BioPharma

“Make beta cells great again:” Type 1 diabetes interventions at ADA 2017

The development of type 1 diabetes starts years before symptoms appear, which raises the possibility of early intervention, prevention, or possibly even reversal of the disease. Such efforts were discussed on Monday at the American Diabetes Association's Scientific Sessions.

Type 1 diabetes blood glucose Nurse using insulin pen on patients finger

From the perspective of patients and their families, Type 1 diabetes can feel like a sudden onset disease.

Symptoms arise seemingly out of nowhere, as the body becomes increasingly hyperglycemic. The person – frequently still a child – becomes extremely thirsty and urinates frequently as his or her body tries to rid itself of the excess blood glucose. It’s a losing battle. The person is eventually diagnosed and prescribed a life-long plan for insulin replacement therapy.

It turns out that the patient’s experience is the proverbial tip of the iceberg. Biological mechanisms and autoimmunity are at play for years before symptoms appear. That raises the possibility of early intervention, prevention, or possibly even reversal of the disease if it can be caught in the earliest stages.

To that end, researchers have been piecing together the hidden progression of type 1 diabetes, as the immune system stealthily destroys the patient’s insulin-producing beta cells. Those findings and the latest intervention studies were presented on Monday at the 77th Scientific Sessions of the American Diabetes Association (ADA) in San Diego, California.

During the well-attended symposium, different researchers shared data from three separate therapeutic interventions, spanning decades and using trial sites around the world.

The studies looked at preventive treatment with insulin, to try to desensitize the immune system to the hormone. Another studied the use of Gleevec (imatinib), a long-standing cancer drug with immunosuppressive properties. Finally, a team looked at the use of GAD, another important antigen that in animal models has shown an ability to help build immune tolerance (the opposite of autoimmunity).

The studies are impressive, to say the least. Two of the earliest intervention endeavors, using insulin, screened over 100,000 healthy participants each to identify children at high risk of developing the disease. In terms of follow-up, the Diabetes Prevention Trial: Type 1 (DPT-1) ran for nine years and a second study called TrialNet ran for a decade. 

Unfortunately, none of the insulin trials demonstrated clear signs of efficacy —though there were glimmers of hope.

A posthoc analysis (after the data had been collected) of the DPT-1 trial showed a subset of patients known as “Stratum 2” did respond to insulin therapy and had a delayed time-to-diagnosis. This cohort had high titers of insulin autoantibodies at the time of screening. Several presenters highlighted this as a significant victory and justification for further research — though that’s easier said than done.

Desmond Schatz, a professor and associate chair of pediatrics at the University of Florida, Gainsville, also noted that the oral insulin studies further supported the idea that not everyone develops diabetes the same way. Science just doesn’t have the tools to define those groups right now. 

Gleevec in newly diagnosed patients

The Gleevec study, supported by the Juvenile Diabetes Research Fund (JDRF), did demonstrate possible benefits.

Gleevec is a tyrosine kinase inhibitor that appears to influence a number of immune pathways, explained Stephen Gitelman, a professor of pediatrics at the University of California, San Francisco Medical School.

The rationale for the study came from prior research using non-obese mouse models. In that setting, Gleevec was not only able to interfere with the disease progression, it actually reversed it.

Good justification for further research. As Gitelman joked during his presentation, the question becomes: “What can we do to make beta cells great again?”

At the time of diagnosis, individuals with type 1 diabetes may have as much as 15-40 percent of beta cells remaining. Preserving those could lead to improved clinical outcomes.

The UCSF study enrolled 67 newly diagnosed patients. At the primary endpoint at one year, participants that received six months of treatment with Gleevec had improved beta cell function compared to the placebo arm. They also had lower supplemental insulin needs.

As Gitelman noted, this is “very garden-fresh data” and more analysis is needed. Participants will be followed for a further 12 months. Side effects were more common in the active arm of the trial, usually related to nausea, lower cell counts, and liver changes. The former tended to resolve on its own after several weeks of therapy, he said, while the latter two were addressed with a dosage change.

The GAD DiAPREV-IT study

Rounding out the session, Helena Elding Larsson of Lund University in Sweden presented results from her study of GAD as a vaccine for children at high risk of developing the disease. Unfortunately, this intervention showed no effect. According to Larsson, the study was small and not powered for subgroup analysis.

Joseph Wolfsdorf, a professor of pediatrics at Boston Children’s Hospital, said it was too early to rule out a possible use for GAD antigens. Many other variables may be at play; timing, the adjuvant, dosing and regimen, route of administration. But the trial and error, as always, is hard. 

Photo: Hero Images, Getty Images

Shares0
Shares0