Something remarkable happens when some women with type 1 diabetes become pregnant: they start producing completely normal levels of insulin.
You read that correctly: one third of pregnant women, including those who’ve had it for 20 years or more, have reduced insulin needs during pregnancy. Some need no injected insulin at all. This knowledge may soon help everyone living with type 1 diabetes. How is this possible?
Two special things happen during pregnancy. First, the body relaxes the immune system to prevent it from harming the fetus. Second, it floods the body with hormones that promote growth. This causes something that researchers long thought was impossible: brand new islet cells start forming and producing insulin.
A Possible Path Towards a Future Free of Insulin Treatments
At last week’s Capital Hill summit on Insulin Independence, researchers from around the world shared a vision of using a combination of therapies built on these same principles to bring perfect blood sugars to those living with type 1 diabetes.
Step 1: Protect Your Body from Itself
In type 1 diabetes, there are two things broken in the body. First, your immune system kills off all of the insulin producing cells. The second issue is that new islet cells aren’t being created. Remarkably, there are FDA-approved drugs that do both of those things today and may be able to restore insulin production.
There is a long history showing that suppressing the immune system can extend the life of insulin-producing islet cells. In 1989, Rome hosted the first international symposium on type 1 diabetes immunotherapy. There was enormous excitement, said summit attendee Dr. Paolo Pozzilli. 692 patients treated with cyclosporine, now a major cause of successful transplants, and saw partial remission of diabetes. He explained that this approach was abandoned because the effect did not last – there was no way to regenerate islet cells — and there were concerns about kidney complications.
These concerns are real. In Miriam Tucker’s report on the event (free registration required), she share’s the response of Dr. Robert Ratner, chief scientific and medical officer of the American Diabetes Association: “The downsides of cyclosporine therapy outweigh the small benefits. We need better immunosuppressive agents. Studies to date have not provided us with reliable agents to increase islet-cell mass or number over a long period of time. Similarly, studies to date have not shown immunosuppressant agents to be safe and effective in preventing autoimmune destruction of islets. The combination of beta-cell regeneration together with protection from autoimmunity makes sense, but first we have to come up with the right agents. I don’t believe we currently have those available.”
Step 2: Create New Islet Cells
For a long time, it was a common myth that the body could not produce new islet cells. However, even a century ago we knew that was not really the case. In those who underwent tubal ligation (i.e. had their pancreas tied off) to treat diabetes, doctors found that new islet cells started growing. These new ones were quickly killed off, so the approach was abandoned.
Then in the 1950s, Dr. Robert Zollinger and Dr. Edwin Ellison, studying people dying with far too much stomach acid and ulcers, and found overgrown islets and people making too much insulin, according to Dr. Donald Bergman. (How they knew this is actually unknown because there was no easy way to measure insulin production levels then.) Later research found that a hormone called “gastrin” was causing new islet cells to grow.
Later studies confirmed this finding. In one, a combination of Gastrin and Epidermal Growth Factor was given to patients with type 1 diabetes for four weeks. The result? A remarkable 75% reduction in insulin requirements! Study participants saw their HbA1cs drop from 6.7% to 4.7%.
According to Dr. Bergman, proton pump inhibitors (PPIs) like Nexium (“the purple pill”) increase production of gastrin, have few side effects, and are promising candidates for a combination therapy.
Gastrin is not the only promising path towards islet regeneration. 1983, Dr. Aaron Vinik rediscovered that wrapping the pancreas with cellophane turned pancreatic ducts into islets. (He jokingly called the discovery “sarandipity”). Even more importantly, he discovered gene called INGAP (islet neogenesis associated protein) that helps stimulate immature cells in the diabetic pancreas to produce insulin. Human studies have found that a 12-week course of treatment is able to measurably increase insulin production and a 1% drop in HbA1c.
Regardless of the approach that works, creating new islet cells does much more than restore insulin production. The five types of islet cells produce at least six hormones that are critical in managing blood sugars:
- Alpha cells producing glucagon
- Beta cells producing insulin and amylin
- Delta cells producing somatostatin
- PP cells (gamma cells) producing pancreatic polypeptide
- Epsilon cells producing ghrelin
Even in the presence of a continued (albeit reduced) autoimmune attack, there is hope. A full 90% of the pancreas are ready-to-become-islets ductal cells. So they big key will be finding a way to safely slow down the immune-system while triggering the body to create islet cells.
The Next Steps for Research
The use of combination therapies to treat diabetes mirrors the successful fight against AIDS, malaria, and other controlled diseases. Rather than focusing on a magic bullet, researchers looked for a variety of medications that could work together to fix each thing that’s broken in the body. It doesn’t necessarily make for an elegant solution, but I doubt you’ll hear complaints from anyone who is able to restore some insulin production.
The Insulin Independence group is pushing researchers to conduct many, short-term studies to see how various immunosuppressants and islet cell growth promoters work in combination. “We should be able to know in these trials in a short time if we are making people insulin independent,” noted summit organizer Dr. Claresa Levetan.
Even if combination therapies are only partially effective, this would be an incredible boon to people living with diabetes. The decade-long DCCT trial that followed over 1400 patients drove home the importance of even minute amounts of insulin production. As Dr. Pozzilli noted, if you aim a sailboat even 10 degrees different, it can send you to a very differently place. “The DCCT found that even a small amount of C-Peptide can protect against complications.”
But Dr. Levetan has loftier ambitions. At the end of the summit, she smiled at the boy sitting to her right who was diagnosed with type 1 diabetes at age 2: “I hope to keep my promise that I will get Louis Cocco Jr. off of insulin before he’s grown up.”
- Claresa Levetan, MD, founder of Perle Bioscience
- Lois Jovanovic, MD, chief scientific officer of Sansum Diabetes Research Institute
- Paolo Pozzilli, MD, professor of endocrinology and metabolic diseases and department chair at University Campus Bio-Medico
- Desmond Schatz, MD, professor, associate chair of pediatrics, and medical director of the Diabetes Center of Excellence at the University of Florida, Gainesville
- Aaron Vinik, MD, PhD, professor of medicine and director of the research neuroendocrine unit at Eastern Virginia Medical School, Norfolk.
Below are the slides from the event. They may be hard to follow without explanation, but include footnotes for the studies discussed here.
Read more about A1c, aaron vinik, American Diabetes Association, amylin, beta cells, claresa levetan, combination therapy, cyclosporine, desmond schatz, Diabetes Research Institute, edwin ellison, FDA, gastrin, immunosuppression, INGAP, insulin, insulin independence, islet cells, lois jovanovic, louis cocco jr, nexium, paolo pozzilli, proton pump inhibitors, robert zollinger.