Thus, disruption of Smad3 in islet β cells promotes E2F3-dependent β cell proliferation as demonstrated by a marked increase in insulin-producing PCNA+ or BrdU+ β cells, suggesting that treatment with a subtherapeutic dose of Smad3KO islets is sufficient to expand β cell mass and inhibits both T1DM in STZ-induced mice and T2DM in db/db mice. This evidence concerns the gene SMAD3 and type 2 diabetes mellitus.