Featured ArticlesVolume 3 | No. 8 | November 2014
|The Polycomb protein, Bmi1, regulates insulin sensitivityCannon and colleagues identify a novel role for the Polycomb protein, Bmi1, in the development of insulin resistance. Reduced Bmi1 levels result in alterations in insulin signaling in liver and muscle tissue, which appear to contribute to a striking improvement in whole-body insulin sensitivity.|
Abstract | PDF
Objective: The Polycomb Repressive Complexes (PRC) 1 and 2 function to epigenetically repress target genes. The PRC1 component, Bmi1, plays a crucial role in maintenance of glucose homeostasis and beta cell mass through repression of the Ink4a/Arf locus. Here we have explored the role of Bmi1 in regulating glucose homeostasis in the adult animal, which had not been previously reported due to poor postnatal survival of Bmi1−/− mice.
Methods: The metabolic phenotype of Bmi1+/− mice was characterized, both in vivo and ex vivo. Glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps were performed. The insulin signaling pathway was assessed at the protein and transcript level.
Results: Here we report a negative correlation between Bmi1 levels and insulin sensitivity in two models of insulin resistance, aging and liver-specific insulin receptor deficiency. Further, heterozygous loss of Bmi1 results in increased insulin sensitivity in adult mice, with no impact on body weight or composition. Hyperinsulinemic-euglycemic clamp reveals increased suppression of hepatic glucose production and increased glucose disposal rate, indicating elevated glucose uptake to peripheral tissues, in Bmi1+/− mice. Enhancement of insulin signaling, specifically an increase in Akt phosphorylation, in liver and, to a lesser extent, in muscle appears to contribute to this phenotype.
Conclusions: Together, these data define a new role for Bmi1 in regulating insulin sensitivity via enhancement of Akt phosphorylation.[Hide abstract]
| CREB has an important role in the β-cell response to GLP-1 receptor signaling Shin and colleagues dispel current opinions about the importance of the bZIP transcription factor CREB in regulating β-cell function and mass. They
show that CREB is required in β-cells for the incretin GLP-1 to exert its full effect in potentiating insulin secretion and to assert its protective
effects against cytokine-induced cell death.|
Abstract | PDF
Objective: Glucagon-like peptide-1 (GLP-1) plays a major role in pancreatic β-cell function and survival by increasing cytoplasmic cAMP levels, which are thought to affect transcription through activation of the basic leucine zipper (bZIP) transcription factor CREB. Here, we test CREB function in the adult β-cell through inducible gene deletion.
Methods: We employed cell type-specific and inducible gene ablation to determine CREB function in pancreatic β-cells in mice.
Results: By ablating CREB acutely in mature β-cells in tamoxifen-treated CrebloxP/loxP;Pdx1-CreERT2 mice, we show that CREB has little impact on β-cell turnover, in contrast to what had been postulated previously. Rather, CREB is required for GLP-1 to elicit its full effects on stimulating glucose-induced insulin secretion and protection from cytokine-induced apoptosis. Mechanistically, we find that CREB regulates expression of the pro-apoptotic gene p21 (Cdkn1a) in β-cells, thus demonstrating that CREB is essential to mediating this critical aspect of GLP-1 receptor signaling.
Conclusions: In sum, our studies using conditional gene deletion put into question current notions about the importance of CREB in regulating β-cell function and mass. However, we reveal an important role for CREB in the β-cell response to GLP-1 receptor signaling, further validating CREB as a therapeutic target for diabetes.[Hide abstract]