Bradykinin improves insulin-stimulated glucose uptake in rat adipocytes via an eNOS-dependent mechanism
Bibliographic record
Abstract
Insulin resistance is a well-documented phenomenon associated with hypertension and type 2 diabetes mellitus. Angiotensin converting enzyme (ACE) inhibitors are commonly used to treat hypertension, and act by inhibiting both the production of angiotensin II and the degradation of bradykinin. Several groups have reported improved insulin sensitivity in rodents treated with either ACE inhibitors or bradykinin. We hypothesised that bradykinin would improve insulin-stimulated glucose uptake in rat adipocytes via an endothelial nitric oxide synthase (eNOS)-dependent mechanism as the result of an enhancement of the insulin signalling pathway. We have found that bradykinin enhances insulin-stimulated glucose uptake in a dose-dependent manner which is mediated by the bradykinin B2 receptor. In many cell types, bradykinin leads to the activation of eNOS and increased nitric oxide (NO) production. Through the use of a variety of pharmacological inhibitors and activators, in addition to an eNOS-/- mouse model, we determined that eNOS and NO are key in bradykinin's effect. In the assessment of bradykinin's effect on the insulin signalling pathway, we found that bradykinin treatment potentiated the insulin signalling pathway at the levels of IRS1, PI3K, PKB and GLUT4 translocation to the plasma membrane. Interestingly, bradykinin reduced insulin-stimulated phosphorylation of ERK1/2 and JNK and subsequent phosphorylation of specific Ser residues on IRS1. Furthermore, adipocytes obtained from JNK1-/- mice exhibited enhanced insulin sensitivity. Treatment of rat adipocytes with a NO donor reduced insulin-stimulated phosphorylation of JNK, while those isolated from eNOS-/- mice exhibited elevated basal JNK phosphorylation levels as compared to control. The use of pharmacological inhibitors and activators of the soluble guanylate cyclase/cGMP/cGMP dependent protein kinase I pathway clearly showed that this cascade must remain intact for bradykinin to elicit its effects. To this point, the mechanism by which bradykinin and NO blocked INK phosphorylation by insulin remained unknown. Interestingly, each bradykinin and a NO donor in concert with insulin induced the expression of MAPK phosphatase-5 (MKP5) mRNA. Together, our data suggest that bradykinin enhances insulin action through an eNOS-mediated inhibition of JNK. These findings may aid in the understanding of how ACE inhibitors enhance 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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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) | 0.001 | 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".