The absence of AMPK beta1 exacerbates the acute olanzapine‐induced hyperglycemia in female mice
Bibliographic record
Abstract
Olanzapine is a second‐generation antipsychotic drug used widely in the treatment of schizophrenia. Though effective in reducing psychoses, acute olanzapine treatment causes acute increases in blood glucose and chronically leads to weight gain. A primary contributor to acute olanzapine‐induced hyperglycemia is glucagon mediated‐increases in liver glucose production. Prior work by our lab demonstrated that exhaustive exercise or treatment with 5‐Aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), approaches which activates the energy sensing enzyme 5′AMP activated protein kinase (AMPK), protect against olanzapine‐induced hyperglycemia. The purpose of this study was to determine if 1) olanzapine‐induced hyperglycemia would be exacerbated in AMPK b1 deficient (KO) mice and 2) if A769662, a specific allosteric activator of AMPK b1 containing complexes, could mitigate the effects of olanzapine on glucose homeostasis. We hypothesized that the absence of AMPK b1, a subunit which is primarily found in the liver, would worsen the acute metabolic effects of olanzapine and that A769662 would prevent olanzapine‐induced hyperglycemia control mice. Female AMPK b1 KO or wild type (WT) mice were treated with olanzapine (5 mg/kg) and blood glucose was taken at baseline and 30, 60 and 90 minutes post‐injection. As anticipated, the protein content and phosphorylation of AMPKa was significantly reduced in liver from AMPK b1 KO mice and this coincided with a greater olanzapine‐induced increase in blood glucose compared to WT mice. Serum glucagon concentration was not significantly different between genotypes after OLZ treatment nor were there any differences in the protein content of the gluconeogenic enzymes PEPCK and G6Pase. Interestingly, when challenged with glucagon (1.0 mg/kg IP) or epinephrine (0.5 mg/kg IP) the rise in blood glucose was greater in KO compared to WT mice, suggesting that an increase in the responsiveness to hormonal gluconeogenic signals could explain the potentiated effect of olanzapine in AMPK b1 KO. Surprisingly, co‐treatment with A769662 (30 mg/kg) did not attenuate olanzapine‐induced increases in blood glucose in female C57BL6/J mice. Our findings provide evidence that reductions in AMPK activity potentiate the effects of acute olanzapine treatment on blood glucose, whereas specifically targeting AMPK b1 containing complexes is not sufficient to protect against olanzapine‐induced hyperglycemia. Support or Funding Information This study was supported by Canadian Institutes of Health Research Support or Funding Information This study was supported by Canadian Institutes of Health Research This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".