Abstract 438: Peripheral but Not Central Glucagon-Like Peptide-1 Receptor Agonism Regulates Fasting Dyslipidemia by Reducing VLDL Production
Bibliographic record
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that reduces plasma glucose levels and thus acts as an important drug target in the treatment of type 2 diabetes (T2D). Our laboratory has further shown that GLP-1 regulates intestinal lipoprotein metabolism and may also play a similar role in the liver. Hepatic lipids are packaged with apolipoprotein B-100 (apoB100) into very low density lipoproteins (VLDL) and secreted into the plasma. Dysregulation of VLDL production results in the fasting dyslipidemia that is observed in T2D. We postulate that GLP-1 receptor (GLP-1R) agonism regulates fasting dyslipidemia by decreasing VLDL production in insulin resistance through a peripheral or central pathway. To test this, experiments were conducted in fructose-fed insulin resistant Syrian golden hamsters. Hamsters were given twice daily intraperitoneal(i.p) injections of the GLP-1R agonist exendin-4 (ex4; 5nM/kg) for 7 days and placed into metabolic cages. Plasma was collected for lipid analysis following i.p poloxamer to prevent lipoprotein uptake and livers were excised. Peripheral ex4 prevented fructose-induced fasting dyslipidemia and decreased fasting plasma- and VLDL-triglyceride (TG), -cholesterol and -apoB100 accumulation. Ex4 also reduced food intake and body weight and thus pair-fed controls were added. Pair-feeding did not account for the full ex4 lipid-lowering effect. In comparison to both controls, ex4 treated hamsters had reduced respiratory exchange ratio and CO 2 production indicating a switch from glucose to fat metabolism as the main source of energy, and also decreased hepatic mRNA markers for de novo lipogenesis. To determine involvement of a central pathway, hamsters received a 4 day intracerebroventricular administration of ex4 (250ng) into the third ventricle. Central ex4 reduced body weight and food intake but did not modulate fasting plasma and VLDL-lipid or apoB100 accumulation, further suggesting that decreases in food intake cannot solely explain the changes in VLDL production. Our studies suggest that GLP-1R agonism reduces fasting dyslipidemia in insulin resistance by decreasing VLDL production through a peripheral pathway. GLP-1R agonism may be a potential therapy in the treatment of fasting dyslipidemia.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.009 | 0.002 |
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".