Type 1 diabetes (T1D) is an autoimmune disease which is driven by a subset of white blood cells known as Th1-lymphocytes. Through a complex series of steps, some known and other poorly understood, the insulin producing pancreatic β-cells are slowly destroyed. This results in a life-long dependency on injected (or infused) insulin, daily self-care responsibilities, and significant risks for short and long term health concerns and complications.
The way type 1 diabetes develops is complex and nuanced. It involves the activation of both major arms of the immune system, known as the humoral and cellular, and an imbalance between certain classes of white blood cells called effector and regulatory T cells (members of the cellular system). A group of white blood cells known as “autoreactive CD4+ and CD8+ Th1 lymphocytes” are directly involved in the production of chemical agents (chemokines and cytokines) which attract a special group of immunity cells (called macrophages) to the islets. A process called insulitis then occurs (immune cells infiltrate and inflame the islets, where the insulin producing beta cells are located). Over time, near complete β-cell destruction occurs.
An “island of Langerhans” as it was once called, is a three-dimensional cluster or ball of cells. In the core of the balls lies most of the β-cells. The immune system is precise in targeting only the β-cells for eventual destruction. As β-cells are laid siege to by the immune system, many will give up and self-destruct (a process known as ‘apoptosis’) whereas other β-cells are actively destroyed by the T-cell invaders. To date, there is no cure or prevention for T1D and, unfortunately, human β-cells cannot yet be properly regenerated once destroyed. β-cells do have a limited capacity to defend and regenerate, but not enough to fend off such a coordinated and relentless immune onslaught.
Dr. Eisenbarth's famous downhill model
It’s important to understand and appreciate how medical researchers approach the prevention of type 1 diabetes. It’s based on the natural history of the evolution of the disease as described thirty years ago, by Dr. George Eisenbarth. He described how β-cells were systematically attacked and destroyed over the span of months to years. The process of destruction starts with a genetically susceptible person who is exposed to an environmental trigger (many have been identified and proposed). Like the lighting of a fuse, the process of β-cell specific autoimmunity is kicked off and diabetes autoantibodies may soon be detected in the bloodstream. As the power of the immune system is unleashed, β-cell mass diminishes. This results in a person progressing from totally normal blood sugar control to abnormal glucose tolerance and, ultimately, to sustained high blood sugars (hyperglycemia) and symptomatic T1D. If you or your child developed diabetic ketoacidosis prior to diagnosis, the autoimmune process had long been at work with your body most likely without your knowledge.
Eisenbarth’s model looked much like the profile of a downhill ski slope. Standing at the top, there is a full complement of β-cells (100%). But there is a pre-existing genetic predisposition waiting for the right circumstances or trigger to light the fire of autoimmunity inside the islets. Now, all is completely normal and there is full insulin production and response by the body.
As the process expands, multiple antibody markers can be detected in the blood circulation. Like the smoke from a fire, these reflect an ongoing process of progressive β-cell destruction and decay. The first drop down the steep slope begins.
Since the pancreas possesses far more β-cells than we need each day, many are inactive or dormant. As clusters of active β-cells are incapacitated, others are recruited from their dormancy to pick of the slack. This only results in the immune system taking notice and starting the process anew in another region of the pancreas. There is some limited ability of the β-cells to fend off this attack, but like the defenders of the Alamo, their fates are largely sealed as time moves along. This is one reason the process of diabetes development can take time compared to your typical short term inflammatory response to a foreign invader.
Eventually, enough β-cell function is lost to result in measurable changes to the blood sugar levels because of impaired insulin production and release. This is still not to the level which would classify a person as having diabetes, so the β-cells are still on the downhill slope but not yet at the bottom. Not until at least 80% of the total β-cell mass of the pancreas is compromised will any diabetes symptoms be experienced. These include increased thirst and urination, poor weight gain or actual weight loss and perhaps an increased appetite. The increased appetite is one way the body compensates for the weight loss, but without enough insulin to help store away the calories eaten as body tissue, the weight loss continues. At this point, the bottom of the slope has been reached.
Finally, if symptoms are not recognized or properly worked up by a doctor, the person might build up such a massive ketone load (due to lack of insulin and increased levels of stress hormones) as to radically alter the acid-base composition of the bloodstream. This results in nausea and vomiting resulting in severe dehydration with a deep labored breathing pattern: classic diabetic ketoacidosis (DKA). This would be equivalent to wiping out at the bottom of the run and crashing into a tree.
Analyses of observational data from groups of high-risk individuals have allowed development of risk scores that can adequately predict the likelihood of developing T1D within a given time window. Per this research, study of at risk individuals has revealed that those with multiple diabetes autoantibodies have an 85% ten-year risk and nearly 100% lifetime risk of developing T1D. Given this inevitability, individuals with multiple autoantibodies +/- dysglycemia (some level of abnormal glucose tolerance) are prime subjects for secondary prevention trials to prevent further losses of β-cell mass.
