Two Minus One: 2017 ADA Annual Meeting

Invited article

Two Minus One:

2017 ADA Annual Meeting with a Paucity of Studies in Type 1 Diabetes


Lawrence Steinman MD

Professor of Pediatrics, Neurology and Neurological Sciences

Stanford University


            We all know the names Banting and Best.  Nearly one century ago in 1923 Frederick Banting and his department chair, John McLeod won the Nobel for the discovery of insulin. Link to reference    Banting shared his prize money with his younger collaborator, Charles Best, who was a medical student at the time.   The saga of Banting, Best and McLeod and the discovery of insulin is legendary.  Yet type 1 diabetes, remains a relatively neglected disease compared to its counterpart, “the other” diabetes known as type 2 diabetes.  At the recent ADA meeting the paucity of presentations aimed at developing disease modifying therapies for type 1 diabetes was glaring.  I refer to the attention given to Type 2 diabetes in comparison to that devoted to Type 1 diabetes as “Two Minus One”.


            Type 1 diabetes deserves far greater attention.  We know that the disease is inflammatory, and probably autoimmune.  We know the identity of the targets of the immune attack-islet antigens including proinsulin, glutamic acid decarboxylase (GAD), zinc transporter, and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP).  We know that in childhood diabetes the development of a high affinity antibody to proinsulin is the harbinger of the development of clinical disease.  The immune attack is highly localized with general sparing of the exocrine pancreas, and pinpoint destruction of the islets of Langerhans.


            Despite this wealth of knowledge gained over the past century since Banting and Best (and McLeod), there have only been a few attempts to tolerize the immune system, so that a “cease fire” could be induced to silence the immune destruction of the insulin-producing islets.  At the recent ADA meeting that concluded two weeks ago in San Diego, the following trials in type 1 diabetes were reported:


Tolerizing to GAD


            Results of a five year study to prevent the onset of type 1 diabetes, by tolerizing the immune system to GAD were presented in a session entitled “Double-blind, Randomized Investigator-initiated Study to Determine the Safety and the Effect of Diamyd® on the Progression to Type 1 Diabetes in Children With Multiple Islet Cell Autoantibodies."  Children at risk for type 1 diabetes who already had GAD antibodies and an antibody to at least one other islet antigen were given two doses of 20 micrograms of GAD in Alum or placebo at entry and 30 days later, a classic prime and boost regimen.   There was no significant effect on preventing type 1 diabetes in the children enrolled in this small trial of 50 individuals.  From my perspective as an immunologist, I have wondered over the years why alum-the only approved adjuvant for vaccines used here in the US, would be added to GAD in an attempt to tolerize.  In many common vaccines ranging from tetanus immunization to HPV immunization, alum is a key component. Alum is added to accomplish the opposite of tolerization, namely vaccination! Fortunately the trial with alum mixed with GAD was safe, and no untoward responses to GAD were reported. Link to reference

Oral Insulin

In a randomized placebo controlled trial of individuals with a relative with type 1 diabetes, who themselves had two or more antibodies directed to beta cell targets, daily administration of 7.5 mg of insulin failed to prevent disease in a study that followed patients for 8 years.  The strategy here was to give insulin orally in an attempt to tolerize the immune system against autoimmune responses to insulin itself.  Unfortunately this was yet another setback in attempts to tolerize the immune system by giving antigen, in this case insulin, via the oral route. Link to reference



Gleevec is a magic bullet in cancers where the Bcr-Abl tyrosine kinase is mutated and “locked” in an “on-state”.  It is approved for chronic myelogenous leukemia, acute lymphoblastic leukemia and certain gastrointestinal stromal tumors.  Gleevec and other tyrosine kinase inhibitors show some benefits in pre-clinical models of autoimmune disease.  An early stage safety trial was done in 67 patients with type 1 diabetes.  Insulin requirements were described as reduced by nineteen percent.  Principal investigator Dr. Stephen Gitelman said, “The conservative estimate is that beta cell function was maybe 19 percent better at one year. So it’s not a slam-dunk home run.”  Slam-dunks and home runs are not often in the same sentence, as they represent metaphors from two sports-basketball and baseball.  Repurposing a cancer drug in an autoimmune disease is like applying a basketball metaphor to the “national pastime”. Link to reference


