Final Report Summary - ISLETMESENCHYME (ß-cell Dysfunction in Diabetes: Elucidating the Role of Islet-Associated Mesenchymal Cells)
Glucose homeostasis relies on the tightly controlled release of insulin by pancreatic beta-cells. Diabetes, characterized by increased blood glucose levels, is a chronic disease that is now reaching epidemic proportions. The most common form of this disease is Type 2 diabetes (T2D), which was previously regarded as a disease of insulin resistance. However, work over the past decade has shifted this paradigm by implicating beta-cell failure as a critical factor in T2D. Despite significant progress, the cellular and molecular basis of T2D is far from being elucidated. Here, we characterize the role of an islet-associated mesenchymal cell population, pericytes, which have close contact with beta-cells in both human and mouse pancreata. Our findings revealed that in the adult pancreas, pericytes function to maintain beta-cell maturity and function, and hence are required for glucose homeostasis. In the new-born, pericytes promote proper proliferation of beta-cells. We further linked genetic predisposition to T2D in human with abnormal pericyte function. Our results indicate that T2D-related changes in pancreatic pericytes lead to impaired beta-cell function, resulting in abnormal glucose regulation. Finally, we found disease-related changes in pericytes production of secreted factors. Our findings point to pancreatic pericytes as a key component of the cellular network required for glucose regulation. Furthermore, our results propose that pathological changes in the islet niche are sufficient to cause beta-cell dysfunction and diabetes.