Objective
We aim to explore the impact of metabolic stress on the beta cell mitochondria which are the powerhouses of the cell. As metabolic stress, caused by factors like high glucose or unhealthy fats, has been associated with beta cell dysfunction in type 2 diabetes, we suspect that such conditions would trigger changes in beta cells that could provoke the immune system.
Through this program, we'll closely examine the genetic code within mitochondria, searching for novel mutations caused by metabolic stress, and evaluate the potential role of these variants as antigens. By deciphering the molecular mechanisms driving the response to metabolic stress we will pave the way for potential advancements in addressing T1D health issues related to metabolic stress.
Background Rationale
The global incidence of diabetes has been consistently rising, affecting hundreds of millions of people worldwide. While type 2 diabetes (T2D) is associated with obesity and overweight leading to beta cell dysfunction, type 1 diabetes (T1D) is characterized by the progressive and specific destruction of the insulin-producing beta cells by the immune system.
Although initially described solely as a consequence of a problem of the immune system, more and more studies illustrate the important role of the beta cells in driving autoimmunity in T1D. Furthermore, the recent association between higher body mass and increased risk for developing T1D suggests that the high demand for insulin could make beta cells more prone to being destroyed. In this new project, we hypothesize that alterations in the metabolism may not only play a role in the development of T2D but also T1D.
Description of Project
In type 1 diabetes, pancreatic beta cells have always been described as a victim of the immune system, but recent studies illustrate an important role for the beta cells actively driving autoimmunity in T1D. The newly reported association between higher body mass and increased risk for developing T1D suggests a metabolic component to the development of islet autoimmunity. We hypothesize that metabolic imbalance can sensitize beta cells, prime the immune system, and trigger the development of autoimmunity in some of the patients. These results will not only improve our knowledge of the molecular mechanisms driving autoimmunity but also shed light on the importance of careful food intake management to prevent T1D in at-risk individuals and to limit beta cell destruction in patients.
Anticipated Outcome
We anticipate that metabolic stress will alter cellular homeostasis and generate errors that will be recognized by the immune system. Such results will demonstrate the importance of the mitochondria in beta cells and the need for a careful management of blood glucose to alleviate cellular stress and further beta cell destruction
Relevance to T1D
The destruction of beta cells in type 1 diabetes is caused by chronic inflammation and autoimmunity. In response to inflammatory signals, the islets of Langerhans activate adaptive mechanisms in which two specific compartments (endoplasmic reticulum and mitochondria) within the beta cells collaborate to restore and maintain cellular balance. In recent years, it has become clear that this adaptation phase can stimulate the development of autoimmunity by producing new beta cell proteins ('self-antigens') subsequently recognized by autoreactive cells. Therefore, it appears that type 1 diabetes is not so much a result of an immune system mistake but rather a misjudgment of stressed beta cells, to which the immune system responds, perhaps with the best intentions.
In this program, we will determine the importance of beta cell ‘fitness’ and unravel the features of stressed beta cells that cause the immune system to respond and destroy them. This knowledge will be essential for the design of novel therapeutic strategies targeting beta-cells to improve their health and ‘happiness’, to be combined with future immune intervention therapies. Importantly, in the short term, knowledge on pathways that derail beta-cells, such as dysglycemia, may help reducing or preventing beta-cell stress. This new knowledge would immediately warn type 1 diabetic patients to optimize their glycemic control, as this will reduce the burden on beta-cells, provide relief of beta cell stress, and offer the diabetes research community the extra time needed to interview and protect these beta-cells from further autoimmune attack. It has become well-established that preserving even a minimal reserve of functional beta-cell mass reduces the risk for diabetic complications, including neuropathy, nephropathy, cardio-vascular disease, and notably hypoglycemia unawareness.