Delaying the Onset of Type 1 Diabetes Through Early Intervention - Episode 2

Pathophysiology of T1D

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Justin M. Gregory, MD, MSC, and Linda A. DiMeglio, MD, provide an overview of the pathophysiology of type 1 diabetes.

Steve Edelman, MD: Justin, talk about the pathophysiology of type 1 diabetes and a suggestion of where that starts.

Justin M. Gregory, MD, MSC: Broadly speaking, we know that the pathophysiology of type 1 diabetes begins with autoimmune destruction of the pancreatic beta cell. What happens is the immune system recognizes beta cells inappropriately as threats. Predominantly, autoreactive T lymphocytes infiltrate into the pancreatic islet and recognize certain antigens on the surface and begin the inflammatory process that we call insulitis. Those autoreactive T cells recognize a host of antigens present on those beta cells. Some of them we know about, things like insulin being an antigen that the immune system is reactive against. There are lesser-known ones like islet cell or islet antigen 2 and glutamic acid decarboxylase. There’s a broad range, and it’s different from patient to patient. That presents some challenges in terms of trying to address breaking down and prevent autoimmune inflammation.

Once the antigens are recognized, those T cells lead to a process where certain cytotoxic chemicals are released, leading to apoptosis of those insulin-producing beta cells. That process is likely influenced by certain genetic predisposing factors. Probably the strongest ones are HLA haplotypes. We think about HLA-DR3 and HLA-DR4 increasing the risk, but there are certain environmental triggers that are still poorly defined. Often individuals want to know what triggered this happening. As a pediatric endocrinologist, the best I can do is speculate, which is a hard thing sometimes as a physician. That beta cell loss eventually leads to the progressive loss of beta cells and the development of type 1 diabetes. From individual to individual, the rate of losing those beta cells differs. In young children, we typically think that the rate of beta cell loss is rapid. In older individuals, by and large it seems to be slower. Different individuals lose beta cells at different rates.

Steve Edelman, MD: Yes, and we diagnose type 1 diabetes later in life, called LADA, latent autoimmune diabetes of adults. Those individuals tend to progress much slower than when I was diagnosed…. When you look at the ratio of healthy regulatory T cells vs autoreactive T cells, the earlier you intervene, the better.

Linda A. DiMeglio, MD: This is a great discussion. The beta cell itself is probably in part at fault. We think that patients who go on to develop type 1 diabetes often had—apologies to those who are living with the disease—wimpy beta cells. Something about the beta cell leads it to be susceptible to that autoimmune attack. There’s something intrinsic. When we get to talk more about therapies, it’s interesting that some beta cell stress agents and things like that are being used in therapies for potentially delaying onset of type 1 diabetes.

Transcript edited for clarity