Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance.
Antipsychotics (APs) are linked to diabetes, even without weight gain. Whether anti-diabetic drugs are efficacious in reversing the direct effects of APs on glucose pathways is largely undetermined. We tested two metformin (Met) doses to prevent impairments seen following a dose of olanzapine (Ola) (3 mg/kg); glucokinetics were measured using the hyperinsulinemic-euglycemic clamp (HIEC). Met (150 mg/kg; n=13, or 400 mg/kg; n=11) or vehicle (Veh) (n=11) was administered through gavage preceding an overnight fast, followed by a second dose prior to the HIEC. Eleven additional animals were gavaged with Veh and received a Veh injection during the HIEC (Veh/Veh); all others received Ola. Basal glucose was similar across treatment groups. The Met 400 group had significantly greater glucose appearance (Ra) in the basal period (i.e., before Ola, or hyperinsulinemia) vs other groups. During hyperinsulinemia, glucose infusion rate (GINF) to maintain euglycemia (reflective of whole-body insulin sensitivity) was higher in Veh/Veh vs other groups. Met 150/Ola animals demonstrated increased GINF relative to Veh/Ola during early time points of the HIEC. Glucose utilization during hyperinsulinemia, relative to basal conditions, was significantly higher in Veh/Veh vs other groups. The change in hepatic glucose production (HGP) from basal to hyperinsulinemia demonstrated significantly greater decreases in Veh/Veh and Met 150/Ola groups vs Veh/Ola. Given the increase in basal Ra with Met 400, we measured serum lactate (substrate for HGP), finding increased levels in Met 400 vs Veh and Met 150. In conclusion, Met attenuates hepatic insulin resistance observed with acute Ola administration, but fails to improve peripheral insulin resistance. Use of supra-therapeutic doses of Met may mask metabolic benefits by increasing lactate.
Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8 Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8 Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Gary J
GJ
Remington
Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Celine
C
Teo
Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Virginia
V
Wilson
Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8 Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Araba
A
Chintoh
Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Melanie
M
Guenette
Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Zohra
Z
Ahsan
Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8 Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Adria
A
Giacca
Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8 Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8 Centre for Addiction and Mental Health250 College Street, Toronto, Ontario, Canada M5T 1R8Institute of Medical ScienceUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of PsychiatryUniversity of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8Department of PhysiologyUniversity of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8 maggie.hahn@utoronto.ca.
Margaret K
MK
Hahn
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001569:Benzodiazepines / Q000009:adverse effects*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D001569:Benzodiazepines; D008687:Metformin; D000077152:Olanzapine
atypical antipsychotics; diabetes; insulin resistance; metformin; olanzapine