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| Status |
Public on Aug 20, 2014 |
| Title |
Metabolic Inflexibility Impairs Insulin Secretion And Results In MODY-like Diabetes In Triple FoxO-deficient Mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Pancreatic b-cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of b-cell mass. It’s unclear how one begets the other. We have shown that loss of b-cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature b-cells results in early-onset, maturity onset diabetes of the young (MODY)-like diabetes, with signature abnormalities of the MODY networks of Hnf4a, Hnf1a, and Pdx1. Transcriptome and functional analyses reveal that FoxO-deficient b-cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as source of acetyl-CoA for mitochondrial oxidative phosphorylation. This results in impaired ATP generation, and reduced Ca2+-dependent insulin secretion. When viewed in the context of prior data illustrating a role of FoxO1 in b-cell dedifferentiation, the present findings define a seamless FoxO-dependent mechanism linking the twin abnormalities of b-cell function in diabetes.
We used microarrays to detail the change of gene expression in pancreatic beta cells after knocking out FoxO1,3 and 4.
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| Overall design |
Primary islets were isolated from pancretic beta cell- specific triple FoxO(1,3, and 4) KO and their littermates control (WT) mice. Gene expression was analyzed by microarray.
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| Contributor(s) |
Accili D, Kim-Muller JY |
| Citation(s) |
25264246 |
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| Submission date |
Aug 19, 2014 |
| Last update date |
Mar 06, 2018 |
| Contact name |
Domenico Accili |
| E-mail(s) |
da230@columbia.edu
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| Organization name |
Columbia University
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| Street address |
1150 St. Nicholas Ave
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| City |
NEW YORK |
| State/province |
NY |
| ZIP/Postal code |
10032 |
| Country |
USA |
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| Platforms (1) |
| GPL6096 |
[MoEx-1_0-st] Affymetrix Mouse Exon 1.0 ST Array [transcript (gene) version] |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA258439 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE60505_RAW.tar |
169.4 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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