Grant: Project Grant

Beta cells are producing insulin, a hormone controlling blood glucose, and are organized in clusters within the pancreas, a structure called islet. In healthy conditions, the activity of beta cells within each islet are "coordinated" to secrete insulin simultaneously in response to glucose. In type 2 diabetes, the coordination between beta cells is lost, and insulin secretion is dysregulated. Vitamin K is an essential micronutrient known to regulate blood coagulation. However, several studies in humans suggest that insufficient vitamin K intake is linked to the development of type 2 diabetes. Yet, we don't fully understand the biological mechanism by which vitamin K prevents diabetes. We are aiming here at understanding the function of vitamin K in pancreatic beta cells and its link with the development of diabetes. Calcium fluctuation in beta cells is essential for insulin secretion. In a recently published article (Lacombe et al. 2023 Cell Reports), we have determined that protein carboxylation, the enzymatic process controlled by vitamin K, modulates calcium levels in these cells. We have also identified a novel carboxylated protein involved in the beneficial impact of vitamin K in beta cells. Additional data suggest that carboxylation is necessary to preserve the coordinated activity of beta cells within islets. In the current project, using genetically modified mice and human beta cells, we will determine how carboxylation protects beta cell function under conditions of metabolic stress, such as obesity. We will also characterize the cellular and molecular mechanisms by which carboxylation regulates calcium levels in beta cells. Finally, we will define the role of vitamin K and carboxylation in preserving the coordinated response of beta cells to glucose. Altogether, these studies will allow us to understand how vitamin K is implicated in the biology of beta cells and how partial vitamin K deficiency contributes to the development of diabetes.