Metabolic diapause in pancreatic beta-cells expressing a gain-of-function mutant of the forkhead protein Foxo1.
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.
Buteau
Jean
J
Berrie Diabetes Center, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA. da230@columbia.edu
Shlien
Adam
A
Foisy
Sylvain
S
Accili
Domenico
D
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002843:Chromatin / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D015398:Signal Transduction; D000071161:Forkhead Box Protein O1
D002843:Chromatin; D016207:Cytokines; D051858:Forkhead Transcription Factors; D005947:Glucose; D007328:Insulin; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1