JDRF Postdoctoral Award Abstract: Altered Immunometabolic Associations With T1D Clinical Status and Genetic Risk

GENERAL AUDIENCE SUMMARY

BACKGROUND: There is an alarming trend that the number of people with type 1 diabetes (T1D) is rising, burdening evermore families. In the U.S. alone, (T1D) may affect as many as 3 million people with a 3-5% annual increase in newly diagnosed cases. Patients are typically required to endure lifestyle restrictions that include constant attention to blood glucose levels, which is usually measured from blood obtained by pricking the fingertips with a small needle, and correction with carefully dosed insulin, often by hypodermic needle injection. While the use of insulin is effective for managing the immediate danger of high blood glucose, it is by no means a cure. Indeed, patients remain at risk for life threatening as well as life altering complications. Therefore, new ways to detect, treat, prevent and reverse T1D are essential. One strategy for developing new treatment tools is to target the immune cells that are responsible for the loss of the body’s original source of insulin. First, however, a better understanding why and when these cells target and attack the source of insulin must be discovered. One possible reason is that their metabolism, that is, how the cells use nutrients for energy and growth, is not properly controlled. In studies using animal models, improper control of metabolism by immune cells has been shown to affect how the immune system works, but whether or not this is also true in human immune cells is poorly understood, especially with regard to T1D.

OBJECTIVE: The objective of this project is to detect when an immune attack on insulin-producing cells is occurring or is likely to occur, and to discover new ways to thwart the attack by taking advantage of metabolic attributes that are unique to these autoreactive cells. To achieve this, we will test our hypothesis that altered metabolism within the cells that drive immune responses may be one of the initiating events in the disease process, eventually allowing for the destruction of insulin producing beta cells.

APPROACH: We have developed a new method to measure the metabolism of different types of immune cells. The results of a preliminary study using this method suggest that metabolism is altered, for at least one type of white blood cell, from T1D patients and at-risk individuals. Based on this result, we will first adjust our metabolic test to be compatible with more of the types of immune cells that are present in blood to increase the likelihood that altered metabolism will be detected. The second Aim is to measure immune metabolism on a more comprehensive set of samples to more accurately assess the utility of this assay for T1D biomarker detection.

ANTICIPATED OUTCOMES: At the conclusion of this study, we will have developed a new and valuable method to measure metabolism in human immune cells. We will also establish how metabolism changes in human immune cells through an immune response. Finally, we will establish whether or not immune metabolism in T1D patients or at-risk individuals is altered. The results from this research will begin to resolve many unanswered questions as to human immune cell metabolism as it pertains to immune function. This is an important step for discovering new ways to target and prevent the immune attack on the source of insulin via treatments that target metabolic pathways. Moreover, this work may spur the development of this technology, resulting in new clinical tests to predict or monitor disease activity.