title: Antidiabetic-drug combination treatment for glucose intolerance in adult female rats treated acutely with olanzapine.
abstract: Second generation antipsychotic drugs are routinely used as treatment for psychotic disorders. Many of these compounds, including olanzapine, cause metabolic side-effects such as impaired glucose tolerance and insulin resistance. Individual antidiabetic drugs can help control elevated glucose levels in patients treated with antipsychotics, but the effects of combining antidiabetics, which routinely occurs with Type 2 diabetes mellitus patients, have never been studied. Presently, we compared the effects of the three different antidiabetics metformin (500mg/kg, p.o.), rosiglitazone (30mg/kg, p.o.) and glyburide (10mg/kg, p.o.) on metabolic dysregulation in adult female rats treated acutely with olanzapine. In addition, dual combinations of each of these antidiabetics were compared head-to-head against each other and the individual drugs. The animals received two daily treatments with antidiabetics and were then treated acutely with olanzapine (10mg/kg, i.p.). Fasting glucose and insulin levels were measured, followed by a 2h glucose tolerance test. Olanzapine caused a large and highly significant glucose intolerance compared to vehicle treated rats. Rosiglitazone decreased glucose levels non-significantly, while both metformin and glyburide significantly decreased glucose levels compared to olanzapine-only treated animals. For antidiabetic dual-drug combinations, the rosiglitazone-metformin group showed an unexpected increase in glucose levels compared to all of the single antidiabetic drugs. However, both the metformin-glyburide and rosiglitazone-glyburide groups showed significantly greater reductions in glucose levels following olanzapine than with single drug treatment alone for metformin or rosiglitazone, bringing glucose levels down to values equivalent to vehicle-only treated animals. These findings indicate that further study of antidiabetic dual-drug combinations in patients treated with antipsychotic drugs is warranted.
authors.affiliation: Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Heidi N
authors.initials: HN
authors.lastname: Boyda
authors.forename: Ric M
authors.initials: RM
authors.lastname: Procyshyn
authors.forename: Yahya
authors.initials: Y
authors.lastname: Asiri
authors.forename: Claire
authors.initials: C
authors.lastname: Wu
authors.forename: Cathy K
authors.initials: CK
authors.lastname: Wang
authors.forename: Ryan
authors.initials: R
authors.lastname: Lo
authors.forename: Catherine C Y
authors.initials: CC
authors.lastname: Pang
authors.forename: William G
authors.initials: WG
authors.lastname: Honer
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Barr
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D005215:Fasting / Q000097:blood; D005260:Female; D018149:Glucose Intolerance / Q000188:drug therapy*; D005951:Glucose Tolerance Test; D005905:Glyburide / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008687:Metformin / Q000627:therapeutic use; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D001569:Benzodiazepines; D005905:Glyburide; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D000077152:Olanzapine; D000077154:Rosiglitazone; D017367:Selective Serotonin Reuptake Inhibitors; D045162:Thiazolidinediones
keywords: AUC; Animal model; Area under the curve; Glyburide; Insulin resistance; Intraperitoneal; LSD; Least significant difference; Metformin; NIH; National Institutes of Health; Olanzapine; PO; PPAR; Per os; Peroxisome proliferator-activated receptor; RPM; Revolutions per minute; Rosiglitazone; Time; UBC; University of British Columbia; i.p.; t