Roles of insulin in olanzapine-induced blood glucose dysregulation in rodents

Abstract

Olanzapine is an effective pharmacologic treatment of psychosis. However, its use is commonly  associated with metabolic side effects. This study was designed to investigate the possible mechanisms of olanzapine-induced blood glucose dysregulation in rats. Olanzapine (10 mg/kg, i.p.), or co-administration of olanzapine (10 mg/kg) and metformin (500 mg/kg), respectively, to rats, acutely or chronic for 28 consecutive days. Fasting glucose and insulin levels, were measured, followed by a 2h glucose tolerance test. Then, blood samples were collected for estimation of biochemical and haematological parameters. The liver, kidney and brain were harvested to estimate the level of oxidative/nitrosative stress status. Subacute administration of olanzapine did not affect body weight but decreased insulin secretion (P<0.05), induced glucose intolerance in OGTT test and enhanced insulin-blood glucose reduction in insulin tolerance test (P<0.001). Both acute treatments with olanzapine and metformin increased insulin secretion but no significant change were seen in subacute study. Conversely, acute injection of olanzapine induced hypoglycemia with concomitant increase in insulin secretion by 1.9 fold (P<0.01) with no significant change in body weight. Sub-chronic olanzapine induced 1.2 fold increase in ALT (P<0.01), 2.1 fold increase in ALP (P<0.01) and 1.8 fold increase in bilirubin (P<0.01) concentration, while decreasing creatinine and urea levels by 1.1 fold (P<0.05) compared with vehicle-treated control. Olanzapine injection decreased anti-oxidant activity (GSH, P<0.05) in the brain by 1.9 fold and in the liver by 17.6 fold (GSH, P<0.0001) with increase in lipid peroxidation by 1.6 fold (P<0.05) and increased nitrosative stress (P<0.05). In contrast, there was an increase in kidney antioxidant level (GSH, P<0.05) by 2.4 fold and increase in lipid peroxidation by 2.5 folds (MDA, P<0.05). Sub-chronic administration of olanzapine induced metabolic syndrome (glucose intolerance, increased TG, reduced HDL), hepatotoxicity, and anemia through induction of oxidative stress.

Keywords: glucose intolerance; insulin resistance; metabolic side-effects; weight gain; oxidative stress