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In beta-cell regeneration, insulinomas hold ‘gold mine’ of key genomic data
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BOSTON — Residual beta cells can be regenerated in people with both type 1 and type 2 diabetes, and the genomic abnormalities found in human insulinomas hold the clues for novel drug targets to potentially reverse disease, according to a speaker at the American Association of Clinical Endocrinologists annual meeting.
“It turns out that all types of diabetes result in an inadequate number of insulin-producing beta cells,” Andrew F. Stewart, MD, director of the Diabetes, Obesity and Metabolism Institute at the Icahn School of Medicine at Mount Sinai, said during a plenary presentation here. “That’s a paradigm change. Everyone thought it was insulin resistance in type 2 and absolute beta cell deficiency in type 1. But most people with diabetes, whether it’s type 1 or type 2, do have residual beta cells.”
Today, none of the clinically available diabetes drugs can drive human beta-cell regeneration, Stewart said. However, via high-throughput drug screening and studying the genomics of human insulinomas, Stewart and other researchers have identified the first regenerative drugs for human beta cells. The work has since been confirmed in both pharma and academia, he said, but much work remains to be done about how to best target these new therapies.
“The mindset of this field has been that beta cells, like neurons in the brain, are terminally differentiated, they will never be replicated, so only a fool will try,” Stewart said. “I happen to be that fool.”
Releasing the ‘brake’
Most of what researchers know about beta-cell biology comes from rodent models. However, Stewart said recent work has shown that human beta-cell biology is quite different than in rodents. In humans, beta cells replicate primarily in the first years of life, generally at a rate of about 1% to 2% per day, and then stop replicating by early adolescence. The key, Stewart said, is to determine which drugs could best restore that rate of beta-cell regeneration in humans.
In a high-throughput drug screening of more than 100,000 agents, Stewart and colleagues discovered that the hallucinogenic alkaloid harmine, also known as telepathine, interacts with and inhibits DYRK1A, a protein responsible for blocking beta-cell regeneration, Stewart said.
“The reason that beta cells won’t replicate in part is that DYRK1A — the ‘brake’ — is on hard,” Stewart said. “Harmine and other drugs in this class block DYRK1A; they take the ‘brake’ off and now beta cells are able to replicate.”
The drug, Stewart said, was shown to make beta cells regenerate at least at the physiological rate of 1% to 2% per day in in vivo models.
“All you would have to do is have every beta cell replicate once in a year and you would be back up to normal,” Stewart said. “If you have type 2, that is pretty neat. For type 1 though, at 1% or 2%, it would take a long time to get beta-cell mass up to normal, so it would be nice to have higher rates of beta-cell replications.”
The research has since served as a basis for synthesizing other drugs, Stewart said, including more than 300 versions of harmine.
Insulinoma clues
The clues to beta-cell regeneration may lie in insulinomas, which are typically but not always associated with multiple endocrine neoplasia type 1 (MEN1), according to Stewart. Usually about 1 to 2 cm in diameter, insulinomas make the right numbers of beta cells, are usually benign and retain enough differentiation to overproduce insulin — sometimes enough to make people hypoglycemic, Stewart said.
“As an endocrinologist, this is pretty obvious,” Stewart said. “Wouldn’t you want to know the genomic recipe or the cell metabolic recipe of how [insulinomas] do it?”
By collecting insulinomas, researchers can learn the pathways required to drive human beta-cell expansion in a way that is benign and also sufficient in a way to fix diabetes, Stewart said. Researchers in Stewart’s lab sequenced the DNA and RNA from dozens of collected insulinomas, finding 13,839 genes differentially expressed in insulinomas vs. beta cell genes, and 80,000 exons expressed — the first exon being DYRK1A.
“We do a high-throughput screening, we screen 100,000 drugs, and we find one drug that is able to make beta cells replicate that is a DYRK1A inhibitor,” Stewart said. “Then, we take a completely different approach, with next generation sequencing of insulinomas, and out of 80,000 exons, the No. 1 hit is DYRK1A. What are the odds of that happening?”
Research continues in this area. Today, while DYRK1A is no longer the No. 1 exon expressed, it remains in the top 100, Stewart said.
“Insulinomas represent a gold mine of genomic information,” Stewart said. “They give us the recipe of how to discover next-generation drugs.”
More work to do
Several obstacles remain before beta-cell regeneration becomes a reality, Stewart said. Researchers must learn how to target drugs specifically to the beta cell so that they do not adversely affect other tissues. Harmine, for example, is a hallucinogen and affects the brain.
“What we don’t have, right now, is a way to target any drug specifically to the beta cells,” Stewart said. “We don’t have a way to image the beta cells and we have no way to deliver any drugs to beta cells. That’s the next big hurdle. And I can tell you that the JDRF, the American Diabetes Association and NIH are now focused like lasers on trying to figure out how to target drugs to beta cells, now that we have beta-cell regenerative drugs.”
The other hurdle, Stewart said, is learning how to control autoimmunity in type 1 diabetes.
“These are exciting times,” Stewart told Endocrine Today. “Progress is happening rapidly on all of these fronts.” – by Regina Schaffer
Reference:
Stewart, A. Beta cell regeneration. Presented at: AACE Annual Scientific and Clinical Congress; May 16-20, 2018; Boston.
Disclosure: Stewart reports no relevant financial disclosures.