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This article originally posted and appeared in  MedicationType 1 DiabetesPathologyPublic HealthIssue 675

Discovery Raises Hope for Type 1 Diabetes Reversal

A two-step process consisting of one drug to induce immune tolerance and another to promote islet regeneration could be key to type 1 diabetes reversal....

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Claresa Levetan, MD, chief medical officer, CureDM, stated that examples of both types of agents, already approved by the FDA, will likely become the first such combination to be tested in protocols that are expected to start by the end of this year.

Also speaking at the symposium were 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.

Robert Ratner, MD, chief scientific and medical officer of the American Diabetes Association, commented that, he does not think the currently available FDA-approved agents are the appropriate choices. Dr. Ratner 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. 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.

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 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.

"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 "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.

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.

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."

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. April 2013 

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This article originally posted 03 May, 2013 and appeared in  MedicationType 1 DiabetesPathologyPublic HealthIssue 675

Past five issues: Diabetes Clinical Mastery Series Issue 225 | Issue 765 | Diabetes Clinical Mastery Series Issue 224 | Issue 764 | Diabetes Clinical Mastery Series Issue 223 |

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