Hope on Horizon for Type 1 Diabetes Reversal

Miriam E. Tucker

April 29, 2013

WASHINGTON, DC — The key to reversing type 1 diabetes could be a 2-step process consisting of one drug to induce immune tolerance and another to promote islet regeneration, researchers said last week at a Capitol Hill summit.

Examples of both types of agents that are already approved by the US Food and Drug Administration (FDA) will likely become the first such combination to be tested in protocols that are expected to start by the end of this year, Claresa Levetan, MD, chief medical officer, CureDM, Wilmington, Delaware, told Medscape Medical News at the event, which was held in the Cannon House Office Building on April 24.

Also speaking were some other well-known names in the diabetes world, including Lois Jovanovic, MD, chief scientific officer of the Sansum Diabetes Research Institute, Santa Barbara, California; Paolo Pozzilli, MD, professor of endocrinology and metabolic diseases and head of the department at the University Campus Bio-Medico, Rome, Italy; Desmond Schatz, MD, professor and associate chair of pediatrics and medical director of the Diabetes Center of Excellence at the University of Florida, Gainesville; and Aaron Vinik, MD, PhD, professor of medicine/pathology/neurobiology and director of the research neuroendocrine unit at Eastern Virginia Medical School, Norfolk.

"All of us who are here are diabetes visionaries. Our panel has not been afraid to look back at the successes and failures in diabetes research. We are not afraid to break from convention and make a breakthrough," Dr. Levetan said in her introduction.

Asked by Medscape Medical News to comment, Robert Ratner, MD, chief scientific and medical officer of the American Diabetes Association, said he believes the concept of a combination approach — promoting the growth of islet cells with one drug while suppressing the immune system with another — is a logical one. However, he does not think the currently available FDA-approved agents are the appropriate choices.

Instead, he expressed optimism about a new discovery, published online April 25 in Cell, describing a novel protein identified in mice that he says might offer a better islet-growing option.

Douglas A. Melton, PhD, the Xander University Professor at Harvard University, Cambridge, Massachusetts, and his postdoctoral fellow Peng Yi identified betatrophin in the liver and fat cells of mice models of insulin resistance. The protein was associated with dramatically increased beta-cell proliferation and beta-cell mass expansion. Betatrophin is now licensed to Janssen Pharmaceuticals and could be in clinical trials within 3 to 5 years, according to a Harvard University statement.

Now Known That Mice and Human Islets Differ

At the Capitol Hill summit, Dr. Levetan said there has been a long history of inducing remission of type 1 diabetes in rodents via immune tolerance but subsequent failure when the therapies were then moved to trials of human subjects with newly diagnosed type 1 diabetes.

It has now become apparent that the islets of mice differ greatly from those of humans, she noted. Mouse islets — designed to accommodate continuous eating — are composed of tightly packed beta cells. Human islets, in contrast, contain 5 cell types that secrete 6 hormones, each of which is necessary for normal human glucose regulation: insulin and amylin made by the beta cells, glucagon produced by alpha cells, somatostatin from delta cells, pancreatic polypeptide from gamma cells, and ghrelin from epsilon cells.

And also, unlike the rodent islets, these cells are directly connected via blood vessels. As a result, once the human beta cells are attacked by the immune system in the course of type 1 diabetes, the islets become completely dysfunctional.

Islet regeneration isn't new. Nearly 100 years ago, the idea that ductal ligation could induce new pancreatic islet formation was proposed by Frederick Banting, the codiscoverer of insulin. In fact, prior to the discovery of insulin, children with type 1 diabetes underwent surgical clamping of their pancreases in order to induce the growth of new islets. This often helped temporarily but later failed as the autoimmune process progressed.

The autoimmune etiology of type 1 diabetes was not established until the 1980s, Dr. Levetan noted.

"What we are saying now is that we have an ability not only to protect the immune system but to generate new islets… Because of the complexity of that islet, we need to give both an immune agent and a regeneration agent [to achieve] insulin independence," she explained.

Dr. Pozzilli said that cyclosporine is being reexamined as a possible immune-tolerance agent. It had fallen out of favor in type 1 trials due to concerns about renal toxicity, but since then data suggest that low doses for up to 1 year will help avoid this side effect.

"The concept of combination therapy using an immune-tolerance agent with a beta-cell regenerative compound should be considered, and among the different immune-tolerance agents, cyclosporin A still holds a prominent role," he noted.

And with regard to islet regeneration, pregnancy — which is accompanied by mild immune suppression and growth-promoting factors — shows the feasibility of the concept, explained Dr. Jovanovic.

She described her findings from 10 pregnant patients with type 1 diabetes of more than 20 years' duration, showing that new insulin production — with an approximate 25% drop in exogenous insulin requirement — was seen by 10 weeks' gestation (Diabetologia 2000;43:1329-1330).

Pregnancy is one of the few times that new islets form, suggesting that a possible hormone cocktail mimicking pregnancy might be used to raise C peptides [a well-recognized measure of beta-cell function], she said.

First Trials Planned for Later This Year

In another example of islet regeneration, Dr. Vinik described his work with a peptide called islet neogenesis–associated protein (INGAP), an initiator of islet neogenesis in animal models that has also been shown to induce transition of human ductal cells into insulin-producing cells.

It may be possible to combine a regenerating agent such as INGAP with antiapoptotic or anti-inflammatory agents, such as currently available incretin drugs, Dr. Vinik said.

And Dr. Donald Bergman, an endocrinologist and internist in private practice in New York City, talked about the potential role of proton-pump inhibitors (PPIs) as regenerative agents due to their effects in raising levels of gastrin, a hormone that stimulates the production of stomach acid and also promotes beta-cell growth.

Several studies in patients with type 2 diabetes and at least 1 in type 1 patients have shown reductions in insulin requirements and improvements in hemoglobin A1c levels using PPIs, Dr. Bergman noted.

Dr. Levetan said that PPIs are likely to be among the first agents, possibly combined with cyclosporine, to be investigated in a series of short trials in type 1 patients who still have measurable C peptide. "We're thinking of doing lots of studies in a shorter period of time, using FDA-approved agents," she said.

The exact protocols are still being worked out, and thus far the funding comes from a private source, she told Medscape Medical News.

Right Concept, but Which Agents?

In conclusion, Dr. Levetan told summit attendees: "I believe if we go back to the past we can make great strides forward in what has worked and what hasn't worked and bring these together for what I believe is a new road for type 1 diabetes."

But Dr. Ratner told Medscape Medical News that while he endorses the concept of a combination approach, he is concerned about the use of currently available agents, particularly cyclosporine. "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," he said.

The Capitol Hill summit was sponsored by Insulin Independence, an organization formed by Dr. Levetan, who is also the cofounder and lead scientist at CureDM, and a shareholder in CureDM Holdings, as well as founder of Pearle Bioscience. Dr. Vinik consults for Merck, Daichi Sankyo, and Ansar and has received funding from Impeto, NeuroMatrix, and Pfizer. Dr. Pozzilli has received grants from and/or consulted for Eli Lilly, Sanofi, Novartis, and Roche. Dr. Bergman has reported no relevant financial relationships. Dr. Ratner is an employee of the American Diabetes Association and has no other disclosures.