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Margaret K Hahn Centre for Addiction and Mental Health, Toronto, Ontario, Canada
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
Banting & Best Diabetes Centre, Toronto, Ontario, Canada

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Adria Giacca Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
Banting & Best Diabetes Centre, Toronto, Ontario, Canada
Department of Physiology, University of Toronto, Toronto, Ontario, Canada

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Sandra Pereira Centre for Addiction and Mental Health, Toronto, Ontario, Canada
Department of Physiology, University of Toronto, Toronto, Ontario, Canada

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Metabolic tests are vital to determine in vivo insulin sensitivity and glucose metabolism in preclinical models, usually rodents. Such tests include glucose tolerance tests, insulin tolerance tests, and glucose clamps. Although these tests are not standardized, there are general guidelines for their completion and analysis that are constantly being refined. In this review, we describe metabolic tests in rodents as well as factors to consider when designing and performing these tests.

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Gary J Remington Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Celine Teo Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Virginia Wilson Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Araba Chintoh Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Melanie Guenette Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Zohra Ahsan Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Adria Giacca Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Margaret K Hahn Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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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.

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