Hormone said to raise insulin lost to diabetes
CAMBRIDGE — Harvard University researchers have discovered a naturally occurring hormone in mice that sharply increases the number of precious, insulin-producing cells found in the pancreas — the beta cells that are lost during diabetes.
The work is still in the early stages and not ready to be tested in people, but the scientists have already partnered with two companies in an attempt to develop a drug that, they hope, could potentially replace or augment daily insulin injections.
“We’ve discovered a new hormone that does this important, interesting thing: robust, rapid expansion of beta cells,” said Douglas Melton, co-director of the Harvard Stem Cell Institute. “It boosts beta cell replication like nothing anyone’s ever seen.”
Outside researchers said the results, published Thursday in the journal Cell, were an exciting research advance against a disease that is a profound public health problem, affecting an estimated 25.8 million people in the United States. Beta cells are lost in both type 1 diabetes, in which they are attacked by the body’s immune system, and in the more common type 2 diabetes, caused by a combination of genetic and lifestyle factors. Researchers have reason to hope that this line of research could one day help both groups of patients.
“This is certainly one of the most important findings, I think, in the last few years in this field,” said Cord Dohrmann, chief scientific officer of a German biotechnology firm, Evotec AG, which has partnered with Harvard and Janssen Pharmaceuticals Inc. to develop a drug based on the research.
Outside scientists cautioned that a slew of questions remain, including whether the hormone works the same way in human cells and in diabetics. The research was done in healthy mice.
Dr. John Anderson, president of medicine and science at the American Diabetes Association, said that the kind of beta cell multiplication the researchers saw was “unique.” Still, he said, it was far too soon to suggest this promising finding in mice could make insulin injections obsolete.
“You’ve got to calm down; everybody’s got to take a step back from saying the cure is here,” Anderson said. “It’s a great path to be on. They are to be admired for this research. . . . Their work at Harvard has really helped in understanding beta cell physiology and offered new targets for how we might intervene in diabetes.”
The research was sparked a few years ago when Melton, best known for his work with embryonic stem cells, read about a molecule called S961 that researchers at the company Novo Nordisk had developed. S961, those researchers reported, inhibited insulin, the hormone that helps control blood sugar levels. It acted like sticking a rubber stopper into receptors — targets on the surface of cells that latch on to insulin.
Melton thought the body might compensate by producing more insulin or more beta cells. Peng Yi, a postdoctoral researcher in Melton’s laboratory, began working on the problem. When the scientists gave S961 to mice, they found that the animals’ beta cells multiplied.
To understand how that happened, they examined tissues outside the pancreas that might be sending signals to the pancreas, and discovered a particular gene in the liver and fat tissue that became active when S961 was administered.
The gene coded for a protein that was hormone-like, and there was a human version. When they spurred the production of the hormone in the mouse liver, Yi got a result he had never seen in years of his own research or in the scientific literature. The beta cells had been tagged with a molecule that caused them to fluoresce if they started making copies of themselves.
He showed a picture to Melton the next day and later found an envelope on his desk. Inside was a card on Harvard stationery, written in elegant cursive.
“Dear Peng, I can barely sleep. I’m so excited by your result. It’s a tribute to your hard work and hard thinking!” Melton wrote, adding that he was excited to see the experiment repeated.
That was February 2011. The Harvard researchers wanted to keep their finding secret while they verified it, so they referred to it with the code name “Rabbit”. The key insight came during the year of the rabbit on the Chinese lunar calendar, and rabbits are known for reproducing wildly.
Further research showed that the hormone, which they dubbed “betatrophin,” could increase the population of beta cells at a rate seventeenfold higher than in animals that did not receive the hormone.
Drug development is still in early stages, but if all goes well, Evotec’s Dohrmann said it is possible a molecule could be tested in people in three to four years.