We have recently reported that Pdx1-Cre-mediated, whole pancreas inactivation of IGF-I gene (in PID mice) results in increased -cell mass and significant protection against both type 1 and type 2 diabetes. As the phenotype is unlikely a direct consequence of IGF-I deficiency, current study was designed to explore possible activation of pro-islet factors in PID mice, using a whole genome DNA microarray. As a result, multiple members of the Reg family genes (Reg2, 3 and 3; previously not known to promote islet cell growth) were significantly upregulated in the pancreas. This finding was subsequently confirmed by Northern blot and/or real-time PCR, which exhibited 2 to 8 fold increases in the level of these mRNAs. Interestingly, these Reg family genes were also activated following streptozotocin-induced -cell damage and diabetes (wild-type T1D mice) when islet cells are undergoing regeneration. Immunohistochemistry revealed increased Reg proteins in exocrine as well as endocrine pancreas, and suggested their potential role in -cell neogenesis in PID or T1D mice. Previously, other Reg proteins (Reg1 and INGAP) have been shown to promote islet cell replication and neogenesis. These uncharacterized Reg proteins may play a similar but more potent role, not only in normal islet cell growth in PID mice, but also in islet cell regeneration after T1D.