By Richard Insel, M.D.
As JDRF remains steadfast in its mission of curing type 1 diabetes, we are also committed to both improving treatments for individuals with the disease and preventing the disorder itself. Our treatment priorities include developing new drugs and devices that significantly improve glucose control, reduce the daily burden of living with type 1 diabetes, and maintain good health until we have a cure. And, as we will describe, JDRF is also prioritizing the prevention of type 1 diabetes. In fact, we strongly believe that the prevention of type 1 diabetes represents a type of “cure” for individuals who are at risk for developing the disease.
The changing incidence and prevalence of type 1 diabetes across the world with its increasing public health burden and the recent impressive scientific advances have catalyzed a more urgent and focused approach to prevention. The incidence of type 1 diabetes has been increasing for the last three to four decades in the United States, Europe, and Australia. What has become quite striking is that the disease is occurring much earlier in life. In European children one to five years of age, the incidence is increasing at a rate of 5.4 percent annually, a rate much higher than other age groups. This increase in incidence will lead to a doubling of the number of cases in that age group in Europe in this decade1. In fact, projections suggest that children between the ages of one to five years will soon represent the peak age of onset of type 1 diabetes in several European countries2. Similar trends are being seen in the United States. In addition to this earlier age of onset of type 1 diabetes, the disease is occurring increasingly in individuals who had been previously considered to be at low-moderate genetic risk, suggesting that there is now a lower threshold for developing the disease3.
Why in such a short period of time—30 to 40 years or so—has the incidence increased, the age of onset decreased, and the threshold for risk been lowered for type 1 diabetes? We know that the cause or “etiology” of type 1 diabetes arises from contributions of both genetics and environmental factors. This alteration in the epidemiology of type 1 diabetes appears likely to arise from environmental factors because it is not possible for genetics to change in such a short period of time. We do not know, however, what specifically in the environment has changed. Not only has type 1 diabetes been increasing in young children, but also allergic disorders such as peanut allergy and other food allergies are far more prevalent in children today than in the past, and the overall rate of autoimmune diseases other than type 1 diabetes has also increased. Each of these diseases or disorders shares a common characteristic: a defect in immunoregulation—the process by which the immune system controls and balances all of its various components and their interactions to prevent reactivity to one’s own tissues and organs.
Early in life, the body establishes immunoregulation through the maturation and education of the immune system. This is accomplished primarily via the microorganisms or so-called microbiota that reside in the gastrointestinal tract and live in a symbiotic relationship with the human body. A testable hypothesis that JDRF is investigating is whether the increasing incidence, earlier age of onset, and lower threshold of risk of development of type 1 diabetes is the result of a change in the microorganism composition within the intestinal tract that leads to less robust immunoregulation, especially in early childhood. Possible explanations for a change in the makeup of the intestinal microbiota in early childhood include administration of antibiotics to mothers or infants, antibiotics in the food supply, changes in breast milk immune factors, or undefined environmental factors.
JDRF is funding research that aims to identify and define the contribution of the microbiota and other potential specific environmental etiologies (viruses, food, toxins, etc.) to type 1 diabetes. One major research effort is a multi-country consortium—The Environmental Determinants of Diabetes in the Young (TEDDY). This study is funded by the NIH Special Diabetes Program (SDP), a program that is made possible in part by JDRF advocacy. TEDDY, a prospective clinical study, is following approximately 8,000 children who have increased genetic risk to sample their environmental exposures and assess their development of the beta cell autoimmunity associated with type 1 diabetes and the onset of the disease. TEDDY is an outgrowth of several JDRF-supported epidemiological and clinical pilot studies conducted in children. JDRF is also organizing its own Microbiome Consortium, comprised of JDRF-funded researchers in the field of type 1 diabetes as well as expert investigators outside of this field—in its effort to expedite progress in this important area of research.
JDRF is pursuing two approaches to prevention of type 1 diabetes—primary and secondary prevention. “Primary prevention” refers to the prevention of the onset of the beta-cell specific autoimmune attack on the insulin-producing beta cells in the pancreas that is associated with type 1 diabetes. “Secondary prevention” refers to the prevention of insulin dependence in at-risk individuals after the onset of beta cell-specific autoimmunity.
For both primary and secondary prevention, JDRF will focus on population-based approaches that target childhood-onset type 1 diabetes. There are several reasons that support targeting the childhood-age population. First is the markedly increased incidence of type 1 diabetes in early childhood and its lowered threshold for development. Second, researchers know more about the actual course or “natural history” of the disease in children compared to what is known in adults. We have come to appreciate that the onset of the autoimmunity associated with type 1 diabetes in childhood commonly begins in the first few years of life although overt diabetes with insulin dependence may not occur until years or even more than a decade later. This prolonged incubation period, which reflects gradual autoimmune destruction of beta cells, provides a window of opportunity for secondary prevention interventions to delay and ultimately prevent insulin dependence.
