novel combination of two classes of drugs that reportedly results in the highest rate of proliferation ever observed in adult human beta cells without harming most other cells in the body.
The findings involved one type of drug known to cause beta cells to proliferate, and another that is already in widespread use in people with diabetes. Together the drugs caused the cells to proliferate at a rate of 5 to 6 percent per day. The study was published in Science Translational Medicine.
“We are very excited about this new drug combination because, for the first time ever, we are able to see rates of human beta cell replication that are sufficient to replenish beta cell mass in humans with diabetes,” said Dr. Andrew Stewart, director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute and lead author of the study.
According to Stewart, there are no drugs currently existing drugs that can induce beta cell regeneration in people with diabetes. In parallel with the Mount Sinai work, other researchers are studying pancreatic transplantation, beta cell transplantation and stem cell replacement of beta cells for people with diabetes — but none of these approaches is in widespread use.
“This is a very exciting discovery in the field of diabetes and is a key next step in drug development for this disease,” remarked Dr. Dennis S. Charney, the Anne and Joel Ehrenkranz Dean at the Icahn School of Medicine at Mount Sinai. “This important work truly holds promise for so many people.”
Stewart and his team combined DYRK1A inhibitors like harmine with a class of beta cell-targeting drugs, also known as GLP1R agonists, which are already in widespread use in people with type 2 diabetes. They showed—both in beta cells from normal people and people with type 2 diabetes, both in tissue culture dishes and in human beta cells transplanted into mice—that combining harmine (or any other DYRK1A inhibitor) with any of the many GLP1R agonist drugs currently on the market for diabetes yields high rates of human beta cell replication, and does so in a way that is highly selective for the beta cell.
The project arose from the Ph.D. thesis of an Icahn School of Medicine graduate student, Courtney Ackeifi, who is now a postdoctoral fellow in Stewart’s lab and first author of the paper. She explored a broad spectrum of potential drug partners that could enhance the beta cell regenerative efficacy and selectivity of harmine.
“The beauty here is that the combination of DYRK1A inhibitors with GLP1R agonists achieves the highest rate of human beta cell replication possible, and does so in a highly specific way,” Ackeifi explained. “This is an important advance in the field of diabetes because we may have found a way to convert a widely used class of diabetes drugs into a potent human beta cell regenerative treatment for all forms of diabetes.”
Next, the researchers plan to perform long-term studies in animals transplanted with human beta cells, and to determine if any cells or organs in the body other than beta cells are affected by the drug combination.