TGFb Receptor Signaling Is Essential for Inflammation- Induced but Not b-Cell Workload–Induced b-Cell Proliferation

Protection and restoration of a functional b-cell mass are fundamental strategies for prevention and treatment of diabetes. Consequently, knowledge of signals that determine the functional b-cell mass is of immense clinical relevance. Transforming growth factor b (TGFb) superfamily signaling pathways play a critical role in development and tissue specification. Nevertheless, the role of these pathways in adult b-cell homeostasis is not well defined. Here, we ablated TGFb receptor I and II genes in mice undergoing two surgical b-cell replication models (partial pancreatectomy or partial duct ligation), representing two triggers for b-cell proliferation, increased b-cell workload, and local inflammation, respectively. Our data suggest that TGFb receptor signaling is necessary for baseline b-cell proliferation. By either provision of excess glucose or treatment with exogenous insulin, we further demonstrated that inflammation and increased b-cell work-load are both stimulants for b-cell proliferation but are TGFb receptor signalingdependent and independent, respectively. Collectively, by using a pancreas-specific TGFb receptor–deleted mouse model, we have identified two distinct pathways that regulate adult b-cell proliferation. Our study thus provides important information for understanding b-cell proliferation during normal growth and in pancreatic diseases.