Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent <i>O</i> -GlcNAcylation of pancreas-duodenum homeobox-1
Bibliographic record
Abstract
The G protein-coupled free fatty acid receptor-1 (FFA1/GPR40) plays a major role in the regulation of insulin secretion by fatty acids. GPR40 is considered a potential therapeutic target to enhance insulin secretion in type 2 diabetes; however, its mode of regulation is essentially unknown. The aims of this study were to test the hypothesis that glucose regulates GPR40 gene expression in pancreatic β-cells and to determine the mechanisms of this regulation. We observed that glucose stimulates GPR40 gene transcription in pancreatic β-cells via increased binding of pancreas-duodenum homeobox-1 (Pdx-1) to the A-box in the HR2 region of the GPR40 promoter. Mutation of the Pdx-1 binding site within the HR2 abolishes glucose activation of GPR40 promoter activity. The stimulation of GPR40 expression and Pdx-1 binding to the HR2 in response to glucose are mimicked by N-acetyl glucosamine, an intermediate of the hexosamine biosynthesis pathway, and involve PI3K-dependent O-GlcNAcylation of Pdx-1 in the nucleus. We demonstrate that O-GlcNAc transferase (OGT) interacts with the product of the PI3K reaction, phosphatidylinositol 3,4,5-trisphosphate (PIP(3)), in the nucleus. This interaction enables OGT to catalyze O-GlcNAcylation of nuclear proteins, including Pdx-1. We conclude that glucose stimulates GPR40 gene expression at the transcriptional level through Pdx-1 binding to the HR2 region and via a signaling cascade that involves an interaction between OGT and PIP(3) at the nuclear membrane. These observations reveal a unique mechanism by which glucose metabolism regulates the function of transcription factors in the nucleus to induce gene expression.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".