Type 1 diabetes prevention is a "downhill" challenge.


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.