Metformin and biomarkers relevant to neoplasia in nondiabetic patients.
Bibliographic record
Abstract
e14615 Background: Use of the anti-diabetic drug Metformin has been associated with reduced risk or improved prognosis of several cancers in both lab models and retrospective population studies of diabetics. Plausible mechanisms of action include (1) reduction in serum levels of insulin or inflammatory cytokines and (2) direct effects on target cells due to action of the drug as an inhibitor of mitochondrial respiration, including activation of AMPK. Methods: Non-diabetic subjects (n = 47) consented to bloodwork and sigmoid biopsy at screening colonoscopy, metformin administration (500 mg TID) for 10 weeks, and end-of-study sigmoid biopsy and bloodwork. Serum assays were performed on both fasting and post standard oral glucose load specimens. Metformin levels were measured by mass spectroscopy. Anti-phospho-histone-3 immunostaining was used to quantify proliferation. Results: Metformin reduced fasting levels of c-peptide, insulin, and IL-6 levels by < 10%, a magnitude of change that laboratory studies suggest is unlikely to be biologically significant. However, postprandial insulin levels following metformin were reduced by 18 % relative to baseline postprandial levels, a finding of potential physiologic relevance. Serum metformin level showed considerable variation between subjects (1005 ± 769 ng/ml) and this variation was not correlated with effects of metformin on epithelial proliferation. Proliferation index fell from 5.9 to 3.3, (p<0.03), a change greater than predicted by in vitro studies of direct action of metformin at the concentrations measured in serum. Conclusions: Metformin lowers insulin levels even in non-diabetic subjects, and post prandial insulin levels are more sensitive indicators of metformin action than fasting biomarkers. As high insulin level has been linked to increased cancer risk and/or worse prognosis (eg J Natl Cancer Inst. 2004;96:546), this systemic action suggests clinical applications. However, direct exposure of colonic epithelial cells to high luminal concentrations of metformin may also be relevant and is one of several factors that may explain the greater inhibitory effect of the drug on colonic epithelium proliferation than that previously reported for breast or prostate.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 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".