NF-κB activity during pancreas development regulates adult β-cell mass by modulating neonatal β-cell proliferation and apoptosis

NF-kappa B is a well-characterized transcription factor, widely known for its roles in inflammation and immune responses, as well as in control of cell division and apoptosis. However, its function in beta-cells is still being debated, as it appears to depend on the timing and kinetics of its activation. To elucidate the temporal role of NF-kappa B in vivo, we have generated two transgenic mouse models, the ToI beta and NOD/ToI beta mice, in which NF-kappa B activation is specifically and conditionally inhibited in beta-cells. In this study, we present a novel function of the canonical NF-kappa B pathway during murine islet beta-cell development. Interestingly, inhibiting the NF-kappa B pathway in beta-cells during embryogenesis, but not after birth, in both ToI beta and NOD/ToI beta mice, increased beta-cell turnover, ultimately resulting in a reduced beta-cell mass. On the NOD background, this was associated with a marked increase in insulitis and diabetes incidence. While a robust nuclear immunoreactivity of the NF-kappa B p65-subunit was found in neonatal beta-cells, significant activation was not detected in beta-cells of either adult NOD/ToI beta mice or in the pancreata of recently diagnosed adult T1D patients. Moreover, in NOD/ToI beta mice, inhibiting NF-kappa B post-weaning had no effect on the development of diabetes or beta-cell dysfunction. In conclusion, our data point to NF-kappa B as an important component of the physiological regulatory circuit that controls the balance of beta-cell proliferation and apoptosis in the early developmental stages of insulin-producing cells, thus modulating beta-cell mass and the development of diabetes in the mouse model of T1D.

Automated summary

NF-kappa B plays a crucial role in the early developmental stages of insulin-producing cells, affecting the balance of beta-cell proliferation and apoptosis. Inhibiting NF-kappa B activation in beta-cells during embryogenesis increases beta-cell turnover, leading to reduced beta-cell mass.