Type 1 Diabetes, TRIGR, and the future of diabetes research: an interview with Dr. Denis Daneman

Type 1 Diabetes, TRIGR, and the future of diabetes research: an interview with Dr. Denis Daneman

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By: Ana Stosic

Walking down the halls of the Hospital for Sick Children (SickKids) with Dr. Denis Daneman meant that seldom were we able to pass by a person who did not recognize and acknowledge him. “You’ll find that when you have spent as much time in one place as I have, you get to know everyone,” he remarked.  As we learn more about Dr. Daneman, we come to see the passion, the dedication, and above all, the perseverance, that has fueled his ground-breaking achievements in diabetes research.

Dr. Daneman completed his medical training in South Africa, and his residency in paediatrics at SickKids in 1975. It was while pursuing his medical training that Dr. Daneman first became involved in research, with an emphasis on type 1 diabetes (T1D), a chronic condition in which the pancreas produces little to no insulin. This ultimately led to a life-long research career that has contributed to shaping the field as we know it today. “Diabetes is a phenomenally complex biochemical condition which essentially affects all bodily systems,” Dr. Daneman remarks.

In 1981, Dr. Daneman began as staff endocrinologist and was later named Head of the Division of Endocrinology at SickKids, a Senior Associate Scientist with the SickKids Research Institutes, and Professor in the Department of Paediatrics in the Faculty of Medicine at the University of Toronto. In 2006, Dr. Daneman was appointed Paediatrician-in-Chief, a position he held until 2016, at which time he was decorated with the Order of Canada for his outstanding achievements and contributions. Reflecting on his time at SickKids, he notes that “there was a strong culture of asking, what are we doing? And how can we do it better? Not being critical, but taking a critical view.”

Dr. Daneman’s research spans from global initiatives, such as the multi-national Trial to Reduce IDDM (insulin dependent diabetes mellitus, another term for T1D) in the Genetically at Risk (TRIGR), to local pioneering initiatives such as addressing and defining eating disorders in the T1D adolescent population. His contributions to the field of diabetes research have increased the depth and breadth of the literature with regards to insulin resistance and sensitivity, its metabolic control, and the early onset of T1D-related complications. In addition, his collaborative research with Dr. Gary Rodin has defined the field of eating disorders in T1D patients.

In January of 2018, the TRIGR Study Group, within which Dr. Daneman leads the Toronto division, published their findings on whether infants at risk for T1D should have revised dietary restrictions (1). The study was an international double-blind randomized clinical trial that began in 2003.

“This study was inspired when a researcher came to Toronto from New Zealand, on a sabbatical, and noted that in Western Samoa there were no children with T1D.  However, when they moved to New Zealand and Australia they began to develop it,” explains Dr. Daneman. “The big difference is that [in Samoa] they drink coconut milk and eat banana bread–no cow’s milk protein and no gluten. So, we wanted to know: can you alter who develops T1D by altering their diet?”

Using BB-rats as a model for T1D, they were able to assay different feeds’ effects on T1D incidence. This model was used to demonstrate that an amino acid diet led to a 15% risk for diabetes. That risk increased to 35% with the addition of gluten to the diet, and further increased to 53% with the addition of cow milk protein. Nearly 35 years’ worth of research from the TRIGR study aimed to determine whether cow’s milk protein increases the risk of developing T1D. “This was one of the first examples of whether cow’s milk protein played a role,” says Dr. Daneman.

Dr. Daneman and the TRIGR group used the pre-clinical results to design a clinical trial to test T1D preventative measures in infants. The inclusion criteria for patients required that newborn infants had a first-degree relative with T1D and defined human leukocyte antigen (HLA) genotypes, indicative of the risk of developing T1D. Infants were randomized into study groups and stratified by study centers across the 15 countries involved. There were no differences in the demographics or the distribution of HLA genotypes within the study and control groups. Infants were fed either the control formula, containing 80% intact cow milk protein and 20% hydrolyzed milk protein, or the intervention formula, composed of extensively hydrolyzed casein.

Ultimately, during the ten-year follow up, 91 children in the intervention group (8.4%) and 82 children in the control group (7.6%) developed diabetes. These results indicated that weaning on a cow milk-based formula was not associated with an increased cumulative incidence of T1D. The difficulty of translating preclinical research with clinical was made apparent.

“The question, does cow’s milk protein increase the expression of type one diabetes? took 35 years to answer.  So, when individuals talk about translating research into care as quickly as possible, we need to be aware of just how long it takes to get definitive answers from research. It is not a quick process,” Dr. Daneman remarked, snapping his fingers. But no matter how difficult, Dr. Daneman continues to forge ahead to find how to improve the outlook of children with T1D.

While Dr. Daneman’s involvement in global projects is as extensive as it is successful, his local contributions are also of significant calibre and importance. In collaboration with Dr. Gary Rodin, Senior Scientist at Princess Margaret Cancer Centre and Toronto General Research Institute, Dr. Daneman has defined the field of eating disorders in children with T1D. Dr. Daneman and Dr. Rodin have published extensively on the challenges in diagnosis, behaviour, and treatment of adolescents with T1D and eating disorders. Their studies found that eating disorders are twice as common in adolescent females with T1D in comparison with non-diabetic controls (2). Subjects with T1D displayed a 10% prevalence for developing eating disorders, relative to 4% of non-diabetic controls. A further study confirmed that the prevalence of eating disorders increases during adolescence in young women, while also being highly predictive of poor metabolic control (3). Over their lifetime, diagnosed individuals tend to show persistently poor metabolic control, which is deemed to be indicative of subsequent health complications.

While the innumerable contributions by Dr. Daneman and his colleagues have made large strides in the field of T1D, he believes in an even more promising future in diabetes research: “the future of T1D is a continued sophistication of the treatment that will ultimately lead to an artificial pancreas with a sensor for glucose that tells a computer how much insulin to distribute–more when the blood sugar is high, less when it is coming down–taking the brain out of the process. The second area will be in the use of stem cells, or something within that field, which can engineer cells to produce insulin.” Dr. Daneman remarked that the technology is there, and believes the research shows much promise.

A career in research is one that can yield great success as well as Herculean setbacks. “If you don’t have setbacks, if things go too smoothly at the Master’s or the PhD level, you probably haven’t asked a big enough question. The best thing that can happen to you along the way is that you get counterintuitive answers,” says Dr. Daneman. “Sometimes counterintuitive results lead you in a whole different direction, which is very positive.” Dr. Daneman ultimately likens research to an inuksuk, where the “rocks” of sustainability and resilience hold up the “rock” of methodology, which lays the foundation for the content–the pinnacle of the inuksuk. Ultimately, much like methodology lays the foundation for experimental designs, Dr. Daneman’s work lays the foundation for the future of T1D research. His legacy transcends his publications and distinguished accolades to a career which has made, and will continue to make, enormous impacts for patients, their families, the research community, and the future of the field.

References:

  1. Knip M, Åkerblom HK, Al Taji E, Becker D, Bruining J, Castano L, Danne T, de Beaufort C, Dosch HM, Dupre J, Fraser WD. Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial. Jama. 2018 Jan 2;319(1):38-48.
  2. Jones JM, Lawson ML, Daneman D, Olmsted MP, Rodin G. Eating disorders in adolescent females with and without type 1 diabetes: cross sectional study. Bmj. 2000 Jun 10;320(7249):1563-6.
  3. Rydall AC, Rodin GM, Olmsted MP, Devenyi RG, Daneman D. Disordered eating behavior and microvascular complications in young women with insulin-dependent diabetes mellitus. New England Journal of Medicine. 1997 Jun 26;336(26):1849-54.