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unmethylated DNA Affects Diabetes

A Simple Method to Monitor β Cell Death in Individuals At-Risk for Type 1 Diabetes

unmethylated DNA Affects DiabetesType 1 diabetes is characterized by death and reduced function of β cells, which produce insulin.

The presence of specific autoantibodies can identify individuals at risk of developing type 1 diabetes, and many of these at-risk individuals exhibit evidence of β cell death before the onset of clinical symptoms. However, the course of β cell death that ultimately leads to the development of type 1 diabetes is poorly understood.

A new study in the Journal of Clinical Investigation reveals that a DNA biomarker can be used to evaluate the extent of β cell death and type 1 diabetes risk. Kevan Herold and colleagues at Yale University measured the amount of unmethylated insulin DNA in blood in healthy individuals and a cohort at risk of developing type 1 diabetes.

Insulin DNA is methylated in most cell types, which prevents its expression. Therefore, the authors predicted that the unmethylated form of DNA would only be present if there had been substantial β cell death and lysis.

At-risk individuals had much higher levels of unmethylated insulin DNA, and the increase in this DNA biomarker also correlated with a reduction in other measures of β cell function. Moreover, the levels of unmethylated DNA further increased in the period prior to clinical onset.

Together, these results of this study indicate that unmethylated insulin DNA can be used as a marker of β cell death.



Title: β Cell death and dysfunction during type 1 diabetes development in at-risk individuals


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Role of the integrated stress response in type 1 diabetes pathogenesis
In individuals with type 1 diabetes (T1D), the insulin-producing beta cells are spontaneously destroyed by their own immune system. The trigger that provokes the immune system to destroy the beta cells is unknown. However, accumulating evidence suggest that signals are perhaps first sent out by the stressed beta cells that eventually attracts the immune cells. Stressed cells adapt different stress mitigation systems as an adaptive response. However, when these adaptive responses go awry, it results in cell death. One of the stress response mechanisms, namely the integrated stress response (ISR) is activated under a variety of stressful stimuli to promote cell survival. However, when ISR is chronically activated, it can be damaging to the cells and can lead to cell death. The role of the ISR in the context of T1D is unknown. Therefore, in this DRC funded study, we propose to study the ISR in the beta cells to determine its role in propagating T1D.
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