SMAD7 enhances adult β cell proliferation without significantly affecting β cell function in mice

The interplay between the transforming growth factor beta (TGF-beta) signaling proteins, SMAD family member 2 (SMAD2) and SMAD3, and the TGF-beta inhibiting SMAD, SMAD7, seems to play a vital role in proper pancreatic endocrine development, and also in normal beta cell function in adult pancreatic islets. Here, we generated conditional SMAD7 knockout mice by crossing insulin1Cre mice with SMAD7fx/fx mice. We also created a beta cell-specific SMAD7 overexpressing mouse line by crossing insulin1Dre mice with HPRT-SMAD7/RosaGFP mice. We analyzed beta cell function in adult islets either when SMAD7 was absent or overexpressed in beta cells. Loss of SMAD7 in beta cells inhibited proliferation, and SMAD7 overexpression enhanced cell proliferation. However, alterations in basic glucose homeostasis were not detectable following either SMAD7 deletion or overexpression in beta cells. Our results show that either the absence or overexpression of SMAD7 affect TGF-beta signaling and modulate beta cell proliferation, but does not appear to alter beta cell function. Reversible, SMAD7 overexpression may represent an attractive therapeutic option to enhance beta cell proliferation without negative effects on beta cell function.