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Scientists identify a trigger for type 1 diabetes in mice

Scientists identify a trigger for type 1 diabetes in mice

Scientists identify a trigger for type 1 diabetes in mice A discovery in mice suggests a new opportunity for reducing the incidence of type 1 diabetes. Type 1 diabetes is on the rise. Scientists are not exactly sure why this is, but the increase in new cases makes the race to understand this life-threatening condition more urgent than ever.

A new study appearing in the journal Science Immunology suggests that a phantom switch causes the body’s immune system to start destroying its insulin, resulting in the onset of diabetes. If this discovery in mice translates to humans, it could enable early detection and the development of preventive therapies for type 1 diabetes.

The problem of diabetes

Human cells derive energy from glucose, which is a sugar in the bloodstream. Insulin, a hormone produced by beta cells in the pancreas’ islets of Langerhans, allows the body to absorb glucose.

In a healthy individual, the beta cells produce enough insulin to allow the body to consume the available glucose in the bloodstream. However, a lack of sufficient insulin can be fatal.

In type 1 diabetes, the body’s immune system attacks and destroys insulin and the beta cells that produce it. This deprives the body’s cells of the energy that glucose would otherwise provide.

In the United States, about 1.25 million people living with type 1 diabetes depend on continual monitoring of blood sugar and injections of insulin. People with type 2 diabetes also need to be vigilant because their beta cells are not producing enough of the hormone.

A landmark study carried out over 40 years ago revealed that the driver of type 1 diabetes is renegade HLA (human leukocyte antigen). These proteins live on the surface of cells and instruct the immune system to attack foreign organisms and substances.

The study identified that a subset of mutated HLAs bearing a distinct genetic signature was binding to insulin molecules and somehow attracting the attention of immune-system T cells, which then sought out and destroyed insulin and beta cells.

How these T cells become weaponized in this manner remains an unanswered question.

A fine grained approach yields results

The new report, authored by scientists from Scripps Research, and led by professor of immunology and microbiology Luc Teyton, M.D., Ph.D., has uncovered a likely mechanism, at least in mice.

Through a series of experiments over 5 years, Prof. Teyton’s team examined blood samples from nondiabetic, overweight mice deemed to be candidates for the disease.

The scientists sequenced individual T cells from the subjects’ blood and then analyzed the 4 terabytes of data their sequencing had produced.

“By using single-cell technologies to study the prediabetic phase of [the] disease, we have been able to mechanistically link specific anti-insulin T cells with the autoimmune response seen in type 1 diabetes,” says Prof. Teyton.

The scientists’ analysis revealed a mechanism they dubbed the “P9 switch.” The switch belonged to CD4+ T cells, and when the switch was active, the T cells responded to the mutated HLAs and proceeded to attack insulin.

However, these switches existed for just a short while, causing a flurry of insulin destruction and then disappearing altogether. This could explain why other researchers have not discovered such a mechanism in people with diabetes — the switch is long gone by the time diabetes symptoms appear.

It also turned out that these anti-insulin T cells resided within the same islets as insulin and beta cells, their proximity making them that much more effective and dangerous.

Looking for a human P9 switch

If these insights apply to humans, they could constitute a first step toward the prevention of type 1 diabetes. “The translational aspect of this study is what’s most exciting to me,” admits Prof. Teyton.

He has received approval to begin investigating whether his findings could apply to humans.

Type 1 diabetes has a strong genetic association — for those who have an immediate relative with the disease, the risk of developing it is 20 times greater.

Prof. Teyton and his team plan to search for the telltale P9 switch in the blood of 30 such at-risk subjects who have not yet experienced symptoms of the disease.

If the researchers do find the switch and confirm its role in human type 1 diabetes, the discovery could offer doctors and people a new opportunity for early detection. It could also provide a time window during which scientists can develop new therapies to prevent the development of this life-threatening condition.


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