Insulin resistance following continuous, chronic olanzapine treatment: an animal model.
Some atypical antipsychotics have been linked to an increased propensity for weight gain and metabolic disturbances, including type II diabetes. The objective of this study was to investigate an animal model to help understand the mechanisms underlying this phenomenon. Female, Sprague-Dawley rats were treated with olanzapine (2.0 or 7.5 mg/kg, via osmotic mini-pump) for 4 weeks, followed by the hyperinsulinemic/euglycemic and hyperglycemic clamp procedures to assess insulin sensitivity and secretion in vivo. Changes in body weight, visceral fat, food intake and locomotor activity were also assessed. Hepatic glucose production (R(A)) was increased in the hyperinsulinemic/euglycemic clamp for both treatment groups compared to control rats, while the high-dose olanzapine group had decreased peripheral glucose utilization (R(D)). No changes in insulin secretion were detected in the hyperglycemic clamp. Olanzapine did not change body weight or food intake, but did result in significant accumulation of visceral fat and decreases in locomotor activity. Like others, we found that a rodent model for antipsychotic-related weight gain per se is not tenable. However, chronic treatment with olanzapine was found to confer both hepatic and peripheral insulin resistance independent of weight gain, indicating a direct effect on glucose dysregulation.
Chintoh
Araba F
AF
Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Mann
Steve W
SW
Lam
Tony K T
TK
Giacca
Adria
A
Remington
Gary
G
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001569:Benzodiazepines / Q000009:adverse effects*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002096:C-Peptide / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006946:Hyperinsulinism / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008124:Locomotion / Q000187:drug effects; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D001786:Blood Glucose; D002096:C-Peptide; D001569:Benzodiazepines; D000077152:Olanzapine