Inverse relationship between peripheral insulin removal and action: studies with metformin
Bibliographic record
Abstract
The interaction of insulin with metformin on muscle glucose metabolism was examined in the perfused rat hindquarter. Glucose, lactate, and insulin were measured at the inflow to and outflow from the hindquarter, which was perfused with human erythrocytes suspended in a Kreb's-Ringer albumin buffer for 120 min. Perfusions were performed with no additions (I) and with insulin infusions targeted to concentrations of 175 (II) and 350 pmol/l (III) as well as infusions targeted to levels of 0 (IV), 70 (V), and 175 pmol/l (VI) but in the presence of metformin (90 microg/ml). In the presence of metformin, identical infusion rates of insulin yielded higher insulin concentrations, namely 283 +/- 19 vs. 202 +/- 31 pmol/l for VI and II, respectively (P < 0.05). Glucose uptake (GU) increased correspondingly to 79.8 +/- 0.8 in VI from 60.8 +/- 2.1 for IV and 50.1 +/- 1.3 for II and 46.1 +/- 2.7 mg/120 min for I (P < 0.05). This enhanced GU was matched by increasing insulin levels using only a higher rate of its infusion (III): GU of 70.2 +/- 2.4 mg/120 min with insulin of 334 +/- 26 pmol/l (P > 0.05). The simple concurrent presence of metformin and insulin [matching insulin concentrations in II rather than infusion rates (IV)] demonstrated no additonal effect on GU above that of metformin. The synergistic effects of metformin and insulin could thus be explained by a metformin-mediated decrease in the extraction of insulin by the hindquarter (4.8 +/- 0.4% vs. 8.6 +/- 0.9%, P < 0.05). This increases interstitial insulin (and, in a closed system, perfusate insulin), which acts on cell surface receptors to increase glucose uptake. The results demonstrate that the extracellular insulin concentration, rather than insulin internalization and degradation, is the primary determinant of insulin action on GU in muscle and that changes in tissue insulin extraction may alter local concentrations and, therefore, systemic insulin sensitivity. This provides both a physiological mechanism and a possible therapeutic target for improving insulin sensitivity.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".