Poster Presentation The International Congress of Neuroendocrinology 2014

Improving Antipsychotic-Induced Metabolic Side-Effects Using a GLP-1 Receptor Agonist (#397)

Ilijana Babic 1 2 , Jessica Hughes 2 3 , Stephen Lillioja 2 3 , Xu-Feng Huang 1 2 4 , Katrina Weston-Green 1 2 4
  1. Centre for Translational Neuroscience, School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia
  2. Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW, Australia
  3. Graduate School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia
  4. Schizophrenia Research Institute, Darlinghurst, NSW, Australia

Introduction: Olanzapine and clozapine are second generation antipsychotics (SGAs) prescribed to treat schizophrenia and bipolar disorder, but have a high risk of causing glucometabolic side-effects, including hyperglycaemia and type 2 diabetes mellitus (T2DM). The anti-diabetic drug liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, may attenuate SGA-induced metabolic side-effects. SGAs effect multiple neurochemical pathways, including adrenergic signalling systems. Sympathetic innervation of pancreatic α-cells results in glucagon secretion and triggers norepinephrine release from the adrenal gland to stimulate hepatic glucose output. SGAs alter norepinephrine and glucagon levels, potentially causing hyperglycaemia side-effects; however, whether liraglutide restores glucagon and norepinephrine levels during SGA treatment is unknown.

Aim: This study aimed to investigate the acute effects of SGA and liraglutide co-treatment on glucose homeostasis, glucagon and norepinephrine levels.

Methods: Rats were treated acutely with olanzapine (1mg/kg), liraglutide (0.4mg/kg), olanzapine+liraglutide co-treatment, clozapine (12mg/kg), or clozapine+liraglutide co-treatment (n=12/group). An oral glucose tolerance test (OGTT) was performed 1-hour post-treatment and area under the curve (AUC) data was analysed. Following a 1-week washout, treatment was re-administered and fasted post-mortem plasma glucagon and norepinephrine levels were examined.

Results: AUC was significantly affected by treatment (F5,62 = 13.76, p<0.01). Olanzapine increased AUC (p<0.05), while no changes were observed in the liraglutide or the olanzapine+liraglutide co-treatment groups compared to the controls (p>0.05). Clozapine and liraglutide+clozapine co-treatment significantly increased the AUC (p<0.01). Clozapine increased norepinephrine (F5,65 = 8.34, p<0.01), while levels in all other groups did not differ to controls (p>0.05). Glucagon increased with olanzapine treatment (p<0.01), but not in the remaining groups compared to controls (p>0.05).

Conclusion: These results suggest that olanzapine and clozapine may induce hyperglycaemia through different mechanisms, though both involving the sympathetic nervous system. Acute liraglutide co-treatment alleviated olanzapine-induced glucose dysfunction but did not improve clozapine-induced hyperglycaemia. Overall, this study presents interesting findings that support a liraglutide co-treatment approach for attenuating olanzapine-induced glucometabolic side-effects.