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.