Can an Old Drug Delay Type 1 Diabetes?

Can an old blood pressure medication block the genetic triggers for the development of Type 1?



Researchers have long known that diabetes runs in families, but it’s only been about 20 years since they have successfully isolated gene and antibody combinations that serve as reliable genetic predictors of the risk of developing Type 1 diabetes.

A great many people who have Type 1 also have inherited genetic codes for antigens known as DR4 and DQ8; an antigen is any substance that may cause your body to produce antibodies against it. Post-diagnostic genetic testing of patients who have developed Type 1 diabetes has shown that about 90% have one or both of these genetic codes, and 60% have the DQ8 gene alone. The DQ8 gene also has been linked, although less conclusively, to a very small population of people with Type 2 diabetes.

The DQ8 gene is heavily distributed among people in Central America and northern South America. It’s also found in high frequency among Americans who live near the Gulf of Mexico and in the Mississippi Valley whose lineages go back to Caribbean and indigenous North American peoples. It’s found frequently in northern Europe, Scandinavia, and Japan, as well.

The Barbara Davis Center for Childhood Diabetes, located at the University of Colorado Medical School, is backing research into a link between DQ8 and Type 1 diabetes. Researchers are trying to see if they can block DQ8 to delay or block the progression of Type 1 diabetes.

To do this, they are undertaking a clinical trial of methyldopa, an oral drug which has been long used to alleviate hypertension. Methyldopa, once commonly branded as Aldomet, was developed in the 1960’s as an anti-anxiety and anti-tremor remedy for patients with neurological disorders. It was later shown to work by dilating blood vessels. As a psychoactive drug, it’s fallen out of favor since being replaced by other formulations for long-term use but it’s still prescribed for relief of short-term high blood pressure (think gestational diabetes).

Dr. Aaron Michels, who is chief investigator for the University of Colorado methyldopa clinical study, is co-author of a paper published in the April 2015 edition of World Journal of Diabetes that describes the potential of using methyldopa to treat newly diagnosed Type 1 patients. The hope is that this approach might slow progression of beta cell loss, and possibly delay or prevent onset of cell loss in patients exhibiting signs of prediabetes.

Methyldopa appears to work as a blocker; it neither interacts with the insulin molecule nor the pancreatic beta cell. Rather, it scrambles the signal from the antibody-summoning HLA DQ8 molecule, which might confer protection to islet cells. Further, researchers see no reason to expect that administering methyldopa will interfere with T-cell functions.

Methyldopa emerged as a candidate for inhibiting the fatal attraction between T cells and pancreatic islet beta cells through complicated chemical analyses aided by Dr. Mark Atkinson and Dr. David Ostrov, researchers at the University of Florida. Dr. Ostrov, a structural biologist, employed a supercomputer to perform what were essentially docking simulations of the DQ8 molecule’s receptor with structures of 140,000 existing small molecule medications – a process involving some 560 million permutations. Methyldopa was one of the finalist medicines that docked well with DQ8. Subsequent in vitro (“test tube”) and in vivo (living organism) tests with mice confirmed the likelihood that the drug would be effective.

Dr. Michels then enrolled 20 volunteer patients for a first phase clinical trial. 17 patients have thus far volunteered to receive methyldopa in three dosages at or below the therapeutic dose for high blood pressure. In the coming months, the study volunteers will continue to return for A1C monitoring and blood glucose testing.

Dr. Michels hopes to have this trial phase completed by early 2016, after which he would like to conduct a next-phase clinical trial with a larger group of recently diagnosed children and adults. The results of this broader, placebo-controlled study could lay the foundation for developing a methyldopa “vaccine” to delay onset or progression of beta cell destruction. The possibility of a remission or delay of even four to six years for a young child amounts to a breakthrough, as every year of maturity allows a child’s body to grow without complications of diabetes, and the child to develop skills to cope with the rigors of diabetes self-care.

If you want to contribute to a fundraising effort to support this type of research, you can go to https://www.crowdrise.com/firedup4cure.

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Jim Cahill is a senior writer for Insulin Nation and Type 2 Nation. Before turning to writing, he was a lawyer in government and private practice who focused on consumer protection and regulatory law. He can be contacted at jcahill@epscomm.com.