title: Metabolic dysregulation with atypical antipsychotics occurs in the absence of underlying disease: a placebo-controlled study of olanzapine and risperidone in dogs.
abstract: Atypical antipsychotics have been linked to weight gain, hyperglycemia, and diabetes. We examined the effects of atypical antipsychotics olanzapine (OLZ) and risperidone (RIS) versus placebo on adiposity, insulin sensitivity (S(I)), and pancreatic beta-cell compensation. Dogs were fed ad libitum and given OLZ (15 mg/day; n = 10), RIS (5 mg/day; n = 10), or gelatin capsules (n = 6) for 4-6 weeks. OLZ resulted in substantial increases in adiposity: increased total body fat (+91 +/- 20%; P = 0.000001) reflecting marked increases in subcutaneous (+106 +/- 24%; P = 0.0001) and visceral (+84 +/- 22%; P = 0.000001) adipose stores. Changes in adiposity with RIS were not different from that observed in the placebo group (P > 0.33). Only OLZ resulted in marked hepatic insulin resistance (hepatic S(I) [pre- versus postdrug]: 6.05 +/- 0.98 vs. 1.53 +/- 0.93 dl . min(-1) . kg(-1)/[microU/ml], respectively; P = 0.009). beta-Cell sensitivity failed to upregulate during OLZ (pre-drug: 1.24 +/- 0.15, post-drug: 1.07 +/- 0.25 microU . ml(-1)/[mg/dl]; P = 0.6). OLZ-induced beta-cell dysfunction was further demonstrated when beta-cell compensation was compared with a group of animals with adiposity and insulin resistance induced by moderate fat feeding alone (+8% of calories from fat; n = 6). These results may explain the diabetogenic effects of atypical antipsychotics and suggest that beta-cell compensation is under neural control.
authors.affiliation: Keck School of Medicine, Department of Physiology and Biophysics, University of Southern California, MMR 624, 1333 San Pablo St., Los Angeles, CA 90033, USA. ader@hsc.usc.edu
authors.forename: Marilyn
authors.initials: M
authors.lastname: Ader
authors.forename: Stella P
authors.initials: SP
authors.lastname: Kim
authors.forename: Karyn J
authors.initials: KJ
authors.lastname: Catalano
authors.forename: Viorica
authors.initials: V
authors.lastname: Ionut
authors.forename: Katrin
authors.initials: K
authors.lastname: Hucking
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Richey
authors.forename: Morvarid
authors.initials: M
authors.lastname: Kabir
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats; D004285:Dogs; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000187:drug effects*; D008297:Male; D000077152:Olanzapine; D018967:Risperidone / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D004041:Dietary Fats; D001569:Benzodiazepines; D018967:Risperidone; D000077152:Olanzapine