O9.2. ANTIPSYCHOTIC DRUGS IMPAIR BRAIN GLUCOSE SENSING RESULTING IN WHOLE BODY INSULIN RESISTANCE
Bibliographic record
Abstract
Abstract Background Antipsychotics (APs) remain the cornerstone treatment for schizophrenia, and are widely used on- and off-label for other psychiatric disorders. However, their use presents a significant risk for serious adverse glycemic effects. Independent of changes in adiposity, APs directly dysregulate whole body glucose metabolism, and this may occur through the central nervous system (CNS). To this end, we have recently demonstrated that the second-generation AP, olanzapine, impairs hypothalamic insulin-action, resulting in dysregulation of whole-body insulin sensitivity. In addition to a critical role of hormones such as insulin in the CNS, glucose-sensing at the hypothalamus is also pivotal for the regulation of whole-body insulin sensitivity. Glucose also represents the primary fuel for brain function, and the hypothalamus represents the key brain center (through glucose sensing neurons) to partition resources to ensure maintenance of key homeostatic systems. In the current study, we set out to examine the effects of a first generation AP (e.g. haloperidol) and second-generation AP(e.g. olanzapine) on hypothalamic-glucose sensing, and subsequent regulation of peripheral glucose metabolism. Methods Gold-standard, pancreatic-euglycemic clamps were used to assess changes in glucose kinetics in response to a primed, continuous intracerebroventricular (ICV) infusion of glucose or vehicle solution (2mM, 5μL/hour, into the 3rd ventricle). Male rats were co-treated with an acute injection of olanzapine (3mg/kg, S.C.), haloperidol (10mg/kg, S.C.) or a weight adjusted vehicle solution. Dosing of APs was based on clinical D2 occupancies. Groups included (ICV–peripheral) vehicle–vehicle (n = 6), glucose–vehicle (n = 8), glucose–olanzapine (n = 6), vehicle–olanzapine (n = 6), glucose-haloperidol (n = 6) and vehicle-haloperidol (n = 7). The peripheral glucose infusion rate needed to maintain euglycemia during the clamp was used as a measure of whole-body insulin sensitivity. Results As expected and previously demonstrated, ICV (central) glucose infusion caused a significant increase in the peripheral glucose infusion rate of glucose (mg/kg.min) compared to vehicle treated rats (Veh-Veh 3.11±0.73 vs Glu-Veh 8.39±1.61), p<0.05). This effect was mitigated by treatment with both olanzapine (Glu-Veh 8.39±1.61, Glu-Ola 0.63±0.37, p<0.05) and haloperidol (Glu-Veh 8.39±1.61, Glu-Hal 3.01±0.46, p<0.05). In summary, olanzapine and haloperidol both impaired central glucose sensing resulting in whole body insulin resistance. Discussion Hypothalamic glucose-sensing is critical for the regulation of peripheral glucose homeostasis. This data, for the first time, demonstrates evidence that both first- and second-generation APs disrupt hypothalamic glucose-mediated regulation of glucose kinetics. Perturbed glucose-sensing in the CNS is expected to have deleterious consequences for metabolic homeostasis, and possibly other brain glucose-dependent functions such as cognition. The study unveils a novel effect of AP treatment to disrupt brain nutrient-sensing, suggesting this may be a mechanism by which these drugs increase risk of type 2 diabetes.
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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 | 0.000 |
| 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) | 0.005 | 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".