TCTP Is Essential for β-Cell Proliferation and Mass Expansion During Development and β-Cell Adaptation in Response to Insulin Resistance

Abstract

The perinatal period is critical for β-cell mass establishment, which is characterized by a transient burst in proliferation to increase β-cell mass in response to the need for glucose homeostasis throughout life. In adulthood, the ability of β-cells to grow, proliferate, and expand their mass is also characteristic of pathological states of insulin resistance. Translationally controlled tumor-associated protein (TCTP), an evolutionarily highly conserved protein that is implicated in cell growth and proliferation, has been identified as a novel glucose-regulated survival-supporting protein in pancreatic β-cells. In this study, the enhanced β-cell proliferation detected both during the perinatal developmental period and in insulin-resistant states in high-fat diet-fed mice was found to parallel the expression of TCTP in pancreatic β-cells. Specific knockout of TCTP in β-cells led to increased expression of total and nuclear Forkhead box protein O1 and tumor suppressor protein 53, and decreased expression of p70S6 kinase phosphorylation and cyclin D2 and cyclin-dependent kinase 2. This resulted in decreased β-cell proliferation and growth, reduced β-cell mass, and insulin secretion. Together, these effects led to hyperglycemia. These observations suggest that TCTP is essential for β-cell mass expansion during development and β-cell adaptation in response to insulin resistance.