UC San Diego

It is well recognized that the regenerative capacity of pancreatic insulin-producing beta cells declines with age, with the most dramatic reduction occurring shortly after birth. However, the mechanism that accounts for this decline remains poorly understood. We sought to determine the molecular changes that attribute to this decrease in beta cell proliferation. Here, we show that activation of the DNA damage response (DDR) coincides with the decline in beta cell proliferation occurring during early postnatal life. In addition, we discovered a postnatal increase in the expression levels of replication stress-related DNA damage markers such as replication protein A (RPA) and phosphorylated Chk1 (pChk1). Furthermore, inhibition of the downstream effector Wee1 increases beta cell proliferation in vitro and in vivo. The results of this study provide insight into age-dependent changes in beta cells that lead to the increased incidence of cell cycle arrest. We hope that these findings will not only contribute to uncovering mechanisms underlying the age-dependent decline in beta cell proliferation, but also assist in the identification of factors that could potentially be pharmacologically targeted to improve beta cell function and stimulate their expansion for the management and treatment of diabetes mellitus.