Differential effects of 3 classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats

J Psychiatry Neurosci. 2012 Nov;37(6):407-15. doi: 10.1503/jpn.110140.


Background: The second-generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However, use of the drug is commonly associated with a range of metabolic side effects, including glucose intolerance and insulin resistance. These symptoms have been accurately modelled in rodents.

Methods: We compared the effects of 3 distinct classes of antidiabetic drugs, metformin (100 and 500 mg/kg, oral), rosiglitazone (6 and 30 mg/kg, oral) and glyburide (2 and 10 mg/kg, oral), on olanzapineinduced metabolic dysregulation. After acutely treating female rats with lower (7.5 mg/kg) or higher (15 mg/kg) doses of olanzapine, we assessed glucose intolerance using the glucose tolerance test and measured insulin resistance using the homeostatic model assessment of insulin resistance equation.

Results: Both doses of olanzapine caused pronounced glucose dysregulation and insulin resistance, which were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to control levels. In contrast, glyburide failed to reverse the glucose intolerance caused by olanzapine despite increasing insulin levels.

Limitations: We evaluated a single antipsychotic drug, and it is unknown whether other antipsychotic drugs are similarly affected by antidiabetic treatments.

Conclusion: The present study indicates that oral hypoglycemic drugs that influence hepatic glucose metabolism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than drugs primarily affecting insulin release, such as glyburide. The current model may be used to better understand the biological basis of glucose dysregulation caused by olanzapine and how it can be reversed.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / administration & dosage
  • Antipsychotic Agents / adverse effects*
  • Benzodiazepines / administration & dosage
  • Benzodiazepines / adverse effects*
  • Female
  • Glucose Intolerance / chemically induced
  • Glucose Intolerance / drug therapy*
  • Glyburide / administration & dosage
  • Glyburide / pharmacology*
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / classification
  • Hypoglycemic Agents / pharmacology*
  • Insulin Resistance / physiology*
  • Metformin / administration & dosage
  • Metformin / pharmacology*
  • Olanzapine
  • Rats
  • Rosiglitazone
  • Thiazolidinediones / administration & dosage
  • Thiazolidinediones / pharmacology*


  • Antipsychotic Agents
  • Hypoglycemic Agents
  • Thiazolidinediones
  • Rosiglitazone
  • Benzodiazepines
  • Metformin
  • Olanzapine
  • Glyburide