Re-expression of IGF-II is important for beta cell regeneration in adult mice.

Abstract

The key factors which support re-expansion of beta cell numbers after injury are largely unknown. Insulin-like growth factor II (IGF-II) plays a critical role in supporting cell division and differentiation during ontogeny but its role in the adult is not known. In this study we investigated the effect of IGF-II on beta cell regeneration.We employed an in vivo model of 'switchable' c-Myc-induced beta cell ablation, pIns-c-MycER(TAM), in which 90% of beta cells are lost following 11 days of c-Myc (Myc) activation in vivo. Importantly, such ablation is normally followed by beta cell regeneration once Myc is deactivated, enabling functional studies of beta cell regeneration in vivo. IGF-II was shown to be re-expressed in the adult pancreas of pIns-c-MycER(TAM)/IGF-II(+/+) (MIG) mice, following beta cell injury. As expected in the presence of IGF-II beta cell mass and numbers recover rapidly after ablation. In contrast, in pIns-c-MycER(TAM)/IGF-II(+/-) (MIGKO) mice, which express no IGF-II, recovery of beta cell mass and numbers were delayed and impaired. Despite failure of beta cell number increase, MIGKO mice recovered from hyperglycaemia, although this was delayed.Our results demonstrate that beta cell regeneration in adult mice depends on re-expression of IGF-II, and supports the utility of using such ablation-recovery models for identifying other potential factors critical for underpinning successful beta cell regeneration in vivo. The potential therapeutic benefits of manipulating the IGF-II signaling systems merit further exploration.