Hormone Dramatically Increases Insulin Production, Possible Diabetes Breakthrough

Date: Apr-26-2013A hormone, called betatrophin, that may significantly improve type 2 diabetes treatment has been discovered by scientists at the Harvard Stem Cell Institute (HSCI), according to a report published in Cell.

The authors wrote that betatrophin might also help patients with type 1 diabetes, or juvenile diabetes when they are first diagnosed.

In animal experiments the researchers found that betatrophin caused laboratory mice to produce beta cells at up to 30 times the normal rate. Beta cells are the insulin-secreting cells in the pancreas - put simply, beta cells produce insulin.

These new beta cells only produce insulin when the body requires it. The scientists explained that this breakthrough could mean that type 2 diabetes patients may have a natural regulation of insulin, plus a considerable reduction in diabetes-related complications. Diabetes is a major cause of amputations and non-genetic loss of vision.

HSCI Co-Director Doug Melton and postdoctoral fellow Peng Yi, who both discovered betatrophin, stressed that a great deal of work remains to be done before trying the hormone out on humans. They added that their work so far, which was mainly funded by a federal research grant, has already attracted the attention of pharmaceutical and biotech companies.

Doug Melton, who is Harvard's Xander University Professor and co-chair of the University's Department of Stem Cell and Regenerative Biology, said:

"If this could be used in people. It could eventually mean that instead of taking insulin injections three times a day, you might take an injection of this hormone once a week or once a month, or in the best case maybe even once a year."

Type 2 diabetes prevalence in the USA has increased considerably over the last thirty years, in parallel with rising obesity rates, the authors explained. The illness causes patients to gradually lose beta cells, as well as the ability to produce enough insulin.

The authors quoted a recent study which estimated the annual costs for pre-diabetes, diabetes treatment and complications in the USA at $218 billion, equivalent to 10% of the country's health bill.

Melton said:

"Our idea here is relatively simple. We would provide this hormone, the type 2 diabetic will make more of their own insulin-producing cells, and this will slow down, if not stop, the progression of their diabetes. I've never seen any treatment that causes such an enormous leap in beta cell replication."
Could betatrophin help type 1 diabetes patients?
Although the scientists wrote mainly about the benefits for type 2 diabetes patients, they believe betatrophin could play a role in treating type 1 too, by boosting the number of beta cells and slowing the progression of the autoimmune disease when it is initially diagnosed.







Melton said "We've done the work in mice, but of course we're not interested in curing mice of diabetes, and we now know the gene is a human gene. We've cloned the human gene and, moreover, we know that the hormone exists in human plasma; betatrophin definitely exists in humans."

Melton believes betarophin may well be in human clinical trials within the next three to five years, which in the course of drug R&D is an extremely short time. He added that much more research is needed before the hormone could be available as a drug for human use.

Working with biotech and pharmaceutical companies
Yi and Melton have already signed a collaborative agreement with German biotech company, Evotec, which currently has 15 researchers working on betatrophin. Betatrophin has been licensed to Johnson & Johnson company, Janssen Pharmaceuticals - which also has personnel working on the hormone.

Merton explained that had it not been for federal funding, nobody today would know about the potential benefits of betatrophin for people with diabetes.
Harvard Provost Alan Garber said "At a time of great uncertainty for federal research funding, the discovery of betatrophin is a reminder of the importance of basic research. Were it not for a National Institutes for Health grant, this promising new approach to treating diabetes might never have come to light."

Melton and Yi initially called betatrophin "Rabbit", because it was the Chinese Year of the Rabbit when they discovered it, and it is the hormone that makes beta cells multiply rapidly.

For more than one-and-a-half decades, Melton concentrated on type 1 diabetes, also known as juvenile diabetes. When his son was diagnosed with type 1 diabetes as an infant, Melton became interested in type 1 research. His daughter was also diagnosed with the same disease later.

The majority of Melton's research involved the use of stem cells as disease treatments and targets for drug breakthroughs. However, the discovery of betatrophin had nothing to do with his stem cell work. It was, he emphasized, a simple case of researchers with adequate resources asking questions, and seeking answers that "fell outside the usual scope of their laboratories and institutes".

Melton said:

"I would like to tell you this discovery came from deep thinking and we knew we would find this, but it was more a bit of luck. We were just wondering what happens when an animal doesn't have enough insulin. We were lucky to find this new gene that had largely gone unnoticed before.

Another hint came from studying something that people know about but don't think much about, which is: What happens during pregnancy? When a woman gets pregnant, her carbohydrate load, her call for insulin, can increase an enormous amount because of the weight and nutrition needs of the fetus. During pregnancy, there are more beta cells needed, and it turns out that this hormone goes up during pregnancy. We looked in pregnant mice and found that when the animal becomes pregnant this hormone is turned on to make more beta cells."

Yi and Melton had their big breakthrough on February 11th, 2011. Yi said "I was just sitting there at the microscope looking at all these replicating beta cells, and I could barely believe my eyes". It was the first time he had ever seen this kind of dramatic replication.

Yi was not quite sure what to do at first - whether to rush to Melton and tell him what he saw straight away or repeat the experiment. He ran into Melton's office, made a print of the image he had been observing, and placed it in front of Melton, saying that they most likely had a dramatic breakthrough. "I showed him this picture and told him this is a secreted protein, and he was really, really excited about this result."

Melton remembers the moment well:

"I remember this very well. It's a black-and-white picture where you're looking at a section, like a section through a sausage, of the whole pancreas. When you normally look at a black-and-white picture of that, it's very hard to tell where the beta cells are, the insulin cells.

But in this test, any cell that was dividing would shine up bright and white, like a sparkle. He showed me this picture where the whole pancreas is largely black, but then there were these clusters, like stars of these white dots, which turned out to be all over the islets, the place where the beta cell sits. I still keep that black-and-white picture. We have much fancier color ones, but I like the black-and-white picture, because it's one of those moments when you know something interesting has happened. This is not by accident. I've never seen any treatment that causes such an enormous leap ... in beta cell replication."

The following morning Yi went to work as usual and sat at his lab bench. He saw a formal-looking envelope on the surface of the bench. He opened it and read a short note from Melton "Dear Peng, I can hardly sleep - I am so excited by your result. It's a tribute to your hard work and hard thinking. Can't wait to see the data from the repeat. Doug."

Written by Christian Nordqvist

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