TGFβ Receptor Signaling Is Essential for Inflammation-Induced but Not β-Cell Workload-Induced β-Cell Proliferation

Protection and restoration of a functional beta-cell mass are fundamental strategies for prevention and treatment of diabetes. Consequently, knowledge of signals that determine the functional beta-cell mass is of immense clinical relevance. Transforming growth factor beta (TGF beta) superfamily signaling pathways play a critical role in development and tissue specification. Nevertheless, the role of these pathways in adult beta-cell homeostasis is not well defined. Here, we ablated TGF beta receptor I and II genes in mice undergoing two surgical beta-cell replication models (partial pancreatectomy or partial duct ligation), representing two triggers for beta-cell proliferation, increased beta-cell workload and local inflammation, respectively. Our data suggest that TGF beta receptor signaling is necessary for baseline beta-cell proliferation. By either provision of excess glucose or treatment with exogenous insulin, we further demonstrated that inflammation and increased beta-cell workload are both stimulants for beta-cell proliferation but are TGF beta receptor signaling dependent and independent, respectively. Collectively, by using a pancreas-specific TGF beta receptor-deleted mouse model, we have identified two distinct pathways that regulate adult beta-cell proliferation. Our study thus provides important information for understanding beta-cell proliferation during normal growth and in pancreatic diseases. Diabetes 62:1217-1226, 2013