Where along the path do we focus our prevention efforts?
Ideally, T1D would best be prevented by stepping in before β-cell autoimmunity can get started. Per our metaphor: basically, stopping you at the top of the hill, hopefully before you even got off the ski lift. This is called “primary prevention” and involves actions and interventions that prevent the earliest stages of the disease from occurring. In T1D, this would need to happen before the development of β-cell specific autoimmunity. Natural history studies of high-risk infants and family members have revealed the presence of diabetes autoantibodies as early as 6 months of age, but typically between 9 and 24 months of age. Using this approach, an intervention would need to occur in high risk babies before 9 months of age. Given this young age, a primary prevention therapy needs to be very safe and easily administered to newborns and infants. Such interventions would include administration of autoantigens or dietary modifications. Perhaps one of the largest hurdles in expanding primary prevention trials in T1D is that greater than 85% of those diagnosed with T1D have zero family history. Therefore, the clear majority of people progressing towards T1D are invisible until the time of their diagnosis. As things stand now, primary prevention is best employed in only high-risk individuals, such as those with affected first-degree relatives or high-risk HLA genotypes (genetic makeup).
Secondary prevention of type 1 diabetes involves interventions that aim to stop progression of disease in the early or pre-symptomatic stages (i.e., blood sugars still normal). This would be like catching you as you are just starting down the ski slope and well before the bottom has been reached. In type 1 diabetes, secondary prevention would occur in those who already have measurable and specific β-cell specific autoimmunity (autoantibody levels). These studies are done when the person has totally normal blood sugar levels and responses, or has ‘pre-symptomatic dysglycemia’. The development of diabetes autoantibodies, currently the most widely established marker of β-cell autoimmunity, typically precedes significant β-cell decline, and these autoantibodies are present months to years before symptomatic disease as mentioned earlier.
Tertiary prevention is an approach that aims to prevent further progression of insulin cell loss in symptomatic individuals and/or develop treatments to minimize diabetes complications. Most tertiary prevention T1D clinical trials have involved suppressing the immune system (called immunosuppression) and/or altering specific immune system responses (called immunomodulatory approaches) in recently diagnosed persons. The rationale is that these patients are most likely to possess clinically significant residual β-cell mass (ability to produce insulin). Therefore, these trials aimed to stop or slow down further β-cell loss, as this could preserve meaningful levels of internal insulin production and/or reduce disease-related complications.
Now that you have an idea of how type 1 diabetes occurs, here is a review of some of the actions which have been attempted so far and what lies ahead.
Early on, T1D clinical trials targeted the adaptive immunity arm of diabetes pathogenesis (special antibodies that targeted and removed certain types of T-cells thought to play a pivotal role in the autoimmune process). Approaches have included monoclonal anti-CD3 antibodies (teplizumab and otelixizumab) and CTLA-Ig (abatacept). Humoral immunity has most notably been targeted with rituximab, a monoclonal anti-CD20 antibody that depletes B cells. B-cells are NOT β-cells. Rather they are immune cells responsible for producing antibodies.
To date, secondary prevention trials have employed some of the same therapeutics used earlier in tertiary T1D prevention trials, such as teplizumab and abatacept. Autoantigen therapy has also been used in secondary prevention. This approach aims to induce immune tolerance through controlled exposure to diabetes-specific autoantigens, such as insulin and glutamic acid decarboxylase-alum. Thus far, secondary preventive approaches have not led to a significant delay in T1D progression.
More recently, trials have attempted to increase the number and/or quality of regulatory T cells (the cellular arm of the immune system). T-regs (as some call them), manage other T cells, usually in a way that reduces or tamps down the aggressiveness of an autoimmune attack. Therapies that block innate immunity have also been tried, most notably with treatments that block interleukin-1 and tumor necrosis factor-α. Innate immunity is used by a variety of cells and tissues to increase or decrease inflammation at the local level. While some of these interventions have resulted in initial β-cell protection, treated subjects ultimately have the same rate of c-peptide decline (loss of internal insulin production) as those who received a placebo.
Immunomodulation (ratcheting up or down certain elements of the immune system) will also likely involve approaches that can restore a more favorable immunological balance by decreasing effector T cells (which act to hit the autoimmunity accelerator pedal) and increasing regulatory T cells (which tend to put the brakes on autoimmunity signals). There will also likely need to be age-specific approaches because recently diagnosed children usually have a more aggressive and harder to stop autoimmune juggernaut than adults with new-onset T1D.
Looking forward, T1D clinical trials will likely involve multi-pronged approaches in which the different points along the pathway of T1D development such as innate immunity, adaptive immunity (antibodies), and intrinsic β-cell dysfunction are targeted at the same time. β-cell defense mechanisms in some cases may be internally compromised by genetic or metabolic factors which might be modified or even reversed in some fashion. Such a “land, sea and air” approach to this process IS the future regarding the prevention of type 1 diabetes.