Primary prevention will focus on developing vaccines for universal infant and childhood immunization, which is likely the most cost-effective approach to the prevention of type 1 diabetes. JDRF is currently at an early stage of investigating the potential of three different types of diabetes vaccines:
- Diabetes-related viral vaccines to prevent infection with viruses associated with the disease in multiple countries over time
- Beta cell antigen-specific immunoregulatory vaccines that prevent the onset or progression of the autoimmune response associated with type 1 diabetes, which is a major priority of JDRF’s Immune Therapy Program. Such vaccines have additional potential applications to prolonging the “honeymoon period” (when insulin is required at lower doses) after disease onset and for being a component of a biologic cure of established disease when combined with beta cell regeneration therapies
- Vaccines to augment or accelerate microbiome-induced immunoregulation in infancy, as discussed above.
For any diabetes vaccine that is developed, both the safety and efficacy in preventing type 1 diabetes will need to be demonstrated in clinical trials.
In contrast to primary prevention with universal childhood intervention, secondary prevention will target specifically a subset of children who have evidence of onset of the beta cell-specific autoimmunity associated with type 1 diabetes. Childhood population-based screening will be required. Children who are identified as being at-risk will subsequently need to be followed to monitor their progression and to intervene to prevent the onset of overt type 1 diabetes with insulin dependence.
Currently, it is possible to screen for the risk of type 1 diabetes. The two approaches that are used include screening at birth for genetic risk and following the at-risk cohort that has been identified for the development of beta cell-specific autoantibodies as evidence of the specific autoimmunity associated with the disease. The second approach is to screen directly for beta cell-specific autoantibodies. Relatives of individuals with type 1 diabetes are at a higher risk of developing type 1 diabetes compared to the general population and many of these individuals are being screened for the presence of autoantibodies. Today, more than 15,000 first- and second-degree relatives of individuals who have type 1 diabetes are being screened for risk each year in the United States, Europe, and Australia. These individuals are screened by detecting for the presence of beta cell-specific autoantibodies as part of the Natural History Study of TrialNet, supported by NIH SDP funding and also directly by JDRF. Individuals identified through screening who are at risk are then being followed prospectively to better understand the natural history of type 1 diabetes and are being offered the opportunity to participate in clinical trials to prevent the onset of type 1 diabetes.
It has been found that the subjects enrolled in these types of natural history trials are usually diagnosed with type 1 diabetes at an earlier stage, and at the time of diagnosis, they tend not to develop diabetic ketoacidosis and avoid hospitalization. Earlier diagnosis also results in greater residual beta cell function being present at both the time of diagnosis and for at least one year after diagnosis, which may prove to confer better glucose control and decreased risk for developing hypoglycemia and long-term diabetic complications. For information about having relatives of affected individuals screened for risk, click here.
JDRF strongly endorses the screening for risk of type 1 diabetes for relatives of individuals with the disease. Unfortunately, this approach can only detect a very small number of the individuals who are at risk of developing type 1 diabetes because only about 10 percent of new onset cases have an affected relative. Thus, population-based and specifically childhood population-based screening approaches need to be developed and they must be more cost-effective than current approaches.
For secondary prevention of type 1 diabetes, JDRF will focus in the future on developing cost-effective screening and improved blood-based markers (called “biomarkers”) for staging and scoring progression to the onset of overt diabetes. JDRF is developing multiple therapeutic interventions to halt the progressive loss of beta cell function in order to delay and ultimately prevent the onset of disease in at-risk populations. These interventions are focused on preserving the survival of beta cells by targeting alone or in combination: inflammation in and around the pancreatic islets; beta cell-specific autoimmunity; strengthening the health and survival of the beta cell directly; and/or addressing glucose intolerance and insulin resistance.
Of interest, these same therapeutic approaches will prove directly applicable to preserving residual beta cell function in newly diagnosed type 1 diabetes and to curing the disease when combined with beta-cell regenerative therapies. Therefore, secondary prevention therapeutic strategies directly overlap with efforts to cure type 1 diabetes.
JDRF recognizes that the safe and effective prevention of type 1 diabetes, whether it is primary or secondary prevention, will have a relatively long developmental timeline because prevention trials must be conducted for years to assess efficacy. Furthermore, JDRF will need to partner and leverage its financial and non-financial resources with that of academia, industry, government organizations, payers, and providers to both develop these approaches and to implement childhood population-based prevention. In spite of these challenges and risks, JDRF is the only organization that can effectively champion the prevention of type 1 diabetes with the broad and ambitious vision outlined here. Our current stakeholders and the next generation demand nothing less.
1. Patterson CC, Dahlquist GG, Gyürüs E, Green A, Soltész G; EURODIAB Study Group. 2009. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet. 373:2027-33.
2. Harjutsalo V, Sjöberg L, Tuomilehto J. 2008. Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study. Lancet. 371:1777-82.
3. Steck AK, Armstrong TK, Babu SR, Eisenbarth GS. Type 1 Diabetes Genetics Consortium. 2011. Stepwise or linear decrease in penetrance of type 1 diabetes with lower-risk HLA genotypes over the past 40 years. Diabetes. 60:1045-9.