β-Cell Pdx1 Expression Is Essential for the Glucoregulatory, Proliferative, and Cytoprotective Actions of Glucagon-Like Peptide-1

β cell-specific deficiency of the stimulatory G protein α-subunit G s α leads to reduced β cell mass and insulin-deficient diabetes

“…Although studies have suggested that incretin hormones and cAMP increase ␤ cell proliferation and survival by induction of the IRS2 gene (Irs2) (11), we found no change in expression of the Irs2 or Irs1 genes in islets from ␤GsKO mice. We also found no change in expression of Akt2 or pancreatic and duodenal homeobox 1 (Pdx1), two other genes that are stimulated by IRS2 and implicated in ␤ cell growth (25)(26)(27). Consistent with these mRNA results, immunohistochemistry showed no reduction of IRS2 or PDX1 protein in islets (Fig.…”

“…Because FOXO1 normally inhibits expression of Pdx1, an islet-specific transcription factor that promotes ␤ cell function (30), induction of the Irs2 pathway by G s ␣ signaling would be predicted to result in increased Pdx1 expression. Consistent with this hypothesis, Pdx1 was shown to be required for the insulinotropic effects and ␤ cell growth and survival effects of GLP1 (25). However, we found no difference in the expression of either Irs2 or Pdx1 at the mRNA or protein levels in ␤GsKO islets even though these mice had marked changes in ␤ cell hormonal function, growth, and survival.…”

Mechanisms of action of glucagon-like peptide 1 in the pancreas

“…Five to six week old IRS2−/− mice treated with Ex-4 failed to demonstrate increases in BrdU incorporation into β cells . Mice with a β cell specific inactivation of PDX-1 also do not display a proliferative response to Ex-4 treatment (Li et al, 2005c). Together all of these reports would suggest the proposed mechanism for proliferation that is shown in Fig.…”

“…Transgenic mice heterozygous for PDX-1 expression exhibit a greater degree of β cell apoptosis and caspase activity (Johnson et al, 2003). When mice with a β cell specific defect in PDX-1 were treated with Ex-4 there was no decrease in apoptotic nuclei compared with wild-type littermates (Li et al, 2005c). Therefore both IRS2 and PDX-1 appear to be important for β cell survival and for the ability of GLP-1R agonists to protect against apoptosis and β cell death in general.…”

“…Indeed PDX-1 is known to regulate acute glucose induction of the insulin gene (Rafiq et al, 1998). Despite earlier reports of PDX-1 knockdown experiments performed in insulinoma cells showing no effect on insulin gene expression (Kajimoto et al, 1997), the central importance for PDX-1 in maintenance of sufficient β cell mass, function, growth and insulin transcription is now clear based on results from both in vivo transgenic models (Kushner et al, 2002;Li et al, 2005c) and from transfection of the human insulin promoter into insulinoma cell lines (Le Lay and Stein, 2006). PDX-1 is also a key effector for the GLP-1R responsive pathways and is critical for the positive effects of GLP-1R agonists on differentiation, proliferation, survival and function of the β cell (Li et al, 2005c).…”