The previously published study of alefacept was featured at the ADA session on Therapies to Preserve Beta Cells in Type 1 Diabetes as an example of a therapy that demonstrated efficacy on the primary endpoint of C-peptide by 24 months. Link to reference The authors had described the 24-month results of the T1DAL trial as providing “the most promising proof of concept to date that a brief course of a targeted, well-tolerated immune intervention in the new-onset period can produce lasting clinical and metabolic benefits, long after cessation of therapy.”  The authors also acknowledged that a similar magnitude of C-peptide preservation was also observed after longer-term follow-up in patients treated with anti-CD3 monoclonal antibodies (teplizumab and otelixizumab), but contrasted the greater safety of alefacept with these agents. Like Gleevec, however, alefacept’s blunt mechanism of action to deplete T cell still causes safety concerns.  It is encouraging to see studies that demonstrate efficacy against T1D autoimmunity, but it is time to limit such trials to agents that start with appropriate safety profiles for the condition being treated or prevented.

Metformin REMOVAL Trial

On the other hand, a JDRF-supported study reported at ADA reflected a large effort to show an effect that the intervention was unlikely to deliver. Metformin was tested in a trial in adult type 1 diabetics. Cardiovascular risk was the primary endpoint with the readout as significant reduction in mean far-wall carotid artery intima-medial thickness (cIMT) at 3 years.  The role of metformin in reducing CV risk in type 2 diabetic patients has been controversial since favorable findings were observed in the non-randomized metformin treatment arm of the UKPDS. Link to reference The double-blind placebo controlled REMOVAL Trial of 1000 mg twice daily or placebo as adjuncts to insulin failed to meet the primary endpoint. Link to referenceCuriously, the report in LANCET Endocrinology and Metabolism cited a tertiary efficacy result to justify the second part of the conclusion: “These data do not support use of metformin to improve glycaemic control in adults with long-standing type 1 diabetes as suggested by current guidelines, but suggest that it might have a wider role in cardiovascular risk to reference  It is unclear what wider role the authors could be referring to. The Removal Trial raises the question: Does JDRF simply not have enough diseases modifying or preventing approachesto support, or is it being distracted from its mission to cure type 1 diabetes?

Going Forward


The trials reported at the ADA for type 1 diabetes were few, and results were in general not encouraging at all.  Type 1 diabetes, that immune disease where the beta cell is quite specifically targeted, remains an unsolved problem. The targets of the immune system in type 1 diabetes are quite well-known.  Several new approaches to specifically tolerizing the immune system to stop the destruction of islets have been designed and some are being taken forward into the clinic. Link to reference 


In the next few years we hope to see successful clinical trials in type 1 diabetes, by which the major pathophysiologic defect-antigen specific autoimmunity-is addressed.  Anthony Cerami, the discoverer of the A1c hemoglobin assay, has written a poignant article about what we can learn from failures in translational medicine: “The hurtful feelings associated with failing can be devastating especially if the failure occurs after the investment of a considerable effort. The reflection of a lifetime of work in translational medicine has revealed that the study of failures can give birth to new insights that can be explored with important consequences.” From Cerami A, The value of failure.  Link to reference


Diabetes congresses that are “Two Minus One” affairs these days, might in the future feature bold investigators who might report success. In type 1 diabetes the last decisive advance, the discovery of insulin, is nearly 100 years old.  Perhaps trials aimed at precise tolerization of the immune response to targets in the beta cells will produce those elusive stories, and at last we would have a disease modifying therapy for type 1 diabetes.


Conflict of Interest: Steinman is a co-founder and Executive Chairman of Tolerion