Estrogen Protects Against Olanzapine‐induced Hyperglycemia
Bibliographic record
Abstract
Olanzapine is a second‐generation antipsychotic (SGA) used frequently in the treatment of schizophrenia and a growing list of off‐label conditions. Though effective in reducing psychoses, acute olanzapine treatment causes rapid increases in blood glucose that are mediated by increases in liver glucose output, skeletal muscle insulin resistance, and beta cell dysfunction. We recently reported that female, compared to male, mice are protected against acute olanzapine‐induced hyperglycemia. To date the mechanism by which female sex confers protection against olanzapine‐induced excursions in blood glucose have not been identified. The purpose of this study was to determine if the protective effects of the female sex against acute olanzapine‐induced hyperglycemia are due, in part, to female sex hormones and if this is mediated by GLP1 signalling. Ovariectomized (OVX) C57BL/6J mice or sham‐operated female controls were treated with olanzapine (5 mg/ kg, IP) or vehicle and blood glucose was measured at baseline, 15, 30, 60, 90, and 120 minutes post‐treatment. These experiments were repeated in female OVX mice following 2‐days of estradiol (E2) treatment (80 ug/kg/day; I.P.) compared to OVX or SHAM mice treated with vehicle. OVX exacerbated the effects of olanzapine on blood glucose, while the add back of E2 rescued olanzapine‐induced impairments in glucose homeostasis in OVX mice. Serum GLP1 concentrations were increased in female compared to male mice and thus, we wanted to determine if GLP1 signaling could be involved in the protective effects of female sex. Female mice were co‐treated with olanzapine and the GLP1 antagonist Exendin 9–39 (25 nmol/kg BW). GLP1 antagonism in female mice exacerbated olanzapine‐induced hyperglycemia. Given the evidence of E2 and GLP1 conferring a protective effect against olanzapine induced hyperglycemia in female mice, we co‐treated male mice with the GLP1 receptor agonist liraglutide (0.4 mg/kg BW) and olanzapine (5 mg/kg, IP). GLP1 agonism protected male mice from olanzapine‐induced hyperglycemia. Taken together, we provide evidence that the protection conferred by female sex on the hyperglycemic effects of olanzapine is due, at least in part, to E2 and GLP1 and that the protective effects of female sex can be recapitulated in male mice treated with liraglutide. Future work will be needed to determine if the protection afforded by female sex hormones on olanzapine‐induced hyperglycemia are dependent on GLP1 and the importance of this proposed mechanism in humans to provide insight into new adjunct treatments to offset the metabolic side effects of SGA treatment.
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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) | 0.000 | 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) | 0.002 | 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".