Inducible Nitric Oxide Synthase Induction Underlies Lipid-Induced Hepatic Insulin Resistance in Mice
Bibliographic record
Abstract
OBJECTIVE: The present study was undertaken to assess the contribution of inducible nitric oxide (NO) synthase (iNOS) to lipid-induced insulin resistance in vivo. RESEARCH DESIGN AND METHODS: Wild-type and iNOS(-/-) mice were infused for 6 h with a 20% intralipid emulsion, during which a hyperinsulinemic-euglycemic clamp was performed. RESULTS: In wild-type mice, lipid infusion led to elevated basal hepatic glucose production and marked insulin resistance as revealed by impaired suppression of liver glucose production and reduced peripheral glucose disposal (R(d)) during insulin infusion. Liver insulin resistance was associated with a robust induction of hepatic iNOS, reduced tyrosine phosphorylation of insulin receptor (IR) beta, insulin receptor substrate (IRS)-1, and IRS-2 but elevated serine phosphorylation of IRS proteins as well as decreased Akt activation. The expression of gluconeogenic enzymes Pepck and G6Pc was also increased in the liver of wild-type mice. In contrast to their wild-type counterparts, iNOS(-/-) mice were protected from lipid-induced hepatic and peripheral insulin resistance. Moreover, neither the phosphorylation of insulin signaling intermediates nor expression of gluconeogenic enzymes were altered in the lipid-infused iNOS(-/-) mice compared with their saline-infused controls. Importantly, lipid infusion induced tyrosine nitration of IRbeta, IRS-1, IRS-2, and Akt in wild-type mice but not in iNOS(-/-) animals. Furthermore, tyrosine nitration of hepatic Akt by the NO derivative peroxynitrite blunted insulin-induced Akt tyrosine phosphorylation and kinase activity. CONCLUSIONS: These findings demonstrate that iNOS induction is a novel mechanism by which circulating lipids inhibit hepatic insulin action. Our results further suggest that iNOS may cause hepatic insulin resistance through tyrosine nitration of key insulin signaling proteins.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".