Abstract
Diabetes is associated with decreased pancreatic beta-cell function and mass. It is unclear whether diabetes treatment should aim at restoring beta-cell performance/mass or at inducing "beta-cell rest" to prevent further deterioration. The transcription factor Foxo1 protects beta-cells against oxidative stress induced by hyperglycemia and prevents beta-cell replication in insulin-resistant states. Here we show that these combined effects are associated with a concerted repression of genes involved in glycolysis, nitric-oxide synthesis, G protein-coupled receptor signaling, and ion transport. Conversely, Foxo1 increases expression of several neurotransmitter receptors and fails to regulate target genes predicted from Caenorhabditis elegans and Drosophila studies. Functional analyses show decreased glucose utilization and insulin secretion in beta-cells overexpressing Foxo1. We propose the definition of "metabolic diapause" for the changes induced by Foxo1 to protect beta-cells against oxidative stress. The data provide genetic underpinning for the concept of beta-cell rest as a treatment goal in diabetes.
Highlights
Agents that reverse or prevent -cell failure play an important role in diabetes treatment, and two new classes of drugs that target -cells have been recently introduced as adjuvant treatments for diabetes [8]
Three conclusions stand out from our analysis of the Foxo1 transcriptional program in pancreatic -cells: (i) Foxo1 induces a state of metabolic diapause [49]; (ii) arguably, such -cell rest could be a goal of diabetes treatment; and (iii) Foxo1 targets in -cells largely differ from canonical diapause targets in Caenorhabditis elegans [50, 51] and show limited overlap with mammalian FoxO1 targets identified by Ramaswami et al [52] in renal carcinoma cells
Foxo1 Activation Induces Metabolic Diapause in -Cells— We have previously shown that Foxo1 nuclear translocation in -cells is induced by hyperglycemia [22]
Summary
Reagents and Cell Culture—Cell culture reagents were from Invitrogen, 5-3H- and U-14C-labeled glucose were from Amersham Biosciences, and anti-Foxo antiserum was from Cell Signaling (Beverly, MA). INS832/13 cells were seeded 2 days before use and transduced with adenovirus encoding Foxo or -galactosidase at a multiplicity of infection of 50 plaque-forming units/cell for 1 h in 1 ml of complete medium. Foxo and -Cell Function allowed to recover for 24 h before the experiment Under these conditions, Ͼ95% of the cells are transduced (not shown). BrdUrd was added to the culture medium for 1 h, and cells were fixed, incubated with peroxidase-conjugated anti-BrdUrd antibody, and the immune complexes were quantified by enzyme-linked immunosorbent assay (Bio-Rad). The mean expression value of samples derived from cells overexpressing Foxo and -galactosidase was compared for each set of probes. ErmineJ performs analyses of gene sets in expression microarray data to determine whether specific biological pathways are significantly altered. We used p Ͻ 0.05 to declare statistically significant differences
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