Type 2 diabetes (T2D) is the most common chronic disease affecting human health. Recent longitudinal and genome-wide association studies provide strong evidence that the ability of pancreatic β-cells to fulfill insulin demand through development, growth, survival, and function is a key determinant of whether an individual will develop T2D under various nutrient conditions. However, there are no effective clinical treatments that target β-cell growth and maintenance of their differentiated identity as insulin producing-cells. These researchers propose that nutrient sensor proteins like mTOR and OGT (O-GlcNAc Transferase), a nutrient-sensor expressed at a very high level in β-cells, have key developmental regulatory properties and the ability to integrate signaling networks to regulate β-cell plasticity in response to insulin demand and nutrient stress. OGT and mTOR couples nutrient and hormonal cues to orchestrate and fine-tune glucose metabolism, and β-cell growth and maintenance of identity under stress responses. Thus, the long-term goal of this research is to define the mechanisms of how OGT and mTOR integrate signaling networks impinging on β-cell plasticity (development and identity) to promote functional β-cells.
The researchers use multiple genetic animal models to understand the role of OGT and mTOR in various stages of β-cell development and under metabolic stress like diet-induced obesity.