IRS1 and diabetes mellitus: Importantly, KEGG analysis revealed that the upregulated genes in Smad3 KO-db/db islets were significantly enriched in the clusters of 'Insulin resistance' (Ppargc1a, Irs1, and G6pc2), 'Type II diabetes mellitus' (Ins1, Ins2, Pdx1, MafA, and Slc2a2), 'Insulin signaling pathway' (Irs1, Pik3cb, Pik3r5, and Akt3), 'Insulin secretion' (Ins1, Ins2, Glp1r, Gck, and Cacna1c), and 'Maturity onset diabetes of young' (Pax6, Pdx1, MafA, and NeuoD1); implying an inhibitory role of Smad3 in multiple beta cell signature genes at transcriptional level (Figure 4E).