F23. OLANZAPINE-INDUCED PERTURBATIONS OF WHOLE-BODY INSULIN SENSITIVITY MAY OCCUR VIA INACTIVATION OF CENTRAL K-ATP CHANNELS
Bibliographic record
Abstract
Antipsychotics are the cornerstone of treatment for schizophrenia and are widely prescribed on- and off- label for other mental illnesses. However, antipsychotic use is associated with excessive weight gain (over 75% of youth will gain >7% body weight) and increased risk of type 2 diabetes. Recent work suggests that antipsychotics can immediately and independently of weight gain induce insulin resistance, and that this may occur via the central nervous system (CNS). To this point, we recently published data demonstrating that olanzapine, a highly effective and widely prescribed antipsychotic, abolishes the ability of a CNS insulin infusion to restrain glucose production by the liver in rodents. These data demonstrate that olanzapine inhibits CNS insulin action, but the mechanism is unknown. The ATP-sensitive potassium (KATP) channel is a key metabolic sensor downstream of CNS insulin signaling in the hypothalamus, which is involved the maintenance of energy and glucose homeostasis. In the present study, we set out to determine whether olanzapine in rodents inhibits CNS KATP channel activation to disrupt peripheral glucose metabolism. Sprague Dawley rats underwent intracerebroventricular (ICV) cannulae implantation into the 3rd ventricle, and following a 1-week recovery, underwent jugular and carotid cannulation surgeries. Gold-standard pancreatic euglycemic clamps were then used to measure glucose kinetics. During the clamp procedure, endogenous insulin secretion is inhibited by a somatostatin infusion, and insulin is replaced at basal levels. Glucose is infused at a variable rate to maintain euglycemia, and the glucose infusion rate is a measure of whole-body insulin sensitivity. Additionally, a continuous infusion of a radioactive glucose tracer allows the measurement of glucose uptake and production. Prior to the clamp, rats were also pre-treated with an acute subcutaneous injection of olanzapine (OLA) or vehicle (VEH). A primed, continuous ICV infusion of the KATP channel activator Diazoxide (DIAZ) or vehicle (VEH) was administered throughout the clamp procedure. Groups included (central-peripheral): VEH-VEH (n=6), VEH-OLA (n=4), DIAZ-VEH (n=9), DIAZ-OLA (n=11). The glucose infusion rate needed to maintain euglycemia during the clamp was significantly higher in DIAZ-VEH rats compared to VEH-VEH or VEH-OLA controls, while DIAZ-OLA rats had a significantly decreased glucose infusion rate compared to DIAZ-VEH, indicative of impaired whole-body insulin sensitivity. We replicated previous findings that ICV DIAZ treatment significantly suppresses glucose production, and interestingly this suppression was undisturbed by OLA co-treatment (DIAZ-OLA). Glucose uptake was significantly increased by ICV DIAZ, and this effect was abolished by OLA co-administration (DIAZ-OLA). These data suggest that olanzapine can inhibit central KATP channel activation to perturb whole body insulin sensitivity, via inhibition of glucose uptake. Combining this with our previous findings that olanzapine impairs central insulin-mediated glucose production, olanzapine may act through potential divergent CNS pathways to regulate glucose production and uptake. Regardless, inactivation of KATP channels (a key central metabolic sensor) is a novel mechanism by which antipsychotics could induce diabetes and disrupt energy homeostasis. Given that KATP channels are also involved in CNS interactions of neurotransmitter systems (i.e. dopamine, glutamate), our findings may also have future implications beyond metabolic side-effects of these drugs to effects on psychopathology.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".