Research

We predict that the unique metabolic preferences and tendencies enabling β-cells to act as glucose sensors are tied to their role in initiating or amplifying inflammatory pathways. By defining the precise molecular players, we aim to develop therapeutic strategies to mitigate unwarranted immune cell activation in diabetes by exploiting metabolic dependencies. We have identified candidate pathways associated with disease in the human Type 1 and Type 2 islet niche. Our ongoing effects apply mechanistic studies to determine whether these candidates have cause vs. effect roles in diabetes.

Our previous studies discovered that favorable glucose metabolism forms a unique and important connection to nitrogen metabolism in the urea cycle. This link protects β-cells from inflammatory and diabetes-related stress at the cell-intrinsic level by restricting β-cell death. Expression of Arginase 2 (ARG2; the β-cell and more ubiquitous isoform) is necessary and sufficient to enhance intrinsic β-cell survival against stress. Since ureagenesis helps eliminate NH4+, we suspect that inflammation causes nitrogen to build up, driven by pro-inflammatory signals. We propose that this nitrogen accumulation plays a critical role in inflammation-induced β-cell loss and perhaps in other settings where autoinflammation leads to destruction of self-cells. Our ongoing research is dedicated to identifying the key mediators that connect nitrogen buildup to cell death pathways, paving the way for targeted interventions.

While methods to generate β-cells from stem cells are rapidly improving, these cells often fall short of resembling native β-cells in vitro functionally and metabolically. Moreover, challenges of immune rejection and autoimmune activation must be overcome to improve stem cell β-cell replacement therapies to treat Type 1 diabetes. Our work harnesses the power of molecular metabolism not only improve β-cell function but also to fortify their defense against inflammatory insults. By minimizing β-cell loss, we aim to moderate the escalation of inflammatory pathways and immune responses, ultimately improving the success and longevity of transplantations. While there are many immune cell types involved during transplantation responses and in autoimmunity, we are focusing on the macrophage as an initiating and activating component.