260-OR: The L-Cell Clock Is Required for Circadian GLP-1 Secretion and Maintenance of Intestinal Homeostasis
Bibliographic record
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin hormone released by the intestinal L cell in response to nutrient intake. Recent studies identified a circadian rhythm in GLP-1 secretion that is disrupted in whole-body Bmal1 KO mice. However, the extent to which the L cell clock regulates circadian GLP-1 secretion and overall diurnal metabolic and intestinal homeostasis is unknown. Gcg-creERT2/+;Bmal1flox/flox KO mice with a disrupted clock in L cells, alpha cells and some CNS cells were thus generated. M/F- and age-matched KO mice had normal body weight and 24hr food intake patterns vs. all genetic and chemical controls. Upon oral glucose gavage at the known peak and trough timepoints of GLP-1 release, KO animals lost the rhythmic GLP-1 secretory pattern in association with impaired secretion (p<0.001) at the peak timepoint. Interestingly, the reduced GLP-1 secretion did not translate to decreased insulin or hyperglycemia, perhaps due to decreased glucagon levels (p<0.05). However, L cell Bmal1 KO caused increases in colonic weight and interleukin-6 (p<0.05) and interferon gamma (p<0.05) expression, suggesting a pro-inflammatory state. In line with findings that altered intestinal epithelial cell function decreases the frequency of intraepithelial CD4+ T cells, KO animals had reduced proportions of these immune cells (p<0.05). Furthermore, 16S rRNA gene analysis revealed increased actinobacteria in the colon, consistent with data from GLP-1 receptor KO mice. KO mice also had decreased levels of cecal bile acids (p<0.05-0.001) and short-chain fatty acids (p<0.05) suggestive of a functional impairment in the KO microbiome. Finally, siRNA-mediated knockdown of Bmal1 in the murine GLUTag L cell line also resulted in impaired rhythmic GLP-1 secretion (p<0.001). Together, these data establish the L cell clock as an essential regulator of circadian GLP-1 secretion which is, then, critical to the maintenance of overall intestinal homeostasis. Disclosure S. E. Martchenko: None. A. Martchenko: None. A. Biancolin: None. P. L. Brubaker: None. Funding Canadian Institutes of Health Research (PJT-15308)
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.011 | 0.005 |
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".