How Immune Checkpoint Inhibitors Can Induce Diabetes

When Ana Luisa Perdigoto, MD, PhD, first joined the lab of Kevan Herold, MD, to study type 1 diabetes, patients were just beginning to develop immune checkpoint inhibitor-induced diabetes. As more people were being treated with this new type of cancer immunotherapy, this side effect was becoming more common.

“I was very interested in the crossroads of endocrinology and immuno-oncology,” says Perdigoto, an assistant professor of medicine (endocrinology and metabolism) at Yale School of Medicine. “So I made a shift toward understanding checkpoint inhibitor-induced diabetes with the idea that it would also potentially help us understand type 1 diabetes.”

While less than 2% of patients who are treated with checkpoint inhibitors develop this kind of diabetes, the condition is considered irreversible, Perdigoto says.

In a Q&A, she discusses how this type of immunotherapy can induce diabetes, which patients may be more susceptible, and how her research seeks to prevent and treat this life-altering condition.

Checkpoint inhibitor therapy targets certain proteins, called checkpoints, on T cells, preventing them from binding to their partner proteins on other cells such as tumor cells. This inhibition leads to T cell activation and tumor cell destruction.

These T cells can also target the body's organs. Checkpoint inhibitor therapies have been shown to cause immune-related adverse events in almost all organ systems. Interestingly, some of the more commonly targeted organs are the endocrine organs, such as the thyroid, pituitary, and pancreas. Involvement of the pancreas can lead to a form of autoimmune diabetes. Once endocrine organs are attacked, patients usually need to be on lifelong hormone therapy, as far as researchers currently understand.

We consider it like type 1 diabetes, with some differences.

Patients who get started on checkpoint inhibitors will often present with very acute and severe hyperglycemia. It's usually very rapid. And a good proportion of patients can present with diabetic ketoacidosis, which is a severe complication, and they'll often have very low amounts of their own insulin. In this type of diabetes, a lot of patients don't make any of their own insulin. And those who do usually lose that ability over weeks. In contrast, some patients diagnosed with type 1 diabetes can maintain some amount of their own insulin, sometimes for a long time, even years.

But checkpoint inhibitor-induced diabetes presents clinically like type 1 diabetes because the immune system is attacking the beta cells in these patients. It is treated similarly to type 1 diabetes.

One of the things that we discovered in collaboration with our oncology colleagues, notably Harriet Kluger, MD, is that a significant proportion of the patients who develop this type of diabetes have a change in a gene called NLRC5. The protein from this gene regulates MHC class 1 presentation of antigens to the immune cells. It might be that these individuals have an increased ability to present pancreatic beta cell antigens to the immune cells, thus making beta cells more susceptible to being killed. This is an area we are currently investigating further.

Checkpoint inhibitor-induced diabetes is a complication that changes patients' lives significantly. Suddenly, they are not only dealing with advanced cancer but also having to constantly monitor their blood sugars, take insulin, and watch what they eat.

I hope that by understanding how this type of diabetes works, my research can potentially find treatments that prevent or reverse it.

Endocrinology and Metabolism, one of 10 sections in the Yale Department of Internal Medicine, improves the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge, applying new information to patient care, and training the next generation of physicians and scientists to become leaders in the field. To learn more, visit Endocrinology and Metabolism.