Pdx1 restores β cell function in Irs2 knockout mice

The insulin receptor substrates (IRS proteins) coordinate many signals during insulin and IGF-1 stimulation, including activation of the phosphatidylinositol (PI) 3-kinase and ERK1/2 cascades (1). Although highly homologous and universally expressed, Irs1 and Irs2 display distinct biological function in mice (2). Irs1 strongly promotes somatic growth and mediates insulin action upon carbohydrate metabolism in skeletal muscle; however, Irs1–/– mice never develop diabetes, owing to islet hyperplasia and lifelong compensatory hyperinsulinemia (2). By contrast, Irs2 plays a significant role in metabolic regulation, as hepatic gluconeogenesis and lipid metabolism are dysregulated in Irs2–/– mice (3). Moreover, Irs2–/– mice develop progressive β cell failure, which exacerbates the peripheral insulin resistance and leads to diabetes (2). The β cells in Irs2–/– mice display increased apoptosis, especially during weaning, which might contribute to the steady decline of β cell mass with increasing age (4). Although moderate hyperinsulinemia compensates for peripheral insulin resistance in young Irs2–/– mice, diabetes occurs between 8 and 10 weeks of age, because the diminishing β cell content fails to secrete sufficient insulin (2). Autosomal dominant forms of early-onset diabetes in young adults (maturity-onset diabetes of the young [MODY]) are linked to mutations in glucokinase or transcription factors that promote normal β cell function, including HNF4α (MODY1), HNF1α (MODY3), PDX1 (MODY4), HNF1β (MODY5), and NeuroD1/BETA2 (MODY6); MODY2 is caused by mutations in glucokinase, whose expression is regulated by PDX1 (5). The regulation of these transcription factors is complicated, but in certain cases it might be linked to insulin/IGF1 signaling though Foxo1 or Hnf3β (6). Pdx1 plays an important role in islet development and β cell function. It is required for pancreas formation during the initial stages of gut development (7, 8). In adult mice, Pdx1 promotes the expression of proinsulin, Glut2, and glucokinase, which mediates glucose-sensitive insulin secretion (9–11). Pdx1 also regulates expression of FGFs and their receptors, which might promote β cell growth and proinsulin processing via the prohormone processing enzyme PC1/3 (12). Consequently, disruption of Pdx1 in murine β cells reduces insulin secretion and causes progressive β cell loss, which culminates in glucose intolerance and diabetes (13). Moreover, PDX1 is required in adult humans to promote normal glucose sensing and insulin secretion, and mutations in PDX1 represent a risk factor for type 2 diabetes (13–15). In this report, we reveal a close relation between Pdx1 and Irs2, which suggests that dysregulation of Pdx1 by genetic or functional mechanisms might be a com-